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Fang YW, Chen CW, Su TC, Wang C, Lin CY. Investigating the associations of blood lead and cadmium with smoking-related DNA methylation and mortality among U.S. adults. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 299:118360. [PMID: 40409187 DOI: 10.1016/j.ecoenv.2025.118360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 02/22/2025] [Accepted: 05/18/2025] [Indexed: 05/25/2025]
Abstract
PURPOSE Lead and cadmium have been linked to alterations in DNA methylation (DNAm) and increased mortality. However, the role of smoking-related DNAm in the link between these heavy metals and mortality remains unclear. APPROACH AND RESULTS We analyzed data from 2110 participants aged 50 and older from the 1999-2002 National Health and Nutrition Examination Survey (NHANES), linked to mortality data from the National Center for Health Statistics (NCHS) with follow-up through 2019. Our study examined the associations between blood lead and cadmium levels, DNA methylation-predicted pack years of smoking (DNAmPackYrs), and mortality outcomes. Our analysis found that higher natural logarithm (Ln)-transformed lead and cadmium levels were positively associated with ln-DNAmPackYrs, with a percent change of 11.34 % (P = 0.001) for lead and 35.57 % (P < 0.001) for cadmium. Participants with both heavy metals above the 50th percentile had the highest DNAmPackYrs, with P for trend < 0.001. Weighted Cox regression analysis demonstrated both ln-lead and ln-DNAmPackYrs were linked to an elevated risk of all mortality outcomes, while ln-cadmium specifically predicted all-cause mortality. A significant interaction between lead and cadmium in relation to all-cause mortality was observed (P for interaction = 0.036). Additionally, significant interactions between DNAmPackYrs and both heavy metals were found in relation to all-cause mortality (P for interaction = 0.001 for lead; P for interaction = 0.013 for cadmium). CONCLUSIONS Drawing from a nationally representative cohort of older U.S. adults, this study provides robust evidence linking blood lead and cadmium levels to smoking-related DNAm and increased mortality risk. Moreover, the analysis revealed additive effects of these metals on smoking-related DNAm, as well as synergistic impacts on all-cause mortality. Additionally, smoking-induced DNAm may play a role in mediating the connection between heavy metal exposure and mortality risk. Additional research is required to investigate the underlying mechanisms of these associations.
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Affiliation(s)
- Yu-Wei Fang
- Division of Nephrology, Department of Internal Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan; School of Medicine, College of Medicine, Fu Jen Catholic University, Taipei 242, Taiwan
| | - Ching-Way Chen
- Department of Cardiology, National Taiwan University Hospital Yunlin Branch, Yunlin 640, Taiwan
| | - Ta-Chen Su
- Department of Environmental and Occupational Medicine, National Taiwan University Hospital, Taipei 100, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan; Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan; Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University, Taipei 100, Taiwan; Department of Internal Medicine, Tungs' Taichung MetroHarbor Hospital, Taichung 435, Taiwan
| | - Chikang Wang
- Department of Environmental Engineering and Health, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan
| | - Chien-Yu Lin
- Division of Nephrology, Department of Internal Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan; Department of Environmental Engineering and Health, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan; Department of Internal Medicine, En Chu Kong Hospital, Taipei 237, Taiwan.
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2
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Li N, Cui N, Li T, Zhao P, Bakry IA, Li Q, Cheng Y, Galaverna G, Yang H, Wang F. Pea Peptides and Heavy Metal Neurotoxicity: Exploring Mechanisms and Mitigation Strategies in PC12 Cells. PLANT FOODS FOR HUMAN NUTRITION (DORDRECHT, NETHERLANDS) 2025; 80:85. [PMID: 40035902 DOI: 10.1007/s11130-025-01322-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 02/09/2025] [Indexed: 03/06/2025]
Abstract
Calsyntenin-1 (Clst1) is a sensitive indicator of lead (Pb) toxicity in neural tissue. This study was designed to investigate the impact of lead exposure on Clst1 expression in PC12 cells and the mitigating effect of pea peptide 4 (PP4) on lead-induced neurotoxicity. Data showed that lead exposure, at varying doses and durations, disrupted the mRNA expression and protein levels of Clstn1 in PC12 cells. However, immunofluorescence results showed that treatment with PP4 significantly increased Clstn1 protein expression in the Pb + PP4 and PP4 groups compared to the Pb groups (P < 0.05). Lead exposure activates the JNK and p38 pathways; at the same time, PP4 treatment enhances ERK pathway activation and reduces JNK and p38 activation.
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Affiliation(s)
- Ning Li
- College of Food Science and Technology, Henan Agricultural University, 63# Agricultural Road, Zhengzhou, 450000, China.
| | - Ningning Cui
- College of Food Science and Technology, Henan Agricultural University, 63# Agricultural Road, Zhengzhou, 450000, China
| | - Tiange Li
- College of Food Science and Technology, Henan Agricultural University, 63# Agricultural Road, Zhengzhou, 450000, China
| | - Peijun Zhao
- College of Food Science and Technology, Henan Agricultural University, 63# Agricultural Road, Zhengzhou, 450000, China
| | - Ibrahim A Bakry
- College of Food Science and Technology, Henan Agricultural University, 63# Agricultural Road, Zhengzhou, 450000, China
| | - Qian Li
- College of Food Science and Technology, Henan Agricultural University, 63# Agricultural Road, Zhengzhou, 450000, China
| | - Yongxia Cheng
- College of Food Science and Technology, Henan Agricultural University, 63# Agricultural Road, Zhengzhou, 450000, China
| | - Gianni Galaverna
- Key Laboratory for Animal Immunology, Henan Academy of Agricultural Sciences, 116# Huayuan Road, Zhengzhou, 450002, PR China
| | - Huijie Yang
- College of Food Science and Technology, Henan Agricultural University, 63# Agricultural Road, Zhengzhou, 450000, China
| | - Fangyu Wang
- Key Laboratory for Animal Immunology, Henan Academy of Agricultural Sciences, 116# Huayuan Road, Zhengzhou, 450002, PR China.
- Food and Drug Department, University of Parma, Parco Area delle Scienze, 17/a, Parma, 43124, Italy.
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Berezovsky A, Nuga O, Datta I, Bergman K, Sabedot T, Gurdziel K, Irtenkauf S, Hasselbach L, Meng Y, Mueller C, . Petricoin EF, Brown S, Purandare N, Aras S, Mikkelsen T, Poisson L, Noushmehr H, Ruden D, deCarvalho AC. Impact of developmental state, p53 status, and interferon signaling on glioblastoma cell response to radiation and temozolomide treatment. PLoS One 2025; 20:e0315171. [PMID: 39919036 PMCID: PMC11805374 DOI: 10.1371/journal.pone.0315171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 11/21/2024] [Indexed: 02/09/2025] Open
Abstract
Glioblastoma (GBM) tumors exhibit extensive genomic, epigenomic, and transcriptional diversity, with significant intratumoral heterogeneity, complicating standard treatment approaches involving radiation (RT) and the DNA-alkylating agent temozolomide (TMZ). In this study, we employed an integrative multi-omics approach, including targeted proteomics, transcriptomics, genomics, and DNA methylation profiling, to investigate the response of a representative panel of GBM patient-derived cancer stem cells (CSCs) to astrocytic differentiation and RT and TMZ treatments. Differentiated CSC progenies retained the expression of key stemness genes and survival pathways, while activating the BMP-Smad signaling pathway and upregulating extracellular matrix components. This was associated with increased resistance to TMZ, though not to RT, across all models. We identified TP53 status as a critical determinant of transcriptional response to both RT and TMZ, which was also modulated by the differentiation state and treatment modality in wildtype (wt) p53 GBM cells. Both mutant and wt p53 models exhibited significant activation of the DNA-damage associated interferon (IFN) response in CSCs and differentiated cells, implicating this pathway in the GBM response to therapy. We observed that activation of NF-κB was positively correlated with the levels of O-6-methylguanine-DNA methyltransferase (MGMT) protein, a direct DNA repair enzyme leading to TMZ resistance, regardless of MGMT promoter methylation status, further supporting the clinical potential for inhibition of NF-kB signaling in GBM treatment. Our integrative analysis of the impact of GBM cell developmental states, in the context of genomic and molecular diversity of patient-derived models, provides valuable insights for pre-clinical studies aimed at optimizing treatment strategies.
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Affiliation(s)
- Artem Berezovsky
- Department of Neurosurgery, Henry Ford Health, Detroit, Michigan, United States of America
- Department of Oncology, Wayne State University, Detroit, Michigan, United States of America
| | - Oluwademilade Nuga
- Department of Neurosurgery, Henry Ford Health, Detroit, Michigan, United States of America
- Department of Pharmacology, Wayne State University, Detroit, Michigan, United States of America
| | - Indrani Datta
- Department of Neurosurgery, Henry Ford Health, Detroit, Michigan, United States of America
| | - Kimberly Bergman
- Department of Neurosurgery, Henry Ford Health, Detroit, Michigan, United States of America
| | - Thais Sabedot
- Department of Neurosurgery, Henry Ford Health, Detroit, Michigan, United States of America
| | - Katherine Gurdziel
- Department of Pharmacology, Wayne State University, Detroit, Michigan, United States of America
- Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan, United States of America
| | - Susan Irtenkauf
- Department of Neurosurgery, Henry Ford Health, Detroit, Michigan, United States of America
| | - Laura Hasselbach
- Department of Neurosurgery, Henry Ford Health, Detroit, Michigan, United States of America
| | - Yuling Meng
- Department of Neurosurgery, Henry Ford Health, Detroit, Michigan, United States of America
| | - Claudius Mueller
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia, United States of America
| | - Emanuel F. . Petricoin
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia, United States of America
| | - Stephen Brown
- Department of Radiation Oncology, Henry Ford Health, Detroit, Michigan, United States of America
| | - Neeraja Purandare
- Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan, United States of America
| | - Sidhesh Aras
- Department of Oncology, Wayne State University, Detroit, Michigan, United States of America
- Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan, United States of America
| | - Tom Mikkelsen
- Precision Medicine Program, Henry Ford Health, Detroit, Michigan, United States of America
| | - Laila Poisson
- Department of Public Health, Henry Ford Health, Detroit, Michigan, United States of America
| | - Houtan Noushmehr
- Department of Neurosurgery, Henry Ford Health, Detroit, Michigan, United States of America
| | - Douglas Ruden
- Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan, United States of America
- Department of Obstetrics and Gynecology, School of Medicine, Wayne State University, Detroit, Michigan, United States of America
| | - Ana C. deCarvalho
- Department of Neurosurgery, Henry Ford Health, Detroit, Michigan, United States of America
- Department of Oncology, Wayne State University, Detroit, Michigan, United States of America
- Department of Pharmacology, Wayne State University, Detroit, Michigan, United States of America
- Department of Physiology, College of Human Medicine, Michigan State University, East Lansing, Michigan, United States of America
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Cui F, Deng S, Fu Y, Xu T, Bao S, Wang S, Lin Y, Wang X, Zhao F, Zhang T, Xu S, Zhang Z, Li W, Yang GY, Tang H, Wang J, Sheng X, Tang Y. Maternal phthalates exposure promotes neural stem cell differentiation into phagocytic astrocytes and synapse engulfment via IRE1α/XBP1s pathway. Cell Rep 2025; 44:115126. [PMID: 39752254 DOI: 10.1016/j.celrep.2024.115126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 11/27/2024] [Accepted: 12/10/2024] [Indexed: 02/01/2025] Open
Abstract
Humans are widely exposed to phthalates, a common chemical plasticizer. Previous cohort studies have revealed that maternal exposure to monobutyl phthalate (MBP), a key metabolite of phthalates, is associated with neurodevelopmental defects. However, the molecular mechanism remains unclear. Here, we demonstrate that maternal exposure to MBP enhances neural stem cell (NSC) differentiation into astrocytes with highly expressed C3 and LCN2 in mouse offspring, resulting in increased synapse phagocytosis and cognitive dysfunction. Mechanistically, we find that MBP exposure activates the IRE1α/XBP1s (spliced XBP1) stress response pathway, which regulates key genes involved in astrocyte differentiation (SOX9 and ATF3) and reactivity (C3 and LCN2). Conditional knockout or pharmacological inhibition of IRE1α markedly inhibits NSC differentiation into astrocytes and astrocyte reactivity, attenuates synapse phagocytosis, and improves cognitive function. This phenotype is further recapitulated in a human brain organoid model. Together, these findings unveil the molecular mechanism underlying the neurodevelopmental deficits caused by a widespread environmental pollutant.
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Affiliation(s)
- Fengzhen Cui
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200031, China; School of Public Health, Guangdong Medical University, Dongguan 523808, China
| | - Shiyu Deng
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200031, China
| | - Yan Fu
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200031, China
| | - Tongtong Xu
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200031, China
| | - Shuangshuang Bao
- MOE Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Hefei 230032, China
| | - Siyi Wang
- Department of Neurology, Wuhan Fourth Hospital, Wuhan 430033, China
| | - Yahang Lin
- Department of Neurology, Wuhan Fourth Hospital, Wuhan 430033, China
| | - Xianghui Wang
- Department of Environmental Health, School of Environmental Science and Engineering, Hainan University, Haikou 570228, China
| | - Faming Zhao
- School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Tingting Zhang
- School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Shunqing Xu
- Department of Environmental Health, School of Environmental Science and Engineering, Hainan University, Haikou 570228, China
| | - Zhijun Zhang
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200031, China
| | - Wanlu Li
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200031, China
| | - Guo-Yuan Yang
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200031, China
| | - Huanwen Tang
- School of Public Health, Guangdong Medical University, Dongguan 523808, China
| | - Jixian Wang
- Department of Rehabilitation, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
| | - Xia Sheng
- Department of Environmental Health, School of Environmental Science and Engineering, Hainan University, Haikou 570228, China; School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Yaohui Tang
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200031, China.
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5
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Hsu YH, Wu CY, Lee HL, Hsieh RL, Huang YL, Shiue HS, Lin YC, Chen MC, Hsueh YM. Combined effects of global DNA methylation, blood lead and total urinary arsenic levels on developmental delay in preschool children. Environ Health 2025; 24:2. [PMID: 39819460 PMCID: PMC11740333 DOI: 10.1186/s12940-024-01151-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 12/24/2024] [Indexed: 01/19/2025]
Abstract
DNA methylation is a critical step in brain development, 5-Methyl-2'-deoxycytidine (5mdC) is one of the global DNA methylation markers. Arsenic and lead exposures have been associated with neurotoxicity, which may be linked to epigenetic changes. Our research sought to investigate the correlation between 5mdC and developmental delay (DD) among preschoolers. Additionally, we assessed whether 5mdC modified the impacts of blood lead and total urinary arsenic levels on DD. We analyzed the concentrations of 5mdC, blood cadmium and lead, and total urinary arsenic in 174 children with DD and 88 healthy children. Global DNA methylation levels are expressed as the ratio 5mdC/2'-dexyguanosine (dG), called 5mdC (%). In our findings, elevated levels of blood lead and total urinary arsenic were significantly associated with DD risk among preschoolers. Furthermore, high 5mdC (%) was related with reduced risk of DD, with an odds ratio (OR) and 95% confidence interval (CI) of 0.14 (0.06 - 0.32). A notable multiplicative interaction was observed between low 5mdC (%) and elevated blood lead levels to increase OR of DD, with OR and 95% CI was 9.51 (4.18 - 21.64). The findings provide evidence of the combined effects of reduced 5mdC (%) and high blood lead concentrations, increasing the OR of DD.
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Affiliation(s)
- Yuu-Hueih Hsu
- Department of Public Health, National Cheng Kung University, Tainan, Taiwan
| | - Chih-Yin Wu
- Department of Family Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- Department of Family Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Hui-Ling Lee
- Department of Chemistry, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Ru-Lan Hsieh
- Department of Physical Medicine and Rehabilitation, Su Memorial Hospital, Shin Kong Wu Ho, Taipei, Taiwan
- Department of Physical Medicine and Rehabilitation, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Ya-Li Huang
- Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Horng-Sheng Shiue
- Department of Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ying-Chin Lin
- Department of Family Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- Department of Family Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Geriatric Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Mei-Chieh Chen
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yu-Mei Hsueh
- Department of Family Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
- Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
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6
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Borrego-Ruiz A, Borrego JJ. Epigenetic Mechanisms in Aging: Extrinsic Factors and Gut Microbiome. Genes (Basel) 2024; 15:1599. [PMID: 39766866 PMCID: PMC11675900 DOI: 10.3390/genes15121599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Revised: 12/03/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND/OBJECTIVES Aging is a natural physiological process involving biological and genetic pathways. Growing evidence suggests that alterations in the epigenome during aging result in transcriptional changes, which play a significant role in the onset of age-related diseases, including cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. For this reason, the epigenetic alterations in aging and age-related diseases have been reviewed, and the major extrinsic factors influencing these epigenetic alterations have been identified. In addition, the role of the gut microbiome and its metabolites as epigenetic modifiers has been addressed. RESULTS Long-term exposure to extrinsic factors such as air pollution, diet, drug use, environmental chemicals, microbial infections, physical activity, radiation, and stress provoke epigenetic changes in the host through several endocrine and immune pathways, potentially accelerating the aging process. Diverse studies have reported that the gut microbiome plays a critical role in regulating brain cell functions through DNA methylation and histone modifications. The interaction between genes and the gut microbiome serves as a source of adaptive variation, contributing to phenotypic plasticity. However, the molecular mechanisms and signaling pathways driving this process are still not fully understood. CONCLUSIONS Extrinsic factors are potential inducers of epigenetic alterations, which may have important implications for longevity. The gut microbiome serves as an epigenetic effector influencing host gene expression through histone and DNA modifications, while bidirectional interactions with the host and the underexplored roles of microbial metabolites and non-bacterial microorganisms such as fungi and viruses highlight the need for further research.
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Affiliation(s)
- Alejandro Borrego-Ruiz
- Departamento de Psicología Social y de las Organizaciones, Universidad Nacional de Educación a Distancia (UNED), 28040 Madrid, Spain;
| | - Juan J. Borrego
- Departamento de Microbiología, Universidad de Málaga, 29071 Málaga, Spain
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Herrera ML, Paraíso-Luna J, Bustos-Martínez I, Barco Á. Targeting epigenetic dysregulation in autism spectrum disorders. Trends Mol Med 2024; 30:1028-1046. [PMID: 38971705 DOI: 10.1016/j.molmed.2024.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 06/08/2024] [Accepted: 06/10/2024] [Indexed: 07/08/2024]
Abstract
Autism spectrum disorders (ASD) comprise a range of neurodevelopmental pathologies characterized by deficits in social interaction and repetitive behaviors, collectively affecting almost 1% of the worldwide population. Deciphering the etiology of ASD has proven challenging due to the intricate interplay of genetic and environmental factors and the variety of molecular pathways affected. Epigenomic alterations have emerged as key players in ASD etiology. Their research has led to the identification of biomarkers for diagnosis and pinpointed specific gene targets for therapeutic interventions. This review examines the role of epigenetic alterations, resulting from both genetic and environmental influences, as a central causative factor in ASD, delving into its contribution to pathogenesis and treatment strategies.
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Affiliation(s)
- Macarena L Herrera
- Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas), Av. Santiago Ramón y Cajal s/n, Sant Joan d'Alacant, 03550 Alicante, Spain
| | - Juan Paraíso-Luna
- Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas), Av. Santiago Ramón y Cajal s/n, Sant Joan d'Alacant, 03550 Alicante, Spain
| | - Isabel Bustos-Martínez
- Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas), Av. Santiago Ramón y Cajal s/n, Sant Joan d'Alacant, 03550 Alicante, Spain
| | - Ángel Barco
- Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas), Av. Santiago Ramón y Cajal s/n, Sant Joan d'Alacant, 03550 Alicante, Spain.
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8
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Kim N, Filipovic D, Bhattacharya S, Cuddapah S. Epigenetic toxicity of heavy metals - implications for embryonic stem cells. ENVIRONMENT INTERNATIONAL 2024; 193:109084. [PMID: 39437622 DOI: 10.1016/j.envint.2024.109084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 09/14/2024] [Accepted: 10/16/2024] [Indexed: 10/25/2024]
Abstract
Exposure to heavy metals, such as cadmium, nickel, mercury, arsenic, lead, and hexavalent chromium has been linked to dysregulated developmental processes, such as impaired stem cell differentiation. Heavy metals are well-known modifiers of the epigenome. Stem and progenitor cells are particularly vulnerable to exposure to potentially toxic metals since these cells rely on epigenetic reprogramming for their proper functioning. Therefore, exposure to metals can impair stem and progenitor cell proliferation, pluripotency, stemness, and differentiation. In this review, we provide a comprehensive summary of current evidence on the epigenetic effects of heavy metals on stem cells, focusing particularly on DNA methylation and histone modifications. Moreover, we explore the underlying mechanisms responsible for these epigenetic changes. By providing an overview of heavy metal exposure-induced alterations to the epigenome, the underlying mechanisms, and the consequences of those alterations on stem cell function, this review provides a foundation for further research in this critical area of overlap between toxicology and developmental biology.
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Affiliation(s)
- Nicholas Kim
- Division of Environmental Medicine, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10010, USA
| | - David Filipovic
- Institute for Quantitative Health Science and Engineering, Division of Systems Biology, Michigan State University, East Lansing, MI 48824, USA
| | - Sudin Bhattacharya
- Institute for Quantitative Health Science and Engineering, Division of Systems Biology, Michigan State University, East Lansing, MI 48824, USA; Department of Biomedical Engineering, College of Engineering, Michigan State University, East Lansing, MI 48824, USA; Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI 48824, USA; Institute for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA.
| | - Suresh Cuddapah
- Division of Environmental Medicine, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10010, USA.
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Dutta S, Ruden DM. Heavy Metals in Umbilical Cord Blood: Effects on Epigenetics and Child Development. Cells 2024; 13:1775. [PMID: 39513881 PMCID: PMC11544782 DOI: 10.3390/cells13211775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 10/24/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024] Open
Abstract
Heavy metals like arsenic, mercury, cadmium, and lead are harmful pollutants that can change how our genes are regulated without altering the DNA sequence, specifically through a process called DNA methylation (DNAm) at 5-methylcytosine, an epigenetic mark that we will focus on in this review. These changes in DNAm are most sensitive during pregnancy, a critical time for development when these modifications can affect how traits are expressed. Historically, most research on these environmental effects has focused on adults, but now there is more emphasis on studying the impacts during early development and childhood. The placenta acts as a protective barrier between the mother and the baby, and by examining it, scientists can identify changes in key genes that might affect long-term health. This review looks at how exposure to heavy metals during pregnancy can cause changes in the gene regulation by DNAm in newborns, as seen in their umbilical cord blood. These changes reflect the baby's genetic state during pregnancy and can be influenced by the mother's environment and genetics, as well as the baby's own genetics.
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Affiliation(s)
- Sudipta Dutta
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA;
| | - Douglas M. Ruden
- C. S. Mott Center for Human Health and Development, Department of Obstetrics and Gynecology, Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48202, USA
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10
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Alampi JD, Lanphear BP, MacFarlane AJ, Oulhote Y, Braun JM, Muckle G, Arbuckle TE, Ashley-Martin J, Hu JM, Chen A, McCandless LC. Combined Exposure to Folate and Lead during Pregnancy and Autistic-Like Behaviors among Canadian Children from the MIREC Pregnancy and Birth Cohort. ENVIRONMENTAL HEALTH PERSPECTIVES 2024; 132:107003. [PMID: 39412272 PMCID: PMC11481933 DOI: 10.1289/ehp14479] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 08/29/2024] [Accepted: 09/20/2024] [Indexed: 10/19/2024]
Abstract
BACKGROUND Folic acid (FA) supplementation may attenuate the associations between gestational exposure to certain chemicals and autism or autistic-like behaviors, but to our knowledge, this has not been assessed for lead. OBJECTIVES We examined whether the relationship between gestational blood-lead levels (BLLs) and autistic-like behaviors was modified by gestational plasma total folate concentrations, FA supplementation, and maternal methylenetetrahydrofolate reductase (MTHFR) 677C>T genotype. METHODS We used data from the Maternal-Infant Research on Environmental Chemicals study (2008-2011), a Canadian pregnancy and birth cohort study. Childhood autistic-like behaviors were documented in 601 children 3-4 y of age with the Social Responsiveness Scale-2 (SRS-2), where higher scores denote more autistic-like behaviors. We measured BLLs and plasma total folate concentrations during the first and third trimesters of pregnancy. We also estimated gestational FA supplementation via surveys and genotyped the maternal MTHFR 677C>T single nucleotide polymorphism (SNP). We estimated the confounder-adjusted associations between log 2 -transformed BLLs and SRS-2 scores by two indicators of folate exposure and maternal MTHFR 677C>T genotype using linear regression. RESULTS Third-trimester BLLs were associated with increased SRS-2 scores [β a d j = 3.3 ; 95% confidence interval (CI): 1.1, 5.5] among participants with low (< 10 th percentile), third-trimester, plasma total folate concentrations, but BLL-SRS-2 associations were null (β a d j = - 0.3 ; 95% CI: - 1.2 , 0.5) among those in the middle category (≥ 10 th and < 80 th percentiles) (p-interaction < 0.001 ). FA supplementation also attenuated these associations. Both folate indicators modified first-trimester BLL-SRS-2 associations, but to a lesser extent. Third-trimester BLL-SRS-2 associations were slightly stronger among participants who were homozygous for the T (minor) allele of the MTHFR 677C>T SNP (β a d j = 0.9 ; 95% CI: - 1.2 , 3.1) than those without the T allele (β a d j = - 0.3 ; 95% CI: - 1.3 , 0.7), but the difference was not statistically significant (p -interaction = 0.28 ). DISCUSSION Folate may modify the associations between gestational lead exposure and childhood autistic-like behaviors, suggesting that it mitigates the neurotoxic effects of prenatal lead exposure. https://doi.org/10.1289/EHP14479.
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Affiliation(s)
- Joshua D. Alampi
- Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Bruce P. Lanphear
- Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Amanda J. MacFarlane
- Texas A&M Agriculture, Food, and Nutrition Evidence Center, Fort Worth, Texas, USA
| | - Youssef Oulhote
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
| | - Joseph M. Braun
- Department of Epidemiology, Brown University, Providence, Rhode Island, USA
| | - Gina Muckle
- Centre Hospitalier Universitaire de Québec Research Centre and School of Psychology, Laval University, Québec City, Québec, Canada
| | - Tye E. Arbuckle
- Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario, Canada
| | - Jillian Ashley-Martin
- Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario, Canada
| | - Janice M.Y. Hu
- Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Aimin Chen
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
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11
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Berezovsky A, Nuga O, Datta I, Bergman K, Sabedot T, Gurdziel K, Irtenkauf S, Hasselbach L, Meng Y, Mueller C, Petricoin EF, Brown S, Purandare N, Aras S, Mikkelsen T, Poisson L, Noushmehr H, Ruden D, deCarvalho AC. Impact of genomic background and developmental state on signaling pathways and response to therapy in glioblastoma patient-derived cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.14.585115. [PMID: 39386580 PMCID: PMC11463645 DOI: 10.1101/2024.03.14.585115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
Abstract
Glioblastoma (GBM) tumors represents diverse genomic epigenomic, and transcriptional landscapes, with significant intratumoral heterogeneity that challenges standard of care treatments involving radiation (RT) and the DNA-alkylating agent temozolomide (TMZ). In this study, we employed targeted proteomics to assess the response of a genomically-diverse panel of GBM patient-derived cancer stem cells (CSCs) to astrocytic differentiation, growth factor withdrawal and traditional high fetal bovine serum culture. Our findings revealed a complex crosstalk and co-activation of key oncogenic signaling in CSCs and diverse patterns of response to these external stimuli. Using RNA sequencing and DNA methylation, we observed common adaptations in response to astrocytic differentiation of CSCs across genomically distinct models, including BMP-Smad pathway activation, reduced cholesterol biosynthesis, and upregulation of extracellular matrix components. Notably, we observed that these differentiated CSC progenies retained a subset of stemness genes and the activation of cell survival pathways. We also examined the impact of differentiation state and genomic background on GBM cell sensitivity and transcriptional response to TMZ and RT. Differentiation of CSCs increased resistance to TMZ but not to RT. While transcriptional responses to these treatments were predominantly regulated by p53 in wild-type p53 GBM cells, its transcriptional activity was modulated by the differentiation status and treatment modality. Both mutant and wild-type p53 models exhibited significant activation of a DNA-damage associated interferon response in CSCs and differentiated cells, suggesting this pathway may play a wider role in GBM response to TMZ and RT. Our integrative analysis of the impact of GBM cell developmental states, in the context of genomic and molecular diversity of patient-derived models, provides valuable insights for pre-clinical studies aimed at optimizing treatment strategies.
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12
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Sampson MM, Morgan RK, Sloan SA, Bakulski KM. Single-cell investigation of lead toxicity from neurodevelopment to neurodegeneration: Current review and future opportunities. CURRENT OPINION IN TOXICOLOGY 2024; 38:100464. [PMID: 39086983 PMCID: PMC11290315 DOI: 10.1016/j.cotox.2024.100464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/02/2024]
Abstract
Human exposure to the metal lead (Pb) is prevalent and associated with adverse neurodevelopmental and neurodegenerative outcomes. Pb disrupts normal brain function by inducing oxidative stress and neuroinflammation, altering cellular metabolism, and displacing essential metals. Prior studies on the molecular impacts of Pb have examined bulk tissues, which collapse information across all cell types, or in targeted cells, which are limited to cell autonomous effects. These approaches are unable to represent the complete biological implications of Pb exposure because the brain is a cooperative network of highly heterogeneous cells, with cellular diversity and proportions shifting throughout development, by brain region, and with disease. New technologies are necessary to investigate whether Pb and other environmental exposures alter cell composition in the brain and whether they cause molecular changes in a cell-type-specific manner. Cutting-edge, single-cell approaches now enable research resolving cell-type-specific effects from bulk tissues. This article reviews existing Pb neurotoxicology studies with genome-wide molecular signatures and provides a path forward for the field to implement single-cell approaches with practical recommendations.
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Affiliation(s)
- Maureen M Sampson
- Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, USA
| | - Rachel K Morgan
- Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | - Steven A Sloan
- Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, USA
| | - Kelly M Bakulski
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
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13
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Park HR, Azzara D, Cohen ED, Boomhower SR, Diwadkar AR, Himes BE, O'Reilly MA, Lu Q. Identification of novel NRF2-dependent genes as regulators of lead and arsenic toxicity in neural progenitor cells. JOURNAL OF HAZARDOUS MATERIALS 2024; 463:132906. [PMID: 37939567 PMCID: PMC10842917 DOI: 10.1016/j.jhazmat.2023.132906] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 10/29/2023] [Accepted: 10/30/2023] [Indexed: 11/10/2023]
Abstract
Lead (Pb) and arsenic (As) are prevalent metal contaminants in the environment. Exposures to these metals are associated with impaired neuronal functions and adverse effects on neurodevelopment in children. However, the molecular mechanisms by which Pb and As impair neuronal functions remain poorly understood. Here, we identified F2RL2, TRIM16L, and PANX2 as novel targets of Nuclear factor erythroid 2-related factor 2 (NRF2)-the master transcriptional factor for the oxidative stress response-that are commonly upregulated with both Pb and As in human neural progenitor cells (NPCs). Using a ChIP (Chromatin immunoprecipitation)-qPCR assay, we showed that NRF2 directly binds to the promoter region of F2RL2, TRIM16L, and PANX2 to regulate expression of these genes. We demonstrated that F2RL2, PANX2, and TRIM16L have differential effects on cell death, proliferation, and differentiation of NPCs in both the presence and absence of metal exposures, highlighting their roles in regulating NPC function. Furthermore, the analyses of the transcriptomic data on NPCs derived from autism spectrum disorder (ASD) patients revealed that dysregulation of F2RL2, TRIM16L, and PANX2 was associated with ASD genetic backgrounds and ASD risk genes. Our findings revealed that Pb and As induce a shared NRF2-dependent transcriptional response in NPCs and identified novel genes regulating NPC function. While further in vivo studies are warranted, this study provides a novel mechanism linking metal exposures to NPC function and identifies potential genes of interest in the context of neurodevelopment.
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Affiliation(s)
- Hae-Ryung Park
- Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA.
| | - David Azzara
- Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA
| | - Ethan D Cohen
- Department of Pediatrics, School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA
| | - Steven R Boomhower
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Avantika R Diwadkar
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA, USA
| | - Blanca E Himes
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA, USA
| | - Michael A O'Reilly
- Department of Pediatrics, School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA
| | - Quan Lu
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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14
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Kumar K, Anjali S, Sharma S. Effect of lead exposure on histone modifications: A review. J Biochem Mol Toxicol 2024; 38:e23547. [PMID: 37867311 DOI: 10.1002/jbt.23547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 08/21/2023] [Accepted: 09/26/2023] [Indexed: 10/24/2023]
Abstract
Lead at any levels can result in detrimental health effects affecting various organ systems. These systematic manifestations under Pb exposure and the underlying probable pathophysiological mechanisms have not been elucidated completely. With advancements in molecular research under Pb exposure, epigenetics is one of the emerging field that has opened many possibilities for appreciating the role of Pb exposure in modulating gene expression profiles. In terms of epigenetic alterations reported in Pb toxicity, DNA methylation, and microRNA alterations are extensively explored in both experimental and epidemiological studies, however, the understanding of histone modifications under Pb exposure is still in its infant stage limited to experimental models. In this review, we aim to present a synoptic view of histone modifications explored in relation to Pb exposure attempting to bring out this potential lacunae in research. The scarcity of studies associating histone modifications with Pb toxicity, and the paucity of their validation in human cohort further emphasizes the strong research potential of this field. We summarize the review by presenting our hypotheses regarding the involvement of these histone modification in various diseases modalities associated with Pb toxicity.
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Affiliation(s)
- Kanishka Kumar
- Department of Biochemistry, AIIMS Jodhpur, Jodhpur, Rajasthan, India
| | - Sudha Anjali
- Department of Biochemistry, AIIMS Jodhpur, Jodhpur, Rajasthan, India
| | - Shailja Sharma
- Department of Biochemistry, AIIMS Jodhpur, Jodhpur, Rajasthan, India
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15
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Mir FA, Amanullah A, Jain BP, Hyderi Z, Gautam A. Neuroepigenetics of ageing and neurodegeneration-associated dementia: An updated review. Ageing Res Rev 2023; 91:102067. [PMID: 37689143 DOI: 10.1016/j.arr.2023.102067] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 09/01/2023] [Accepted: 09/06/2023] [Indexed: 09/11/2023]
Abstract
Gene expression is tremendously altered in the brain during memory acquisition, recall, and forgetfulness. However, non-genetic factors, including environmental elements, epigenetic changes, and lifestyle, have grabbed significant attention in recent years regarding the etiology of neurodegenerative diseases (NDD) and age-associated dementia. Epigenetic modifications are essential in regulating gene expression in all living organisms in a DNA sequence-independent manner. The genes implicated in ageing and NDD-related memory disorders are epigenetically regulated by processes such as DNA methylation, histone acetylation as well as messenger RNA editing machinery. The physiological and optimal state of the epigenome, especially within the CNS of humans, plays an intricate role in helping us adjust to the changing environment, and alterations in it cause many brain disorders, but the mechanisms behind it still need to be well understood. When fully understood, these epigenetic landscapes could act as vital targets for pharmacogenetic rescue strategies for treating several diseases, including neurodegeneration- and age-induced dementia. Keeping this objective in mind, this updated review summarises the epigenetic changes associated with age and neurodegeneration-associated dementia.
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Affiliation(s)
- Fayaz Ahmad Mir
- Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | | | | | - Zeeshan Hyderi
- Department of Biotechnology, Alagappa University, Karaikudi, India
| | - Akash Gautam
- Centre for Neural and Cognitive Sciences, University of Hyderabad, Hyderabad, India.
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16
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Shayota BJ. Downstream Assays for Variant Resolution: Epigenetics, RNA Sequnncing, and Metabolomics. Pediatr Clin North Am 2023; 70:929-936. [PMID: 37704351 DOI: 10.1016/j.pcl.2023.05.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/15/2023]
Abstract
As the availability of advanced molecular testing like whole exome and genome sequencing expands, it comes with the added complication of interpreting inconclusive results, including determining the relevance of variants of uncertain significance or failing to find a variant in an otherwise suspected specific genetic disorder. This complication necessitates the use of alternative testing methods to gather more information in support of, or against, a particular genetic diagnosis. Therefore, new genome-wide approaches, including DNA epigenetic testing, RNA sequencing, and metabolomics, are increasingly being used to increase the diagnostic yield when used in conjunction with more conventional genetic tests.
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Affiliation(s)
- Brian J Shayota
- University of Utah, 295 Chipeta Way, Salt Lake City, UT 84108, USA; Primary Children's Hospital, Salt Lake City, UT, USA.
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17
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Xie J, Wu S, Szadowski H, Min S, Yang Y, Bowman AB, Rochet JC, Freeman JL, Yuan C. Developmental Pb exposure increases AD risk via altered intracellular Ca 2+ homeostasis in hiPSC-derived cortical neurons. J Biol Chem 2023; 299:105023. [PMID: 37423307 PMCID: PMC10413359 DOI: 10.1016/j.jbc.2023.105023] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 06/21/2023] [Accepted: 06/22/2023] [Indexed: 07/11/2023] Open
Abstract
Exposure to environmental chemicals such as lead (Pb) during vulnerable developmental periods can result in adverse health outcomes later in life. Human cohort studies have demonstrated associations between developmental Pb exposure and Alzheimer's disease (AD) onset in later life which were further corroborated by findings from animal studies. The molecular pathway linking developmental Pb exposure and increased AD risk, however, remains elusive. In this work, we used human iPSC-derived cortical neurons as a model system to study the effects of Pb exposure on AD-like pathogenesis in human cortical neurons. We exposed neural progenitor cells derived from human iPSC to 0, 15, and 50 ppb Pb for 48 h, removed Pb-containing medium, and further differentiated them into cortical neurons. Immunofluorescence, Western blotting, RNA-sequencing, ELISA, and FRET reporter cell lines were used to determine changes in AD-like pathogenesis in differentiated cortical neurons. Exposing neural progenitor cells to low-dose Pb, mimicking a developmental exposure, can result in altered neurite morphology. Differentiated neurons exhibit altered calcium homeostasis, synaptic plasticity, and epigenetic landscape along with elevated AD-like pathogenesis markers, including phosphorylated tau, tau aggregates, and Aβ42/40. Collectively, our findings provide an evidence base for Ca dysregulation caused by developmental Pb exposure as a plausible molecular mechanism accounting for increased AD risk in populations with developmental Pb exposure.
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Affiliation(s)
- Junkai Xie
- Davidson School of Chemical Engineering, Purdue University, West Lafayette, Indiana, USA
| | - Shichen Wu
- Davidson School of Chemical Engineering, Purdue University, West Lafayette, Indiana, USA
| | - Hailey Szadowski
- Agriculture and Biological Engineering, Purdue University, West Lafayette, Indiana, USA
| | - Sehong Min
- Department of Medicinal Chemistry and Molecular Pharmacy, Purdue University, West Lafayette, Indiana, USA
| | - Yang Yang
- Department of Medicinal Chemistry and Molecular Pharmacy, Purdue University, West Lafayette, Indiana, USA; Purdue Institute of Integrated Neuroscience, Purdue University, West Lafayette, Indiana, USA
| | - Aaron B Bowman
- Purdue Institute of Integrated Neuroscience, Purdue University, West Lafayette, Indiana, USA; School of Health Sciences, Purdue University, West Lafayette, Indiana, USA
| | - Jean-Christophe Rochet
- Department of Medicinal Chemistry and Molecular Pharmacy, Purdue University, West Lafayette, Indiana, USA; Purdue Institute of Integrated Neuroscience, Purdue University, West Lafayette, Indiana, USA
| | - Jennifer L Freeman
- Purdue Institute of Integrated Neuroscience, Purdue University, West Lafayette, Indiana, USA; School of Health Sciences, Purdue University, West Lafayette, Indiana, USA; Purdue Center of Cancer Research, Purdue University, West Lafayette, Indiana, USA
| | - Chongli Yuan
- Davidson School of Chemical Engineering, Purdue University, West Lafayette, Indiana, USA; Purdue Institute of Integrated Neuroscience, Purdue University, West Lafayette, Indiana, USA; Purdue Center of Cancer Research, Purdue University, West Lafayette, Indiana, USA.
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18
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Ruden DM, Singh A, Rappolee DA. Pathological epigenetic events and reversibility review: the intersection between hallmarks of aging and developmental origin of health and disease. Epigenomics 2023; 15:741-754. [PMID: 37667910 PMCID: PMC10503466 DOI: 10.2217/epi-2023-0224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 08/07/2023] [Indexed: 09/06/2023] Open
Abstract
We discuss pathological epigenetic events that are reversible (PEERs). A recent study by Poganik and colleagues showed that severe stress in mice and humans transiently elevates biological age of several tissues, and this transient age increase is reversible when the stress is removed. These studies suggest new strategies for reversing normal aging. However, it is important to note that developmental origin of health and disease studies have shown that developmental exposure to toxic chemicals such as lead causes permanent changes in neuron shape, connectivity and cellular hyperplasia of organs such as the heart and liver. In this review, the PEER hypothesis speculates that the hallmarks of aging and the hallmarks of developmental origin of health and disease intersect at PEERs.
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Affiliation(s)
- Douglas M Ruden
- CS Mott Center for Human Health and Development, Wayne State University, Detroit, MI 48201, USA
- Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA
- Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48201, USA
| | - Aditi Singh
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA
| | - Daniel A Rappolee
- CS Mott Center for Human Health and Development, Wayne State University, Detroit, MI 48201, USA
- Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA
- Department of Physiology, Wayne State University, Detroit, MI 48201, USA
- Reproductive Stress, Grosse Pointe Farms, MI 48236, USA
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19
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Joint Action Toxicity of Arsenic (As) and Lead (Pb) Mixtures in Developing Zebrafish. Biomolecules 2022; 12:biom12121833. [PMID: 36551261 PMCID: PMC9776292 DOI: 10.3390/biom12121833] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 12/01/2022] [Accepted: 12/05/2022] [Indexed: 12/13/2022] Open
Abstract
Arsenic (As) and lead (Pb) are environmental pollutants found in common sites and linked to similar adverse health effects. Multiple studies have investigated the toxicity of each metal individually or in complex mixtures. Studies defining the joint interaction of a binary exposure to As and Pb, especially during the earliest stages of development, are limited and lack confirmation of the predicted mixture interaction. We hypothesized that a mixture of As (iAsIII) and Pb will have a concentration addition (CA) interaction informed by common pathways of toxicity of the two metals. To test this hypothesis, developing zebrafish (1-120 h post fertilization; hpf) were first exposed to a wide range of concentrations of As or Pb separately to determine 120 hpf lethal concentrations. These data were then used in the CA and independent action (IA) models to predict the type of mixture interaction from a co-exposure to As and Pb. Three titration mixture experiments were completed to test prediction of observed As and Pb mixture interaction by keeping the Pb concentration constant and varying As concentrations in each experiment. The prediction accuracy of the two models was then calculated using the prediction deviation ratio (PDR) and Chi-square test and regression modeling applied to determine type of interaction. Individual metal exposures determined As and Pb concentrations at which 25% (39.0 ppm Pb, 40.2 ppm As), 50% (73.8 ppm Pb, 55.4 ppm As), 75% (99.9 ppm Pb, 66.6 ppm As), and 100% (121.7 ppm Pb, 77.3 ppm As) lethality was observed at 120 hpf. These data were used to graph the predicted mixture interaction using the CA and IA models. The titration experiments provided experimental observational data to assess the prediction. PDR values showed the CA model approached 1, whereas all PDR values for the IA model had large deviations from predicted data. In addition, the Chi-square test showed most observed results were significantly different from the predictions, except in the first experiment (Pb LC25 held constant) with the CA model. Regression modeling for the IA model showed primarily a synergistic response among all exposure scenarios, whereas the CA model indicated additive response at lower exposure concentrations and synergism at higher exposure concentrations. The CA model was a better predictor of the Pb and As binary mixture interaction compared to the IA model and was able to delineate types of mixture interactions among different binary exposure scenarios.
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20
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Bolognesi G, Bacalini MG, Pirazzini C, Garagnani P, Giuliani C. Evolutionary Implications of Environmental Toxicant Exposure. Biomedicines 2022; 10:3090. [PMID: 36551846 PMCID: PMC9775150 DOI: 10.3390/biomedicines10123090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/25/2022] [Accepted: 11/27/2022] [Indexed: 12/03/2022] Open
Abstract
Homo sapiens have been exposed to various toxins and harmful compounds that change according to various phases of human evolution. Population genetics studies showed that such exposures lead to adaptive genetic changes; while observing present exposures to different toxicants, the first molecular mechanism that confers plasticity is epigenetic remodeling and, in particular, DNA methylation variation, a molecular mechanism proposed for medium-term adaptation. A large amount of scientific literature from clinical and medical studies revealed the high impact of such exposure on human biology; thus, in this review, we examine and infer the impact that different environmental toxicants may have in shaping human evolution. We first describe how environmental toxicants shape natural human variation in terms of genetic and epigenetic diversity, and then we describe how DNA methylation may influence mutation rate and, thus, genetic variability. We describe the impact of these substances on biological fitness in terms of reproduction and survival, and in conclusion, we focus on their effect on brain evolution and physiology.
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Affiliation(s)
- Giorgia Bolognesi
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, via San Giacomo 12, 40126 Bologna, Italy
- Laboratory of Molecular Anthropology, Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences, University of Bologna, via Francesco Selmi 3, 40126 Bologna, Italy
| | - Maria Giulia Bacalini
- IRCCS Istituto Delle Scienze Neurologiche di Bologna, via Altura 3, 40139 Bologna, Italy
| | - Chiara Pirazzini
- IRCCS Istituto Delle Scienze Neurologiche di Bologna, via Altura 3, 40139 Bologna, Italy
| | - Paolo Garagnani
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, via San Giacomo 12, 40126 Bologna, Italy
| | - Cristina Giuliani
- Laboratory of Molecular Anthropology, Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences, University of Bologna, via Francesco Selmi 3, 40126 Bologna, Italy
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21
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Yohannes YB, Nakayama SM, Yabe J, Toyomaki H, Kataba A, Nakata H, Muzandu K, Miyashita C, Ikenaka Y, Choongo K, Ishizuka M. Methylation profiles of global LINE-1 DNA and the GSTP1 promoter region in children exposed to lead (Pb). Epigenetics 2022; 17:2377-2388. [PMID: 36131534 PMCID: PMC9665151 DOI: 10.1080/15592294.2022.2123924] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 07/12/2022] [Accepted: 09/05/2022] [Indexed: 11/03/2022] Open
Abstract
Lead (Pb) exposure has adverse health effects and altered DNA methylation may contribute to Pb toxicity. LINE-1 is an interspersed repeated DNA that is used as a surrogate marker for estimating genomic DNA methylation levels, and GSTP1 is an isozyme that detoxifies xenobiotics like Pb, and its expression is inhibited by methylation. Thus, to assess the effects of Pb exposure on global hypomethylation and gene-specific promoter hypermethylation, we examined DNA methylation at LINE-1 repetitive elements and the GSTP1 promoter region. Blood samples were obtained from children (N = 123) living in Pb-polluted areas (as exposed children) and children (N = 63) living in Pb-unpolluted areas (as control children) in Kabwe, Zambia. ICP-MS was used to determine blood lead levels (BLLs), and pyrosequencing and a fluorescence-based polymerase chain reaction assay were used to determine levels of LINE-1 methylation and GSTP1 promoter methylation, respectively. Inverse association was found between BLLs and LINE-1 methylation (β = - 0.046, p = 0.006). The highest quartile of BLL had significant hypomethylation of LINE-1 (p for trend = 0.03), suggesting the higher the BLL, the lower LINE-1 methylation. GSTP1 methylation levels did not differ significantly between the two areas (p = 0.504), nor was it associated with Pb poisoning risk (OR = 1.03, p = 0.476), indicating GSTP1 methylation may not be a reliable biomarker of Pb exposure in healthy people. Therefore, Pb-related health problems could result from global DNA methylation changes due to high BLLs.
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Affiliation(s)
- Yared Beyene Yohannes
- Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
- Department of Chemistry, College of Natural and Computational Science, University of Gondar, Gondar, Ethiopia
| | - Shouta M.M. Nakayama
- Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
- School of Veterinary Medicine, The University of Zambia, Lusaka, Zambia
| | - John Yabe
- School of Veterinary Medicine, The University of Zambia, Lusaka, Zambia
- Department of Veterinary Para-Clinical Studies, School of Veterinary Medicine, University of Namibia, Windhoek, Namibia
| | - Haruya Toyomaki
- Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Andrew Kataba
- School of Veterinary Medicine, The University of Zambia, Lusaka, Zambia
| | - Hokuto Nakata
- Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Kaampwe Muzandu
- School of Veterinary Medicine, The University of Zambia, Lusaka, Zambia
| | - Chihiro Miyashita
- Center for Environmental and Health Sciences, Hokkaido University, Sapporo, Japan
| | - Yoshinori Ikenaka
- Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
- Water Research Group, Unit for Environmental Sciences and Management, Potchefstroom Campus, North-West University, Potchefstroom, South Africa
- Translational Research Unit, Veterinary Teaching Hospital, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
- One Health Research Center, Hokkaido University, Sapporo, Japan
| | - Kennedy Choongo
- School of Veterinary Medicine, The University of Zambia, Lusaka, Zambia
- College of Agriculture, Fisheries & Forestry, School of Animal and Veterinary Sciences, Fiji National University, Koronivia Campus, Suva, Fiji
| | - Mayumi Ishizuka
- Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
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22
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Tung PW, Kennedy EM, Burt A, Hermetz K, Karagas M, Marsit CJ. Prenatal lead (Pb) exposure is associated with differential placental DNA methylation and hydroxymethylation in a human population. Epigenetics 2022; 17:2404-2420. [PMID: 36148884 PMCID: PMC9665158 DOI: 10.1080/15592294.2022.2126087] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 09/02/2022] [Accepted: 09/12/2022] [Indexed: 11/03/2022] Open
Abstract
Prenatal lead (Pb) exposure is associated with adverse developmental outcomes and to epigenetic alterations such as DNA methylation and hydroxymethylation in animal models and in newborn blood. Given the importance of the placenta in foetal development, we sought to examine how prenatal Pb exposure was associated with differential placental DNA methylation and hydroxymethylation and to identify affected biological pathways linked to developmental outcomes. Maternal (n = 167) and infant (n = 172) toenail and placenta (n = 115) samples for prenatal Pb exposure were obtained from participants in a US birth cohort, and methylation and hydroxymethylation data were quantified using the Illumina Infinium MethylationEPIC BeadChip. An epigenome-wide association study was applied to identify differential methylation and hydroxymethylation associated with Pb exposure. Biological functions of the Pb-associated genes were determined by overrepresentation analysis through ConsensusPathDB. Prenatal Pb quantified from maternal toenail, infant toenail, and placenta was associated with 480, 27, and 2 differentially methylated sites (q < 0.05), respectively, with both increases and decreases associated with exposure. Alternatively, we identified 2, 1, and 14 differentially hydroxymethylated site(s) associated with maternal toenail, infant toenail, and placental Pb, respectively, with most showing increases in hydroxymethylation with exposure. Significantly overrepresented pathways amongst genes associated with differential methylation and hydroxymethylation (q < 0.10) included mechanisms pertaining to nervous system and organ development, calcium transport and regulation, and signalling activities. Our results suggest that both methylation and hydroxymethylation in the placenta can be variable based on Pb exposure and that the pathways impacted could affect placental function.
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Affiliation(s)
- Pei Wen Tung
- Gangarosa Department of Environmental Health, Emory University, Atlanta, GA, USA
| | - Elizabeth M. Kennedy
- Gangarosa Department of Environmental Health, Emory University, Atlanta, GA, USA
| | - Amber Burt
- Gangarosa Department of Environmental Health, Emory University, Atlanta, GA, USA
| | - Karen Hermetz
- Gangarosa Department of Environmental Health, Emory University, Atlanta, GA, USA
| | - Margaret Karagas
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, Lebanon
| | - Carmen J. Marsit
- Gangarosa Department of Environmental Health, Emory University, Atlanta, GA, USA
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23
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Liu M, Liu R, Wang R, Ba Y, Yu F, Deng Q, Huang H. Lead-induced neurodevelopmental lesion and epigenetic landscape: Implication in neurological disorders. J Appl Toxicol 2022. [PMID: 36433892 DOI: 10.1002/jat.4419] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 11/20/2022] [Accepted: 11/20/2022] [Indexed: 11/27/2022]
Abstract
Lead (Pb) was implicated in multiple genotoxic, neuroepigenotoxic, and chromosomal-toxic mechanisms and interacted with varying synaptic plasticity pathways, likely underpinning previous reports of links between Pb and cognitive impairment. Epigenetic changes have emerged as a promising biomarker for neurological disorders, including cognitive disorders, Alzheimer's disease (AD), and Parkinson's disease (PD). In the present review, special attention is paid to neural epigenetic features and mechanisms that can alter gene expression patterns upon environmental Pb exposure in rodents, primates, and zebrafish. Epigenetic modifications have also been discussed in population studies and cell experiment. Further, we explore growing evidence of potential linkage between Pb-induced disruption of regulatory pathway and neurodevelopmental and neurological disorders both in vivo and in vitro. These findings uncover how epigenome in neurons facilitates the development and function of the brain in response to Pb insult.
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Affiliation(s)
- Mengchen Liu
- Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, Henan province, 450001, China
| | - Rundong Liu
- Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, Henan province, 450001, China
| | - Ruike Wang
- Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, Henan province, 450001, China
| | - Yue Ba
- Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, Henan province, 450001, China
| | - Fangfang Yu
- Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, Henan province, 450001, China
| | - Qihong Deng
- Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, Henan province, 450001, China
| | - Hui Huang
- Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, Henan province, 450001, China
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24
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Lodge EK, Dhingra R, Martin CL, Fry RC, White AJ, Ward-Caviness CK, Wani AH, Uddin M, Wildman DE, Galea S, Aiello AE. Serum lead, mercury, manganese, and copper and DNA methylation age among adults in Detroit, Michigan. ENVIRONMENTAL EPIGENETICS 2022; 8:dvac018. [PMID: 36330039 PMCID: PMC9620967 DOI: 10.1093/eep/dvac018] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 09/03/2022] [Accepted: 09/19/2022] [Indexed: 06/16/2023]
Abstract
Although the effects of lead, mercury, manganese, and copper on individual disease processes are well understood, estimating the health effects of long-term exposure to these metals at the low concentrations often observed in the general population is difficult. In addition, the health effects of joint exposure to multiple metals are difficult to estimate. Biological aging refers to the integrative progression of multiple physiologic and molecular changes that make individuals more at risk of disease. Biomarkers of biological aging may be useful to estimate the population-level effects of metal exposure prior to the development of disease in the population. We used data from 290 participants in the Detroit Neighborhood Health Study to estimate the effect of serum lead, mercury, manganese, and copper on three DNA methylation-based biomarkers of biological aging (Horvath Age, PhenoAge, and GrimAge). We used mixed models and Bayesian kernel machine regression and controlled for participant sex, race, ethnicity, cigarette use, income, educational attainment, and block group poverty. We observed consistently positive estimates of the effects between lead and GrimAge acceleration and mercury and PhenoAge acceleration. In contrast, we observed consistently negative associations between manganese and PhenoAge acceleration and mercury and Horvath Age acceleration. We also observed curvilinear relationships between copper and both PhenoAge and GrimAge acceleration. Increasing total exposure to the observed mixture of metals was associated with increased PhenoAge and GrimAge acceleration and decreased Horvath Age acceleration. These findings indicate that an increase in serum lead or mercury from the 25th to 75th percentile is associated with a ∼0.25-year increase in two epigenetic markers of all-cause mortality in a population of adults in Detroit, Michigan. While few of the findings were statistically significant, their consistency and novelty warrant interest.
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Affiliation(s)
- Evans K Lodge
- *Correspondence address. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, NC 27599, USA. Tel: +574-339-0253; Fax: +919-966-2089; E-mail:
| | - Radhika Dhingra
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, 135 Dauer Dr, Chapel Hill, NC 27599, USA
- Institute for Environmental Health Solutions, University of North Carolina at Chapel Hill, 135 Dauer Dr, Chapel Hill, NC 27599, USA
| | - Chantel L Martin
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, 135 Dauer Dr, Chapel Hill, NC 27599, USA
- Carolina Population Center, University of North Carolina at Chapel Hill, 123 W Franklin St, Chapel Hill, NC 27516, USA
- Center for Environmental Health & Susceptibility, University of North Carolina at Chapel Hill, 135 Dauer Dr, Chapel Hill, NC 27599, USA
| | - Rebecca C Fry
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, 135 Dauer Dr, Chapel Hill, NC 27599, USA
- Center for Environmental Health & Susceptibility, University of North Carolina at Chapel Hill, 135 Dauer Dr, Chapel Hill, NC 27599, USA
| | - Alexandra J White
- Epidemiology Branch, National Institute of Environmental Health Sciences, A323 David P Rall Building, Research Triangle Park, NC 27709, USA
| | - Cavin K Ward-Caviness
- Center for Public Health and Environmental Assessment, US Environmental Protection Agency, 104 Mason Farm Rd, Chapel Hill, NC 27514, USA
| | - Agaz H Wani
- Genomics Program, College of Public Health, University of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA
| | - Monica Uddin
- Genomics Program, College of Public Health, University of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA
| | - Derek E Wildman
- Genomics Program, College of Public Health, University of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA
| | - Sandro Galea
- School of Public Health, Boston University, 715 Albany St, Boston, MA 02118, USA
| | - Allison E Aiello
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, 135 Dauer Dr, Chapel Hill, NC 27599, USA
- Carolina Population Center, University of North Carolina at Chapel Hill, 123 W Franklin St, Chapel Hill, NC 27516, USA
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25
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Ruden DM. 10 Years of Toxicogenomics section in Frontiers in Genetics: Past discoveries and Future Perspectives. Front Genet 2022; 13:979761. [PMID: 36171875 PMCID: PMC9510767 DOI: 10.3389/fgene.2022.979761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 08/11/2022] [Indexed: 11/13/2022] Open
Abstract
The Frontiers Media family has over 200 journals, which are each headed by usually one Field Chief Editor, and several thousand specialty sections, which are each headed by one or more Specialty Chief Editors. The year 2021 was the 10th anniversary of the founding of the Frontiers in Genetics journal and the Frontiers in Toxicogenomics specialty section of this journal. In 2021, we also announce one of the newest of the Frontiers journals-Frontiers in Toxicology which is part of the Frontiers Media family of journals but independent of Frontiers in Genetics. Dr. Ruden is the founding, and currently sole, Specialty Chief Editor of Frontiers in Toxicogenomics and one of 9 Specialty Chief Editors of Frontiers in Toxicology. As of 2021, Frontiers in Toxicogenomics has published over 138 articles and has over 370 Editors including 90 Associate Editors and 280 Review Editors. The Frontiers in Genetics impact factor was initially approximately 2.5 when it was first listed in PubMed in 2015 and has risen steadily to its current value of 4.8, which is typical for the majority of the over 200 Frontiers journals that have established impact factors. In this overview of the first decade of Frontiers in Toxicogenomics, we discuss the top 5 articles with the highest Scopus citations, which were all written in the first few years of the journal. The article with the highest number of citations, with 353 Scopus over 600 Google Scholar citations, and the highest average number of citations (67) that steadily increased from 10 citations in 2013 to 119 citations in 2021, was written in 2012 by Dr. Ruden's laboratory and titled, "Using Drosophila melanogaster as a model for genotoxic chemical mutational studies with a new program, SnpSift." The five most influential authors who published in the journal in the past 10 years based on Scopus citations of a particular paper are Dr. Ruden's laboratory, with 353 Scopus citations for the SnpSift paper mentioned above; Drs. Brock Christensen and Carmen J. Marsit, with 86 Scopus citations for their review, "Epigenomics in environmental health"; Dr. Michael Aschner and colleagues, with 61 Scopus citations for their paper "Genetic factors and manganese-induced neurotoxicity"; and Dr. Sandra C. dos Santos and colleagues, with 59 Scopus citations for their paper, "Yeast toxicogenomics: genome-wide responses to chemical stresses with impact in environmental health, pharmacology, and biotechnology." While the top 5 papers were published in the early years of the journal, we will also discuss a more recent article published in 2018 on a comparison of RNA-seq and microarray methods by Dr. Michael Liguori's laboratory, "Comparison of RNA-Seq and Microarray Gene Expression Platforms for the Toxicogenomic Evaluation of Liver From Short-Term Rat Toxicity Studies," that far exceeds the number of downloads and views of all the other articles published in the first 10 years of the journal and will likely be a top cited paper in the second decade highlights of this journal. Finally, we discuss where the Frontiers in Toxicogenomics specialty journal and the Frontiers in Toxicology journal will go to advance the field of toxicogenomics, and more generally, toxicology, in the future.
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Affiliation(s)
- Douglas M. Ruden
- Institute of Environmental Health Sciences, C. S. Mott Center for Human Health and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, United States
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26
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Islam F, Shohag S, Akhter S, Islam MR, Sultana S, Mitra S, Chandran D, Khandaker MU, Ashraf GM, Idris AM, Emran TB, Cavalu S. Exposure of metal toxicity in Alzheimer's disease: An extensive review. Front Pharmacol 2022; 13:903099. [PMID: 36105221 PMCID: PMC9465172 DOI: 10.3389/fphar.2022.903099] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 07/14/2022] [Indexed: 11/13/2022] Open
Abstract
Metals serve important roles in the human body, including the maintenance of cell structure and the regulation of gene expression, the antioxidant response, and neurotransmission. High metal uptake in the nervous system is harmful because it can cause oxidative stress, disrupt mitochondrial function, and impair the activity of various enzymes. Metal accumulation can cause lifelong deterioration, including severe neurological problems. There is a strong association between accidental metal exposure and various neurodegenerative disorders, including Alzheimer's disease (AD), the most common form of dementia that causes degeneration in the aged. Chronic exposure to various metals is a well-known environmental risk factor that has become more widespread due to the rapid pace at which human activities are releasing large amounts of metals into the environment. Consequently, humans are exposed to both biometals and heavy metals, affecting metal homeostasis at molecular and biological levels. This review highlights how these metals affect brain physiology and immunity and their roles in creating harmful proteins such as β-amyloid and tau in AD. In addition, we address findings that confirm the disruption of immune-related pathways as a significant toxicity mechanism through which metals may contribute to AD.
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Affiliation(s)
- Fahadul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh
| | - Sheikh Shohag
- Department of Genetic Engineering and Biotechnology, Faculty of Earth and Ocean Science, Bangabandhu Sheikh Mujibur Rahman Maritime University, Dhaka, Bangladesh
| | - Shomaya Akhter
- Department of Genetic Engineering and Biotechnology, Faculty of Earth and Ocean Science, Bangabandhu Sheikh Mujibur Rahman Maritime University, Dhaka, Bangladesh
| | - Md. Rezaul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh
| | - Sharifa Sultana
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh
| | - Saikat Mitra
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka, Bangladesh
| | - Deepak Chandran
- Department of Veterinary Sciences and Animal Husbandry, Amrita School of Agricultural Sciences, Amrita Vishwa Vidyapeetham University, Coimbatore, India
| | - Mayeen Uddin Khandaker
- Centre for Applied Physics and Radiation Technologies, School of Engineering and Technology, Sunway University, Subang Jaya, Malaysia
| | - Ghulam Md Ashraf
- Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Abubakr M. Idris
- Department of Chemistry, College of Science, King Khalid University, Abha, Saudi Arabia
- Research Center for Advanced Materials Science (RCAMS), King Khalid University, Abha, Saudi Arabia
| | - Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong, Bangladesh
| | - Simona Cavalu
- Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
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27
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Cuomo D, Foster MJ, Threadgill D. Systemic review of genetic and epigenetic factors underlying differential toxicity to environmental lead (Pb) exposure. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:35583-35598. [PMID: 35244845 PMCID: PMC9893814 DOI: 10.1007/s11356-022-19333-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 02/17/2022] [Indexed: 05/03/2023]
Abstract
Lead (Pb) poisoning is a major public health concern in environmental justice communities of the USA and in many developing countries. There is no identified safety threshold for lead in blood, as low-level Pb exposures can lead to severe toxicity in highly susceptible individuals and late onset of diseases from early-life exposure. However, identifying "susceptibility genes" or "early exposure biomarkers" remains challenging in human populations. There is a considerable variation in susceptibility to harmful effects from Pb exposure in the general population, likely due to the complex interplay of genetic and/or epigenetic factors. This systematic review summarizes current state of knowledge on the role of genetic and epigenetic factors in determining individual susceptibility in response to environmental Pb exposure in humans and rodents. Although a number of common genetic and epigenetic factors have been identified, the reviewed studies, which link these factors to various adverse health outcomes following Pb exposure, have provided somewhat inconsistent evidence of main health effects. Acknowledging the compelling need for new approaches could guide us to better characterize individual responses, predict potential adverse outcomes, and identify accurate and usable biomarkers for Pb exposure to improve mitigation therapies to reduce future adverse health outcomes of Pb exposure.
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Affiliation(s)
- Danila Cuomo
- Department of Molecular and Cellular Medicine, Texas A&M University, College Station, TX, USA.
| | - Margaret J Foster
- Medical Sciences Library, Texas A&M University, College Station, TX, USA
| | - David Threadgill
- Department of Molecular and Cellular Medicine and Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA.
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28
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Amadi CN, Orish CN, Frazzoli C, Orisakwe OE. Association of autism with toxic metals: A systematic review of case-control studies. Pharmacol Biochem Behav 2021; 212:173313. [PMID: 34896416 DOI: 10.1016/j.pbb.2021.173313] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 12/05/2021] [Accepted: 12/06/2021] [Indexed: 02/07/2023]
Abstract
Environmental factors have been associated with the etiology of autism spectrum disorder ASD in recent times. The involvement of toxic metals in the generation of reactive oxygen species and their epigenetics effects have been implicated in ASD. This systemic review examines the association of toxic metals with autism in children. A systematic literature search was performed in scientific databases such as PubMed, Google scholar, and Scopus. Case-control studies evaluating toxic metal levels in different tissues of ASD children and comparing them to healthy children (control group) were identified. The Newcastle-Ottawa Scale was used to evaluate the risk of bias of the included studies. Six case-control studies with 425 study subjects met our inclusion criteria. A total of four studies indicated higher levels of As, Pb, Hg, Cd, Al, Sn, Sb, Ba, TI, W, and Zr in whole blood, RBC, in whole blood, RBC, and hair samples of children with autism compared with control suggestive of a greater toxic metal exposure (immediate and long-term). Three studies identified significantly higher concentrations of Cd, Pb and Hg in urine and hair samples of autistic children compared to control suggesting decreased excretion and possible high body burden of these metals. The findings from this review demonstrate that high levels of toxic metals are associated with ASD, therefore, critical care is necessary to reduce body burden of these metals in children with ASD as a major therapeutic strategy.
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Affiliation(s)
- Cecilia N Amadi
- Department of Experimental Pharmacology & Toxicology, Faculty of Pharmacy, University of Port Harcourt, PMB, 5323 Port Harcourt, Choba, Nigeria
| | - Chinna N Orish
- Department of Anatomy, Faculty of Basic Medical Sciences, College of Health Sciences, University of Port Harcourt, PMB, 5323 Port Harcourt, Choba, Nigeria
| | - Chiara Frazzoli
- Department for Cardiovascular, Dysmetabolic and Aging Diseases, Istituto Superiore di Sanità, Rome, Italy
| | - Orish E Orisakwe
- Department of Experimental Pharmacology & Toxicology, Faculty of Pharmacy, University of Port Harcourt, PMB, 5323 Port Harcourt, Choba, Nigeria; African Centre of Excellence for Public Health and Toxicological Research (ACE-PUTOR), University of Port Harcourt, PMB, 5323 Port Harcourt, Choba, Nigeria.
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29
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Cui F, Pan Q, Wang S, Zhao F, Wang R, Zhang T, Song Y, He J, Zhang H, Weng Q, Jin Y, Xia W, Li Y, Yang G, De Vos WH, Timmermans J, Xu S, Tang Y, Sheng X. Maternal Benzophenone Exposure Impairs Hippocampus Development and Cognitive Function in Mouse Offspring. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2102686. [PMID: 34713618 PMCID: PMC8655188 DOI: 10.1002/advs.202102686] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 08/19/2021] [Indexed: 06/13/2023]
Abstract
Benzophenones are widely supplemented in personal care products, but little is known about its neurodevelopmental toxicity. The previous epidemiological study discovered a negative correlation between maternal exposure to a benzophenone metabolite 4-hydroxybenzophenone (4HBP) and child's neurodevelopment, yet the causal relationship and detailed mechanism remain to be defined. Here, it is reported that prenatal, but not postnatal, exposure to environmentally relevant level of 4HBP impairs hippocampus development and causes cognitive dysfunction in offspring mice. Transcriptomic analyses reveal that 4HBP induces the endoplasmic reticulum stress-induced apoptotic signaling and inflammatory response in hippocampal neural stem cells. Mechanistically, 4HBP exposure activates protein kinase R-like ER kinase (PERK) signaling, which induces CHOP, inhibits IκB translation, and transactivates p65, thereby promoting inflammation and apoptosis on multiple levels. Importantly, genetic or pharmacological inhibition of PERK pathway significantly attenuates 4HBP-induced NFκB signaling and neurodevelopmental abnormalities in mice and in a human brain organoid model. The study uncovers the neurodevelopmental toxicity of BP and cautions its exposure during pregnancy.
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Affiliation(s)
- Fengzhen Cui
- Key Laboratory of Environment and HealthMinistry of Education & Ministry of Environmental ProtectionSchool of Public HealthTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Qingfei Pan
- Department of Computational BiologySt. Jude Children's Research HospitalMemphisTN38105USA
| | - Siyi Wang
- Department of NeurologyWuhan Fourth Hospital/Pu'ai HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430033China
| | - Faming Zhao
- Key Laboratory of Environment and HealthMinistry of Education & Ministry of Environmental ProtectionSchool of Public HealthTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Runxin Wang
- Key Laboratory of Environment and HealthMinistry of Education & Ministry of Environmental ProtectionSchool of Public HealthTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Tingting Zhang
- Key Laboratory of Environment and HealthMinistry of Education & Ministry of Environmental ProtectionSchool of Public HealthTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Yaying Song
- Neuroscience and Neuroengineering Research CenterMed‐X Research Institute and School of Biomedical EngineeringShanghai Jiao Tong UniversityShanghai200030China
| | - Jun He
- Department of Histology and EmbryologySchool of Basic Medical SciencesTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei430030China
| | - Haolin Zhang
- Laboratory of Animal PhysiologyCollege of Biological Sciences and TechnologyBeijing Forestry UniversityBeijing100083China
| | - Qiang Weng
- Laboratory of Animal PhysiologyCollege of Biological Sciences and TechnologyBeijing Forestry UniversityBeijing100083China
| | - Yang Jin
- Department of BiosciencesUniversity of OsloOslo0316Norway
| | - Wei Xia
- Key Laboratory of Environment and HealthMinistry of Education & Ministry of Environmental ProtectionSchool of Public HealthTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Yuanyuan Li
- Key Laboratory of Environment and HealthMinistry of Education & Ministry of Environmental ProtectionSchool of Public HealthTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Guo‐Yuan Yang
- Neuroscience and Neuroengineering Research CenterMed‐X Research Institute and School of Biomedical EngineeringShanghai Jiao Tong UniversityShanghai200030China
| | - Winnok H. De Vos
- Laboratory of Cell Biology and HistologyUniversity of AntwerpWilrijkAntwerp2610Belgium
- µNEURO Research Excellence ConsortiumUniversity of AntwerpWilrijkAntwerp2610Belgium
| | | | - Shunqing Xu
- Key Laboratory of Environment and HealthMinistry of Education & Ministry of Environmental ProtectionSchool of Public HealthTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Yaohui Tang
- Neuroscience and Neuroengineering Research CenterMed‐X Research Institute and School of Biomedical EngineeringShanghai Jiao Tong UniversityShanghai200030China
| | - Xia Sheng
- Key Laboratory of Environment and HealthMinistry of Education & Ministry of Environmental ProtectionSchool of Public HealthTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
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30
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Childebayeva A, Goodrich JM, Chesterman N, Leon-Velarde F, Rivera-Ch M, Kiyamu M, Brutsaert TD, Bigham AW, Dolinoy DC. Blood lead levels in Peruvian adults are associated with proximity to mining and DNA methylation. ENVIRONMENT INTERNATIONAL 2021; 155:106587. [PMID: 33940396 PMCID: PMC9903334 DOI: 10.1016/j.envint.2021.106587] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 04/12/2021] [Accepted: 04/13/2021] [Indexed: 06/05/2023]
Abstract
BACKGROUND Inorganic lead (Pb) is common in the environment, and is toxic to neurological, renal, and cardiovascular systems. Pb exposure influences the epigenome with documented effects on DNA methylation (DNAm). We assessed the impact of low levels of Pb exposure on DNAm among non-miner individuals from two locations in Peru: Lima, the capital, and Cerro de Pasco, a highland mining town, to study the effects of Pb exposure on physiological outcomes and DNAm. METHODS Pb levels were measured in whole blood (n = 305). Blood leukocyte DNAm was determined for 90 DNA samples using the Illumina MethylationEPIC chip. An epigenome-wide association study was performed to assess the relationship between Pb and DNAm. RESULTS Individuals from Cerro de Pasco had higher Pb than individuals from Lima (p-value = 2.00E-16). Males had higher Pb than females (p-value = 2.36E-04). Pb was positively associated with hemoglobin (p-value = 8.60E-04). In Cerro de Pasco, blood Pb decreased with the distance from the mine (p-value = 0.04), and association with soil Pb was approaching significance (p-value = 0.08). We identified differentially methylated positions (DMPs) associated with genes SOX18, ZMIZ1, and KDM1A linked to neurological function. We also found 45 differentially methylated regions (DMRs), seven of which were associated with genes involved in metal ion binding and nine to neurological function and development. CONCLUSIONS Our results demonstrate that even low levels of Pb can have a significant impact on the body including changes to DNAm. We report associations between Pb and hemoglobin, Pb and distance from mining, and between blood and soil Pb. We also report associations between loci- and region-specific DNAm and Pb.
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Affiliation(s)
- Ainash Childebayeva
- Department of Anthropology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA; Department of Archaeogenetics, Max Planck Institute for the Science of Human History, Jena 07745, Germany.
| | - Jaclyn M Goodrich
- Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA
| | - Nathan Chesterman
- School for Environment and Sustainability, University of Michigan, Ann Arbor, MI 48109, USA
| | - Fabiola Leon-Velarde
- Departamento de Ciencias Biológicas y Fisiológicas, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, Peru
| | - Maria Rivera-Ch
- Departamento de Ciencias Biológicas y Fisiológicas, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, Peru
| | - Melisa Kiyamu
- Departamento de Ciencias Biológicas y Fisiológicas, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, Peru
| | - Tom D Brutsaert
- Department of Exercise Science, Syracuse University, Syracuse, NY 13244, USA
| | - Abigail W Bigham
- Department of Anthropology, University of California, Los Angeles, CA 90095, USA
| | - Dana C Dolinoy
- Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA; Department of Nutritional Sciences, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA
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Yamazaki J, Toyomaki H, Nakayama SMM, Yabe J, Muzandu K, Jelinek J, Yokoyama S, Ikenaka Y, Takiguchi M, Ishizuka M. Genome-wide DNA methylation analysis of dogs with high lead exposure living near a lead mining area in Kabwe, Zambia. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2021; 286:117229. [PMID: 33975213 DOI: 10.1016/j.envpol.2021.117229] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/12/2021] [Accepted: 04/22/2021] [Indexed: 06/12/2023]
Abstract
Lead (Pb) is a heavy metal that has been proven to be toxic to both animals and humans. Genom-wide DNA methylation in domestic dogs exposed to high levels of Pb in Kabwe, Zambia was analyzed in this study. Using next-generation sequencing on samples from 20 domestic dogs (mean blood Pb concentration: 43.6 μg/dL and 7.2 μg/dL in the high and low exposure groups), a digital restriction enzyme analysis of methylation was performed to identify the genomic locations of differentially methylated CpG sites. A validation study on an additional 20 dogs followed (blood Pb concentration: 4.9-29.7 μg/dL). The cluster analysis resolved two broad clusters indicating high and low Pb exposure. The study identified 827 (1.2%) CpG sites with differences in methylation (101 CpG sites were hypermethylated in the low exposure group and 726 were hypermethylated in the high exposure group). The sites corresponded to 26 genes with differentially methylated CpG sites at their promoter regions, including the NGF gene. The methylation of four CpG sites was validated using bisulfite pyrosequencing. The results indicate that aberrant hypermethylation is prevalent in dogs exposed to Pb. The altered DNA methylation of the genes identified in this study contributes to a greater understanding of the epigenetic changes caused by Pb exposure and highlights novel biomarker discoveries across species.
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Affiliation(s)
- Jumpei Yamazaki
- Translational Research Unit, Veterinary Teaching Hospital, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, 060-0818, Japan; One Health Research Center, Hokkaido University, Japan
| | - Haruya Toyomaki
- Laboratory of Toxicology, Faculty of Veterinary Medicine, Hokkaido University, Japan
| | - Shouta M M Nakayama
- Laboratory of Toxicology, Faculty of Veterinary Medicine, Hokkaido University, Japan.
| | - John Yabe
- School of Veterinary Medicine, The University of Zambia, P.O. Box 32379, Lusaka, Zambia; Dept of Pathobiology, Faculty of Agriculture & Natural Resources, School of Veterinary Medicine, University of Namibia, Windhoek, Namibia
| | - Kaampwe Muzandu
- School of Veterinary Medicine, The University of Zambia, P.O. Box 32379, Lusaka, Zambia
| | | | - Shoko Yokoyama
- Veterinary Teaching Hospital, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, 060-0818, Japan
| | - Yoshinori Ikenaka
- Translational Research Unit, Veterinary Teaching Hospital, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, 060-0818, Japan; Laboratory of Toxicology, Faculty of Veterinary Medicine, Hokkaido University, Japan; One Health Research Center, Hokkaido University, Japan; Water Research Group, Unit for Environmental Sciences and Management, North-West University, Potchefstroom, South Africa
| | - Mitsuyoshi Takiguchi
- Veterinary Teaching Hospital, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, 060-0818, Japan
| | - Mayumi Ishizuka
- Laboratory of Toxicology, Faculty of Veterinary Medicine, Hokkaido University, Japan
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Shiek SS, Mani MS, Kabekkodu SP, Dsouza HS. Health repercussions of environmental exposure to lead: Methylation perspective. Toxicology 2021; 461:152927. [PMID: 34492314 DOI: 10.1016/j.tox.2021.152927] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 07/23/2021] [Accepted: 09/01/2021] [Indexed: 12/15/2022]
Abstract
Lead (Pb) exposure has been a major public health concern for a long time now due to its permanent adverse effects on the human body. The process of lead toxicity has still not been fully understood, but recent advances in Omics technology have enabled researchers to evaluate lead-mediated alterations at the epigenome-wide level. DNA methylation is one of the widely studied and well-understood epigenetic modifications. Pb has demonstrated its ability to induce not just acute deleterious health consequences but also alters the epi-genome such that the disease manifestation happens much later in life as supported by Barkers Hypothesis of the developmental origin of health and diseases. Furthermore, these alterations are passed on to the next generation. Based on previous in-vivo, in-vitro, and human studies, this review provides an insight into the role of Pb in the development of several human disorders.
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Affiliation(s)
- Sadiya Sadiq Shiek
- Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Monica Shirley Mani
- Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
| | - Herman S Dsouza
- Department of Radiation Biology and Toxicology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
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Mäkinen H, van Oers K, Eeva T, Ruuskanen S. The effect of experimental lead pollution on DNA methylation in a wild bird population. Epigenetics 2021; 17:625-641. [PMID: 34369261 DOI: 10.1080/15592294.2021.1943863] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
Anthropogenic pollution is known to negatively influence an organism's physiology, behaviour, and fitness. Epigenetic regulation, such as DNA methylation, has been hypothesized as a potential mechanism to mediate such effects, yet studies in wild species are lacking. We first investigated the effects of early-life exposure to the heavy metal lead (Pb) on DNA methylation levels in a wild population of great tits (Parus major), by experimentally exposing nestlings to Pb at environmentally relevant levels. Secondly, we compared nestling DNA methylation from a population exposed to long-term heavy metal pollution (close to a copper smelter), where birds suffer from pollution-related decrease in food quality, and a control population. For both comparisons, the analysis of about one million CpGs covering most of the annotated genes revealed that pollution-related changes in DNA methylation were not genome wide, but enriched for genes underlying developmental processes. However, the results were not consistent when using binomial or beta binomial regression highlighting the difficulty of modelling variance in CpGs. Our study indicates that post-natal anthropogenic heavy metal exposure can affect methylation levels of development related genes in a wild bird population.
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Affiliation(s)
- Hannu Mäkinen
- Department of Biological and Environmental Sciences, University of Jyväskylä, Turku, Finland
| | - Kees van Oers
- Department of Animal Ecology, Netherlands Institute of Ecology (NIOO-KNAW), Wageningen, The Netherlands
| | - Tapio Eeva
- Department of Biological and Environmental Sciences, University of Jyväskylä, Turku, Finland
| | - Suvi Ruuskanen
- Department of Biological and Environmental Sciences, University of Jyväskylä, Turku, Finland
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Ma H, Yu J, Xie J, Liu D, Zhang Z, Wang Z, Wang C. Genome-wide identification and functional analysis of long non-coding RNAs and mRNAs in male mice testes at the onset of puberty after low dose lead exposure. Toxicol Appl Pharmacol 2021; 422:115556. [PMID: 33932463 DOI: 10.1016/j.taap.2021.115556] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 04/23/2021] [Accepted: 04/26/2021] [Indexed: 01/25/2023]
Abstract
Many researchers have studied the relationship between lead (Pb) and testis injury, but the underlying mechanisms are still unknown. The participation of long non-coding RNAs (lncRNAs) in biological processes has been proposed. To comprehensively gain insight into the molecular toxicity of Pb, expression patterns are analysed through RNA sequencing (RNA-seq) in male mice treated with 200 mg/L of Pb through the drinking water for 90 days at the onset of puberty. A total of 614 differentially expressed (DE) lncRNAs were included (p ≤ 0.05 and fold change ≥2), of which 288 were up-regulated, and 326 were down-regulated. A total of 2295 DE mRNAs (p ≤ 0.05 and fold change ≥2), including 1202 up-regulated and 1093 down-regulated ones, were found in the testes of Pb-exposed group. Functional analysis results showed that several lncRNAs might be implicated in the bio-pathway of mitogen-activated protein kinase (MAPK) signaling pathway. Finally, seven pairs of lncRNA-mRNA co-expression were established in mice testes and confirmed by RT-qPCR. Moreover, the DE genes were also altered in Sertoli cells. Therefore, our research might be helpful for future exploring the effects of Pb exposure on lncRNA in testis, as well as its function.
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Affiliation(s)
- Haitao Ma
- Department of Preventive Medicine, School of Health Sciences, Wuhan University, Wuhan, 430071, Hubei Province, China
| | - Jun Yu
- Department of Preventive Medicine, School of Basic Medical Sciences, Hubei University of Science and Technology, Xianning, 437100, Hubei Province, China
| | - Jie Xie
- Department of Preventive Medicine, School of Health Sciences, Wuhan University, Wuhan, 430071, Hubei Province, China
| | - Duanya Liu
- Department of Preventive Medicine, School of Health Sciences, Wuhan University, Wuhan, 430071, Hubei Province, China
| | - Zhaoyu Zhang
- Department of Preventive Medicine, School of Health Sciences, Wuhan University, Wuhan, 430071, Hubei Province, China
| | - Ziqiong Wang
- Department of Preventive Medicine, School of Health Sciences, Wuhan University, Wuhan, 430071, Hubei Province, China
| | - Chunhong Wang
- Department of Preventive Medicine, School of Health Sciences, Wuhan University, Wuhan, 430071, Hubei Province, China.
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Yan R, Chen XL, Xu YM, Lau ATY. Epimutational effects of electronic cigarettes. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:17044-17067. [PMID: 33655478 DOI: 10.1007/s11356-021-12985-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Accepted: 02/11/2021] [Indexed: 02/06/2023]
Abstract
Electronic cigarettes (e-cigarettes), since they do not require tobacco combustion, have traditionally been considered less harmful than conventional cigarettes (c-cigarettes). In recent years, however, researchers have found many toxic compounds in the aerosols of e-cigarettes, and numerous studies have shown that e-cigarettes can adversely affect the human epigenome. In this review, we provide an update on recent findings regarding epigenetic outcomes of e-cigarette aerosols. Moreover, we discussed the effects of several typical e-cigarette ingredients (nicotine, tobacco-specific nitrosamines, volatile organic compounds, carbonyl compounds, and toxic metals) on DNA methylation, histone modifications, and noncoding RNA expression. These epigenetic effects could explain some of the diseases caused by e-cigarettes. It also reminds the public that like c-cigarettes, inhaling e-cigarette aerosols could also be accompanied with potential epigenotoxicity on the human body.
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Affiliation(s)
- Rui Yan
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, 515041, People's Republic of China
- Clinical Research Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, 515041, People's Republic of China
| | - Xu-Li Chen
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, 515041, People's Republic of China
- Clinical Research Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, 515041, People's Republic of China
| | - Yan-Ming Xu
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, 515041, People's Republic of China.
- Clinical Research Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, 515041, People's Republic of China.
| | - Andy T Y Lau
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, 515041, People's Republic of China.
- Clinical Research Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, 515041, People's Republic of China.
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36
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Childebayeva A, Goodrich JM, Leon-Velarde F, Rivera-Chira M, Kiyamu M, Brutsaert TD, Dolinoy DC, Bigham AW. Genome-Wide Epigenetic Signatures of Adaptive Developmental Plasticity in the Andes. Genome Biol Evol 2020; 13:5981114. [PMID: 33185669 PMCID: PMC7859850 DOI: 10.1093/gbe/evaa239] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/09/2020] [Indexed: 01/03/2023] Open
Abstract
High-altitude adaptation is a classic example of natural selection operating on the human genome. Physiological and genetic adaptations have been documented in populations with a history of living at high altitude. However, the role of epigenetic gene regulation, including DNA methylation, in high-altitude adaptation is not well understood. We performed an epigenome-wide DNA methylation association study based on whole blood from 113 Peruvian Quechua with differential lifetime exposures to high altitude (>2,500) and recruited based on a migrant study design. We identified two significant differentially methylated positions (DMPs) and 62 differentially methylated regions (DMRs) associated with high-altitude developmental and lifelong exposure statuses. DMPs and DMRs were found in genes associated with hypoxia-inducible factor pathway, red blood cell production, blood pressure, and others. DMPs and DMRs associated with fractional exhaled nitric oxide also were identified. We found a significant association between EPAS1 methylation and EPAS1 SNP genotypes, suggesting that local genetic variation influences patterns of methylation. Our findings demonstrate that DNA methylation is associated with early developmental and lifelong high-altitude exposures among Peruvian Quechua as well as altitude-adaptive phenotypes. Together these findings suggest that epigenetic mechanisms might be involved in adaptive developmental plasticity to high altitude. Moreover, we show that local genetic variation is associated with DNA methylation levels, suggesting that methylation associated SNPs could be a potential avenue for research on genetic adaptation to hypoxia in Andeans.
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Affiliation(s)
- Ainash Childebayeva
- Department of Anthropology, University of Michigan.,Department of Environmental Health Sciences, School of Public Health, University of Michigan.,Department of Archaeogenetics, Max Planck Institute for the Study of Human History, Jena, Germany
| | - Jaclyn M Goodrich
- Department of Environmental Health Sciences, School of Public Health, University of Michigan
| | - Fabiola Leon-Velarde
- Departamento de Ciencias Biológicas y Fisiológicas, Universidad Peruana Cayetano Heredia, Lima, Peru
| | - Maria Rivera-Chira
- Departamento de Ciencias Biológicas y Fisiológicas, Universidad Peruana Cayetano Heredia, Lima, Peru
| | - Melisa Kiyamu
- Departamento de Ciencias Biológicas y Fisiológicas, Universidad Peruana Cayetano Heredia, Lima, Peru
| | | | - Dana C Dolinoy
- Department of Environmental Health Sciences, School of Public Health, University of Michigan.,Department of Nutritional Sciences, School of Public Health, University of Michigan
| | - Abigail W Bigham
- Department of Anthropology, University of California, Los Angeles
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Lin CY, Lee HL, Hwang YT, Huang PC, Wang C, Sung FC, Wu C, Su TC. Urinary heavy metals, DNA methylation, and subclinical atherosclerosis. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2020; 204:111039. [PMID: 32738627 DOI: 10.1016/j.ecoenv.2020.111039] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 07/05/2020] [Accepted: 07/13/2020] [Indexed: 06/11/2023]
Abstract
PURPOSE Lead (Pb) or cadmium (Cd) exposure has been linked to atherosclerosis. Co-exposure of these two heavy metals often occurs in humans. Recent evidence has indicated a crucial role of DNA methylation in atherosclerosis, while Pb or Cd exposure has also been shown to alter DNA methylation. However, it is still unknown whether DNA methylation plays a role in the pathological mechanism of these two heavy metals in atherosclerosis. APPROACH AND RESULTS We enrolled 738 participants (12-30 years) to investigate the association among concentrations of urine Pb or Cd, the 5mdC/dG value (a global DNA methylation marker) and the carotid intima-media thickness (CIMT). When each heavy metal was modeled separately, the results showed urine Pb and Cd concentrations were positively associated with the 5mdC/dG value and CIMT, respectively. When the two heavy metals were analyzed in the same model, urinary Pb concentrations were positively associated with the 5mdC/dG value and CIMT, while urinary Cd concentrations were only positively associated with the CIMT. When Pb and Cd are simultaneously considered in the same logistic regression model, the odds ratios (OR) of thicker CIMT (greater than 75th percentile) with one unit increase in ln-Pb level was 1.67 (95% C.I. = 1.17-2.46, P = 0.005) when levels of 5mdC/dG were above 50th percentile, which is higher than 5mdC/dG bellow the 50th percentile (OR = 1.50 (95% C.I. = 0.96-2.35), P = 0.076). In structural equation model (SEM), Pb or Cd levels are directly associated with CIMT. Moreover, Pb or Cd had an indirect association with CIMT through the 5mdC/dG. When we considered Pb and Cd together, Pb levels had a direct association with CIMT and an indirect association with CIMT through the 5mdC/dG value, while Cd only had a direct association with CIMT. CONCLUSIONS Our findings imply that Pb and Cd exposure might be associated with subclinical atherosclerosis, and global DNA methylation might mediate Pb-associated subclinical atherosclerosis in this young population. Future effort is necessary to elucidate the causal relationship.
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Affiliation(s)
- Chien-Yu Lin
- Department of Internal Medicine, En Chu Kong Hospital, New Taipei City, 237, Taiwan; School of Medicine, Fu Jen Catholic University, New Taipei City, 242, Taiwan; Department of Environmental Engineering and Health, Yuanpei University of Medical Technology, Hsinchu, 300, Taiwan.
| | - Hui-Ling Lee
- Department of Chemistry, Fu Jen Catholic University, New Taipei City, 242, Taiwan
| | - Yi-Ting Hwang
- Department of Statistics, National Taipei University, New Taipei City, 237, Taiwan
| | - Po-Chin Huang
- National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, 350, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 404, Taiwan
| | - Chikang Wang
- Department of Environmental Engineering and Health, Yuanpei University of Medical Technology, Hsinchu, 300, Taiwan
| | - Fung-Chang Sung
- Department of Health Services Administration, College of Public Health, China Medical University, Taichung, 404, Taiwan
| | - Charlene Wu
- Global Health Program, National Taiwan University, College of Public Health, 10055, Taiwan
| | - Ta-Chen Su
- Department of Environmental and Occupational Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan; Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan; Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University, Taipei, 100, Taiwan.
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Krauskopf J, Bergdahl IA, Johansson A, Palli D, Lundh T, Kyrtopoulos SA, de Kok TM, Kleinjans JC. Blood Transcriptome Response to Environmental Metal Exposure Reveals Potential Biological Processes Related to Alzheimer's Disease. Front Public Health 2020; 8:557587. [PMID: 33194959 PMCID: PMC7609776 DOI: 10.3389/fpubh.2020.557587] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 09/16/2020] [Indexed: 01/09/2023] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease which is manifested by a progressive and irreversible decline of cognition, memory loss, a shortened attention span, and changes in personality. Aging and genetic pre-dispositions, particularly the presence of a specific form of apolipoprotein E (APOE), are main risk factors of sporadic AD; however, a large body of evidence has shown that multiple environmental factors, including exposure to toxic metals, increase the risk for late onset AD. Lead (Pb) and cadmium (Cd) are ubiquitous toxic metals with a wide range of applications resulting in global distribution in the environment and exposure of all living organisms on earth. In addition to being classified as carcinogenic (Cd) and possibly carcinogenic (Pb) to humans by the International Agency for Research on Cancer, both compounds disrupt metal homeostasis and can cause toxic responses at the cellular and organismal levels. Pb toxicity targets the central nervous system and evidence for that has emerged also for Cd. Recent epidemiological studies show that both metals possibly are etiological factors of multiple neurodegenerative diseases, including Alzheimer's disease (AD). To further explore the association between metal exposure and AD risk we applied whole transcriptome gene expression analysis in peripheral blood leukocytes (PBLs) from 632 subjects of the general population, taken from the EnviroGenomarkers project. We used linear mixed effect models to associate metal exposure to gene expression after adjustment for gender, age, BMI, smoking, and alcohol consumption. For Pb exposure only few associations were identified, including a downregulation of the human eukaryotic translation initiation factor 5 (eIF5). In contrast, Cd exposure, particularly in males, revealed a much stronger transcriptomic response, featuring multiple pathways related to pathomolecular mechanisms of AD, such as endocytosis, neutrophil degranulation, and Interleukin-7 signaling. A gender stratified analysis revealed that the Cd responses were male-specific and included a downregulation of the APOE gene in men. This exploratory study revealed novel hypothetical findings which might contribute to the understanding of the neurotoxic effects of chronic Pb and Cd exposure and possibly improve our knowledge on the molecular mechanisms linking metal exposure to AD risk.
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Affiliation(s)
- Julian Krauskopf
- Department of Toxicogenomics, Maastricht University, Maastricht, Netherlands
| | - Ingvar A. Bergdahl
- Section of Sustainable Health, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
| | | | - Domenico Palli
- Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy
| | - Thomas Lundh
- Division of Occupational and Environmental Medicine, Lund University Hospital, Lund, Sweden
| | | | - Theo M. de Kok
- Department of Toxicogenomics, Maastricht University, Maastricht, Netherlands
| | - Jos C. Kleinjans
- Department of Toxicogenomics, Maastricht University, Maastricht, Netherlands
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Akemann C, Meyer DN, Gurdziel K, Baker TR. TCDD-induced multi- and transgenerational changes in the methylome of male zebrafish gonads. ENVIRONMENTAL EPIGENETICS 2020; 6:dvaa010. [PMID: 33214906 PMCID: PMC7660120 DOI: 10.1093/eep/dvaa010] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 06/01/2020] [Accepted: 06/09/2020] [Indexed: 05/23/2023]
Abstract
The legacy endocrine disrupting chemical and aryl hydrocarbon receptor agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is produced as a byproduct of industrial processes and causes adverse health effects ranging from skin irritation to cancer. TCDD endpoints are also observed in subsequent, unexposed generations; however, the mechanisms of these multi- and transgenerational effects are unknown. We hypothesized an epigenetic mechanism, specifically DNA methylation for the transgenerational, male-mediated reproductive effects of developmental TCDD exposure. Using whole genome bisulfite sequencing, we evaluated DNA methylation changes in three generations of zebrafish, the first of which was exposed to TCDD during sexual development at 50 ppt for 1 h at both 3- and 7-week post-fertilization. We discovered that TCDD induces multi- and transgenerational methylomic changes in testicular tissue from zebrafish with decreased reproductive capacity, but most significantly in the indirectly exposed F1 generation. In comparing differentially methylated genes to concurrent transcriptomic changes, we identified several genes and pathways through which transgenerational effects of low level TCDD exposure are likely inherited. These include significant differential methylation of genes involved in reproduction, endocrine function, xenobiotic metabolism, and epigenetic processing. Notably, a number of histone modification genes were both differentially methylated and expressed in all generations, and many differentially methylated genes overlapped between multiple generations. Collectively, our results suggest that DNA methylation is a promising mechanism to explain male-mediated transgenerational reproductive effects of TCDD exposure in zebrafish, and these effects are likely inherited through integration of multiple epigenetic pathways.
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Affiliation(s)
- Camille Akemann
- Department of Pharmacology, Wayne State University, Detroit, 540 E. Canfield, Detroit, MI, 48201, USA
- Institute of Environmental Health Sciences, Wayne State University, Detroit, 5135 Woodward Ave. Detroit, MI, 48202, USA
| | - Danielle N Meyer
- Department of Pharmacology, Wayne State University, Detroit, 540 E. Canfield, Detroit, MI, 48201, USA
- Institute of Environmental Health Sciences, Wayne State University, Detroit, 5135 Woodward Ave. Detroit, MI, 48202, USA
| | - Katherine Gurdziel
- School of Medicine, Applied Genome Technology Center, Wayne State University, Detroit, 261 E Hancock St, Detroit, MI, 4820, USA
| | - Tracie R Baker
- Department of Pharmacology, Wayne State University, Detroit, 540 E. Canfield, Detroit, MI, 48201, USA
- Institute of Environmental Health Sciences, Wayne State University, Detroit, 5135 Woodward Ave. Detroit, MI, 48202, USA
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40
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Wang T, Zhang J, Xu Y. Epigenetic Basis of Lead-Induced Neurological Disorders. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17134878. [PMID: 32645824 PMCID: PMC7370007 DOI: 10.3390/ijerph17134878] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 07/01/2020] [Accepted: 07/01/2020] [Indexed: 02/06/2023]
Abstract
Environmental lead (Pb) exposure is closely associated with pathogenesis of a range of neurological disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), attention deficit/hyperactivity disorder (ADHD), etc. Epigenetic machinery modulates neural development and activities, while faulty epigenetic regulation contributes to the diverse forms of CNS (central nervous system) abnormalities and diseases. As a potent epigenetic modifier, lead is thought to cause neurological disorders through modulating epigenetic mechanisms. Specifically, increasing evidence linked aberrant DNA methylations, histone modifications as well as ncRNAs (non-coding RNAs) with AD cases, among which circRNA (circular RNA) stands out as a new and promising field for association studies. In 23-year-old primates with developmental lead treatment, Zawia group discovered a variety of epigenetic changes relating to AD pathogenesis. This is a direct evidence implicating epigenetic basis in lead-induced AD animals with an entire lifespan. Additionally, some epigenetic molecules associated with AD etiology were also known to respond to chronic lead exposure in comparable disease models, indicating potentially interlaced mechanisms with respect to the studied neurotoxic and pathological events. Of note, epigenetic molecules acted via globally or selectively influencing the expression of disease-related genes. Compared to AD, the association of lead exposure with other neurological disorders were primarily supported by epidemiological survey, with fewer reports connecting epigenetic regulators with lead-induced pathogenesis. Some pharmaceuticals, such as HDAC (histone deacetylase) inhibitors and DNA methylation inhibitors, were developed to deal with CNS disease by targeting epigenetic components. Still, understandings are insufficient regarding the cause–consequence relations of epigenetic factors and neurological illness. Therefore, clear evidence should be provided in future investigations to address detailed roles of novel epigenetic factors in lead-induced neurological disorders, and efforts of developing specific epigenetic therapeutics should be appraised.
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Affiliation(s)
| | | | - Yi Xu
- Correspondence: ; Tel.: +86-183-2613-5046
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Quintanilla-Mena M, Gold-Bouchot G, Zapata-Pérez O, Rubio-Piña J, Quiroz-Moreno A, Vidal-Martínez VM, Aguirre-Macedo ML, Puch-Hau C. Biological responses of shoal flounder (Syacium gunteri) to toxic environmental pollutants from the southern Gulf of Mexico. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2020; 258:113669. [PMID: 31806456 DOI: 10.1016/j.envpol.2019.113669] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 10/23/2019] [Accepted: 11/21/2019] [Indexed: 06/10/2023]
Abstract
The Gulf of Mexico (GoM) is exposed to a diversity of contaminants, such as hydrocarbons and heavy metal(oid)s, either from natural sources or as a result of uncontrolled coastal urbanisation and industrialisation. To determine the effect of these contaminants on the marine biota along the Mexican GoM, the biological responses of the shoal flounder Syacium gunteri, naturally exposed, were studied. The study area included all the Mexican GoM, which was divided into three areas: West-southwest (WSW), South-southwest (SSW) and South-southeast (SSE). The biological responses included the global DNA methylation levels, the expression of biomarker genes related to contaminants (cytochrome P450 1A, glutathione S-transferase, glutathione reductase, glutathione peroxidase, catalase, and vitellogenin), histopathological lesions and PAH metabolites in bile (hydroxynaphthalene, hydroxyphenanthrene, hydroxypyrene and Benzo[a]pyrene). The correlation between the biological responses and the concentration of contaminants (hydrocarbons and metal(oid)s), present in both sediments and organisms, were studied. The shoal flounders in WSW and SSW areas presented higher DNA hypomethylation, less antioxidative response and biotransformation gene expression and a higher concentration of PAH metabolites in bile than SSE area; those responses were associated with total hydrocarbons and metals such as chromium (Cr). SSE biological responses were mainly associated with the presence of metals, such as cadmium (Cd) and copper (Cu), in the tissue of shoal flounders. The results obtained on the physiological response of the shoal flounder can be used as part of a permanent active environmental surveillance program to watch the ecosystem health of the Mexican GoM.
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Affiliation(s)
- Mercedes Quintanilla-Mena
- Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Departamento de Recursos del Mar, Unidad Mérida. Km. 6, Antigua Carretera a Progreso, Apdo. Postal 73-Cordemex, 97310 Mérida, Yucatán, Mexico
| | - Gerardo Gold-Bouchot
- Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Departamento de Recursos del Mar, Unidad Mérida. Km. 6, Antigua Carretera a Progreso, Apdo. Postal 73-Cordemex, 97310 Mérida, Yucatán, Mexico; Department of Oceanography and Geochemical and Environmental Research Group (GERG), Texas A&M University, College Station, TX, United States
| | - Omar Zapata-Pérez
- Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Departamento de Recursos del Mar, Unidad Mérida. Km. 6, Antigua Carretera a Progreso, Apdo. Postal 73-Cordemex, 97310 Mérida, Yucatán, Mexico
| | - Jorge Rubio-Piña
- Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Departamento de Recursos del Mar, Unidad Mérida. Km. 6, Antigua Carretera a Progreso, Apdo. Postal 73-Cordemex, 97310 Mérida, Yucatán, Mexico
| | - Adriana Quiroz-Moreno
- Centro de Investigación Científica de Yucatán, Calle 43 No. 130, Colonia Chuburna de Hidalgo, 97200 Mérida, Yucatán, Mexico
| | - Víctor Manuel Vidal-Martínez
- Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Departamento de Recursos del Mar, Unidad Mérida. Km. 6, Antigua Carretera a Progreso, Apdo. Postal 73-Cordemex, 97310 Mérida, Yucatán, Mexico
| | - Ma Leopoldina Aguirre-Macedo
- Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Departamento de Recursos del Mar, Unidad Mérida. Km. 6, Antigua Carretera a Progreso, Apdo. Postal 73-Cordemex, 97310 Mérida, Yucatán, Mexico
| | - Carlos Puch-Hau
- Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Departamento de Recursos del Mar, Unidad Mérida. Km. 6, Antigua Carretera a Progreso, Apdo. Postal 73-Cordemex, 97310 Mérida, Yucatán, Mexico.
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Mao G, Liu H, Ding Y, Zhang W, Chen H, Zhao T, Feng W, Wu X, Yang L. Evaluation of combined developmental neurological toxicity of di (n-butyl) phthalates and lead using immature mice. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2020; 27:9318-9326. [PMID: 31916169 DOI: 10.1007/s11356-019-06692-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Accepted: 10/01/2019] [Indexed: 06/10/2023]
Abstract
In this study, the immature mice were taken to assess the potential neurological toxicity of lead (Pb) and di (n-butyl) phthalates (DBP) combination exposure. Mouse administration with DBP combination with Pb exhibited longer escape latency and lower average number of crossing of the platform. Pb content in the tissues was increased, especially in the brain, after Pb exposure as compared to those without Pb exposure. The alterations of oxidative damages in tissues (MDA and SOD) and biochemical indicators in the brain (AChE, TNOS, and iNOS) were observed, as well as the synergistic effect of joint exposure. Expressions of apoptosis-related protein (bax/bcl-2 ratio and caspase-3) were significantly increased in the hippocampus, while the bcl-2 was remarkably decreased and no significant differences were observed on the bax. The results suggested that the possible mechanisms for the learning and memory ability impairments were as follows: Firstly, the combination exposure induced the occurrence of lipid peroxidation in the brain, leading to damage to the brain cells. Secondly, it destroyed the normal metabolic balance of ACh, causing nerve damage in mice. Thirdly, it induced apoptosis in mouse hippocampal cells. The overall findings revealed that Pb and DBP co-exposure greatly influenced the developmental nervous system and accompanied with synergistic toxic effect.
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Affiliation(s)
- Guanghua Mao
- School of the Environment and Safety Engineering, Jiangsu University, Zhenjiang, China
| | - Hongyang Liu
- School of the Environment and Safety Engineering, Jiangsu University, Zhenjiang, China
| | - Yangyang Ding
- School of the Environment and Safety Engineering, Jiangsu University, Zhenjiang, China
| | - Weijie Zhang
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, China
| | - Hui Chen
- School of the Environment and Safety Engineering, Jiangsu University, Zhenjiang, China
| | - Ting Zhao
- School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang, China
| | - Weiwei Feng
- School of the Environment and Safety Engineering, Jiangsu University, Zhenjiang, China
| | - Xiangyang Wu
- School of the Environment and Safety Engineering, Jiangsu University, Zhenjiang, China.
| | - Liuqing Yang
- School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang, China.
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43
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Wu QL, Cheng YQ, Liu AJ, Zhang WD. Formononetin recovered injured nerve functions by enhancing synaptic plasticity in ischemic stroke rats. Biochem Biophys Res Commun 2020; 525:S0006-291X(20)30281-3. [PMID: 32081422 DOI: 10.1016/j.bbrc.2020.02.015] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Accepted: 02/05/2020] [Indexed: 11/16/2022]
Abstract
BACKGROUND AND OBJECTIVES Formononetin has protective effect against ischemic stroke. It's unclear whether it can restore the nerve functions after stroke. METHODS SD rats were subjected with middle cerebral artery occlusion (MCAO), and divided into sham, model and formononetin (30 mg/kg) groups. Neurobehavioral tests (modified Neurological Severity Score [mNSS] and rotarod) were performed before and at 1, 3, 7 and 14 days after MCAO. Then, the rats were sacrificed and the brain sections were processed for neuronal differentiation and synaptic plasticity. RESULTS Compared with the sham group, the scores of mNSS were significantly increased, and the residence time on the rotating drum was significantly decreased in the MCAO rats. Compared with the model group, the scores of mNSS were significantly decreased, and the residence time on the rotating drum was increased in the formononetin (30 mg/kg) group. Formononetin significantly increased the number of neuronal dendritic spines and the expression of β III-tubulin, GAP-43, NGF, BDNF, p-Trk A, p-Trk B, p-AKT and p-ERK 1/2. CONCLUSIONS Formononetin recovered injured nerve functions after ischemic stroke. PI3K/AKT/ERK pathway might involve in the beneficial effect of formononetin on the neuronal differentiation and synaptic plasticity.
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Affiliation(s)
- Qiu-Ling Wu
- School of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China; Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| | - Yan-Qiong Cheng
- Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China; Department of Pharmacy Research, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China
| | - Ai-Jun Liu
- Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China; Department of Pharmacy Research, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China.
| | - Wei-Dong Zhang
- School of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China; Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.
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44
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Fan B, Rusinek CA, Thompson CH, Setien M, Guo Y, Rechenberg R, Gong Y, Weber AJ, Becker MF, Purcell E, Li W. Flexible, diamond-based microelectrodes fabricated using the diamond growth side for neural sensing. MICROSYSTEMS & NANOENGINEERING 2020; 6:42. [PMID: 32685185 PMCID: PMC7355183 DOI: 10.1038/s41378-020-0155-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 03/06/2020] [Accepted: 03/25/2020] [Indexed: 05/02/2023]
Abstract
Diamond possesses many favorable properties for biochemical sensors, including biocompatibility, chemical inertness, resistance to biofouling, an extremely wide potential window, and low double-layer capacitance. The hardness of diamond, however, has hindered its applications in neural implants due to the mechanical property mismatch between diamond and soft nervous tissues. Here, we present a flexible, diamond-based microelectrode probe consisting of multichannel boron-doped polycrystalline diamond (BDD) microelectrodes on a soft Parylene C substrate. We developed and optimized a wafer-scale fabrication approach that allows the use of the growth side of the BDD thin film as the sensing surface. Compared to the nucleation surface, the BDD growth side exhibited a rougher morphology, a higher sp 3 content, a wider water potential window, and a lower background current. The dopamine (DA) sensing capability of the BDD growth surface electrodes was validated in a 1.0 mM DA solution, which shows better sensitivity and stability than the BDD nucleation surface electrodes. The results of these comparative studies suggest that using the BDD growth surface for making implantable microelectrodes has significant advantages in terms of the sensitivity, selectivity, and stability of a neural implant. Furthermore, we validated the functionality of the BDD growth side electrodes for neural recordings both in vitro and in vivo. The biocompatibility of the microcrystalline diamond film was also assessed in vitro using rat cortical neuron cultures.
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Affiliation(s)
- Bin Fan
- Department of Electrical and Computer Engineering, Michigan State University, East Lansing, MI USA
| | - Cory A. Rusinek
- Fraunhofer USA Center for Coatings and Diamond Technologies, East Lansing, MI USA
| | - Cort H. Thompson
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI USA
| | - Monica Setien
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI USA
| | - Yue Guo
- Department of Electrical and Computer Engineering, Michigan State University, East Lansing, MI USA
| | - Robert Rechenberg
- Fraunhofer USA Center for Coatings and Diamond Technologies, East Lansing, MI USA
| | - Yan Gong
- Department of Electrical and Computer Engineering, Michigan State University, East Lansing, MI USA
| | - Arthur J. Weber
- Department of Physiology, Michigan State University, East Lansing, MI USA
| | - Michael F. Becker
- Fraunhofer USA Center for Coatings and Diamond Technologies, East Lansing, MI USA
| | - Erin Purcell
- Department of Electrical and Computer Engineering, Michigan State University, East Lansing, MI USA
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI USA
| | - Wen Li
- Department of Electrical and Computer Engineering, Michigan State University, East Lansing, MI USA
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45
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Monear NC, Xhabija B. The effect of lead during the Flint water crisis on mouse embryonic stem cells self-renewal and differentiation markers. Toxicol In Vitro 2019; 63:104719. [PMID: 31715224 DOI: 10.1016/j.tiv.2019.104719] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 10/05/2019] [Accepted: 11/07/2019] [Indexed: 01/28/2023]
Abstract
During the Flint water crisis, the residents of Flint, Michigan experienced a significant increase in blood lead levels. For some this resulted in an increase as high as 40 μg/dL from 5 μg/dL, which is considered to be safe by the Center for Disease Control and Prevention. Since the extent of the effect of the lead exposure in early embryonic development is not greatly investigated, the aim of this study is to explore the effect of lead exposure at concentrations present in Flint, MI during the Flint water crisis in the embryonic development. The expression of pluripotency and self-renewal markers (Oct4, Sox2, Nanog and Zfp-42) coupled with morphological and alkaline phosphatase assays revealed that mouse embryonic stem cells (mESC) pluripotency and self-renewal capabilities are perturbed following exposure in a lead acetate concentration dependent manner. Moreover, mouse embryoid bodies (mEB), which provide ideal models for testing toxicity in vitro, revealed that lead acetate exposure induces fewer but larger mEBs, whereas gene expression analysis of lineage specific transcription factors showed an increased mRNA level of endodermal (Gata 4, Gata 6, Sox 7) and mesodermal markers (Eomes, Hand 1, Slug 1) while the mRNA level of ectodermal markers (Otx 2, Noggin, Sox 1) decreased. Taken all together, these results indicate that lead acetate disturbs the pluripotency of mESC and differentiation potential of mEBs by inhibiting differentiation towards ectodermal lineages and inducing it towards endodermal and mesodermal lineages.
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Affiliation(s)
- Nicodemus C Monear
- Department of Chemistry and Biochemistry, University of Michigan- Flint, Flint, MI 48502, United States of America
| | - Besa Xhabija
- Department of Chemistry and Biochemistry, University of Michigan- Flint, Flint, MI 48502, United States of America.
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46
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Wang J, Li CL, Tu BJ, Yang K, Mo TT, Zhang RY, Cheng SQ, Chen CZ, Jiang XJ, Han TL, Peng B, Baker PN, Xia YY. Integrated Epigenetics, Transcriptomics, and Metabolomics to Analyze the Mechanisms of Benzo[a]pyrene Neurotoxicity in the Hippocampus. Toxicol Sci 2019; 166:65-81. [PMID: 30085273 DOI: 10.1093/toxsci/kfy192] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Benzo[a]pyrene (B[a]P) is a common environmental pollutant that is neurotoxic to mammals, which can cause changes to hippocampal function and result in cognitive disorders. The mechanisms of B[a]P-induced impairments are complex .To date there have been no studies on the association of epigenetic, transcriptomic, and metabolomic changes with neurotoxicity after B[a]P exposure. In the present study, we investigated the global effect of B[a]P on DNA methylation patterns, noncoding RNAs (ncRNAs) expression, coding RNAs expression, and metabolites in the rat hippocampus. Male Sprague Dawley rats (SD rats) received daily gavage of B[a]P (2.0 mg/kg body weight [BW]) or corn oil for 7 weeks. Learning and memory ability was analyzed using the Morris water maze (MWM) test and change to cellular ultrastructure in the hippocampus was analyzed using electron microscope observation. Integrated analysis of epigenetics, transcriptomics, and metabolomics was conducted to investigate the effect of B[a]P exposure on the signaling and metabolic pathways. Our results suggest that B[a]P could lead to learning and memory deficits, likely as a result of epigenetic and transcriptomic changes that further affected the expression of CACNA1C, Tpo, etc. The changes in expression ultimately affecting LTP, tyrosine metabolism, and other important metabolic pathways.
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Affiliation(s)
- Jing Wang
- Department of Occupational and Environmental Hygiene, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, China
| | - Chun-Lin Li
- Department of Occupational and Environmental Hygiene, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, China
| | - Bai-Jie Tu
- Department of Occupational and Environmental Hygiene, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, China
| | - Kai Yang
- Chengdu Center for Disease Control & Prevention, Chengdu, China
| | - Ting-Ting Mo
- Department of Occupational and Environmental Hygiene, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, China
| | - Rui-Yuan Zhang
- Department of Occupational and Environmental Hygiene, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, China
| | - Shu-Qun Cheng
- Department of Occupational and Environmental Hygiene, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, China
| | - Cheng-Zhi Chen
- Department of Occupational and Environmental Hygiene, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, China
| | - Xue-Jun Jiang
- Department of Occupational and Environmental Hygiene, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, China
| | - Ting-Li Han
- China-Canada-New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China.,The Liggins Institute, University of Auckland, Auckland, New Zealand
| | - Bin Peng
- Department of Statistics, School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Philip N Baker
- College of Medicine, Biological Sciences and Psychology, University of Leicester, Leicester LE1 9HN, UK
| | - Yin-Yin Xia
- Department of Occupational and Environmental Hygiene, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, China.,China-Canada-New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China
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Reis CF, de Souza ID, Morais DAA, Oliveira RAC, Imparato DO, de Almeida RMC, Dalmolin RJS. Systems Biology-Based Analysis Indicates Global Transcriptional Impairment in Lead-Treated Human Neural Progenitor Cells. Front Genet 2019; 10:791. [PMID: 31552095 PMCID: PMC6748217 DOI: 10.3389/fgene.2019.00791] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 07/26/2019] [Indexed: 01/19/2023] Open
Abstract
Lead poisoning effects are wide and include nervous system impairment, peculiarly during development, leading to neural damage. Lead interaction with calcium and zinc-containing metalloproteins broadly affects cellular metabolism since these proteins are related to intracellular ion balance, activation of signaling transduction cascades, and gene expression regulation. In spite of lead being recognized as a neurotoxin, there are gaps in knowledge about the global effect of lead in modulating the transcription of entire cellular systems in neural cells. In order to investigate the effects of lead poisoning in a systemic perspective, we applied the transcriptogram methodology in an RNA-seq dataset of human embryonic-derived neural progenitor cells (ES-NP cells) treated with 30 µM lead acetate for 26 days. We observed early downregulation of several cellular systems involved with cell differentiation, such as cytoskeleton organization, RNA, and protein biosynthesis. The downregulated cellular systems presented big and tightly connected networks. For long treatment times (12 to 26 days), it was possible to observe a massive impairment in cell transcription profile. Taking the enriched terms together, we observed interference in all layers of gene expression regulation, from chromatin remodeling to vesicle transport. Considering that ES-NP cells are progenitor cells that can originate other neural cell types, our results suggest that lead-induced gene expression disturbance might impair cells’ ability to differentiate, therefore influencing ES-NP cells’ fate.
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Affiliation(s)
- Clovis F Reis
- Bioinformatics Multidisciplinary Environment - IMD, Federal University of Rio Grande do Norte, Natal, Brazil
| | - Iara D de Souza
- Bioinformatics Multidisciplinary Environment - IMD, Federal University of Rio Grande do Norte, Natal, Brazil
| | - Diego A A Morais
- Bioinformatics Multidisciplinary Environment - IMD, Federal University of Rio Grande do Norte, Natal, Brazil
| | - Raffael A C Oliveira
- Bioinformatics Multidisciplinary Environment - IMD, Federal University of Rio Grande do Norte, Natal, Brazil
| | - Danilo O Imparato
- Bioinformatics Multidisciplinary Environment - IMD, Federal University of Rio Grande do Norte, Natal, Brazil
| | - Rita M C de Almeida
- Institute of Physics and National Institute of Science and Technology: Complex Systems, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Rodrigo J S Dalmolin
- Bioinformatics Multidisciplinary Environment - IMD, Federal University of Rio Grande do Norte, Natal, Brazil.,Department of Biochemistry - CB, Federal University of Rio Grande do Norte, Natal, Brazil
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Worley JR, Parker GC. Effects of environmental stressors on stem cells. World J Stem Cells 2019; 11:565-577. [PMID: 31616535 PMCID: PMC6789190 DOI: 10.4252/wjsc.v11.i9.565] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 07/12/2019] [Accepted: 09/04/2019] [Indexed: 02/06/2023] Open
Abstract
Environmental toxicants are ubiquitous, and many are known to cause harmful health effects. However, much of what we know or think we know concerning the targets and long-term effects of exposure to environmental stressors is sadly lacking. Toxicant exposure may have health effects that are currently mischaracterized or at least mechanistically incompletely understood. While much of the recent excitement about stem cells (SCs) focuses on their potential as therapeutic agents, they also offer a valuable resource to give us insight into the mechanisms and risks of toxicant effects. Not only as a response to the increasing ethical pressure to reduce animal testing, SC studies allow us valuable insight into the true effects of human exposure to environmental stressors under controlled conditions. We present a review of the history of publications on the effects of environmental stressors on SCs, followed by a consolidation of the literature over the past five years on a subset of key environmental stressors of importance to human health and their effects on both embryonic and tissue SCs. The review will make constructive suggestions as to areas of toxicant research where further studies are needed, as well as making indications of the potential utility for advancing knowledge and directing research on environmental toxicology.
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Affiliation(s)
- Jessica R Worley
- Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI 48202, United States
| | - Graham C Parker
- Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI 48202, United States
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49
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Gurbanov R, Tunçer S, Mingu S, Severcan F, Gozen AG. Methylation, sugar puckering and Z-form status of DNA from a heavy metal-acclimated freshwater Gordonia sp. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2019; 198:111580. [DOI: 10.1016/j.jphotobiol.2019.111580] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 07/07/2019] [Accepted: 07/29/2019] [Indexed: 01/27/2023]
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50
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Zhou Y, Fu Y, Bai Z, Li P, Zhao B, Han Y, Xu T, Zhang N, Lin L, Cheng J, Zhang J, Zhang J. Neural Differentiation of Mouse Neural Stem Cells as a Tool to Assess Developmental Neurotoxicity of Drinking Water in Taihu Lake. Biol Trace Elem Res 2019; 190:172-186. [PMID: 30465171 DOI: 10.1007/s12011-018-1533-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 09/24/2018] [Indexed: 10/27/2022]
Abstract
In this study, we used neural stem cells (NSCs) as a toxicology tool to assess the potential developmental neurotoxicity of drinking water from Taihu Lake. We found that the condensed drinking water could inhibit the proliferation and differentiation of NSCs, especially the tap water. Inductively coupled plasma mass spectrometry and high-performance liquid chromatography analysis showed that nickel was detected in the tap water with a high concentration. Our study revealed that nickel could inhibit NSCs proliferation and differentiation, which is induced not only by the intracellular reactive oxygen species generation, but also by the protein levels upregulation of p-c-Raf, p-MEK1/2 and p-Erk1/2 through the axon guidance signal pathways. These findings will provide a new way of research insight for investigation of nickel-induced neurotoxicity. Meanwhile, our test method confirmed the feasibility and reliability of stem cell assays for developmental neurotoxicity testing.
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Affiliation(s)
- Yang Zhou
- Stem Cell Translational Research Center, Tongji Hospital, School of Life Science and Technology, Tongji University, Shanghai, 200065, People's Republic of China
- Department of Regenerative Medicine, Tongji University School of Medicine, 1239 Siping Road, Shanghai, 200092, People's Republic of China
| | - Yu Fu
- Stem Cell Translational Research Center, Tongji Hospital, School of Life Science and Technology, Tongji University, Shanghai, 200065, People's Republic of China
| | - Zhendong Bai
- Department of Regenerative Medicine, Tongji University School of Medicine, 1239 Siping Road, Shanghai, 200092, People's Republic of China
| | - Peixin Li
- Department of Regenerative Medicine, Tongji University School of Medicine, 1239 Siping Road, Shanghai, 200092, People's Republic of China
| | - Bo Zhao
- Stem Cell Translational Research Center, Tongji Hospital, School of Life Science and Technology, Tongji University, Shanghai, 200065, People's Republic of China
| | - Yuehua Han
- Stem Cell Translational Research Center, Tongji Hospital, School of Life Science and Technology, Tongji University, Shanghai, 200065, People's Republic of China
| | - Ting Xu
- College of Environmental Science and Engineering, Tongji University, Key Laboratory of Yangtze River Water Environment, Ministry of Education, Shanghai, 200092, People's Republic of China
| | - Ningyan Zhang
- Stem Cell Translational Research Center, Tongji Hospital, School of Life Science and Technology, Tongji University, Shanghai, 200065, People's Republic of China
| | - Lin Lin
- Department of Regenerative Medicine, Tongji University School of Medicine, 1239 Siping Road, Shanghai, 200092, People's Republic of China
| | - Jian Cheng
- Stem Cell Translational Research Center, Tongji Hospital, School of Life Science and Technology, Tongji University, Shanghai, 200065, People's Republic of China
| | - Jun Zhang
- Department of Regenerative Medicine, Tongji University School of Medicine, 1239 Siping Road, Shanghai, 200092, People's Republic of China.
| | - Jing Zhang
- Stem Cell Translational Research Center, Tongji Hospital, School of Life Science and Technology, Tongji University, Shanghai, 200065, People's Republic of China.
- Tongji Hospital, School of Life Science and Technology, Tongji University, 389 Xincun Road, 200065, Shanghai, People's Republic of China.
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