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1
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Chen L, An S, Liu Y, Jiang Q, Ge Y, Yu G. Lead exposure disrupts cytoskeletal arrangement and perturbs glucose metabolism in nerve cells through activation of the RhoA/ROCK signaling pathway. J Trace Elem Med Biol 2025; 89:127663. [PMID: 40315746 DOI: 10.1016/j.jtemb.2025.127663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 04/20/2025] [Accepted: 04/24/2025] [Indexed: 05/04/2025]
Abstract
Lead (Pb) is a heavy metal environmental pollutant with strong biological toxicity. Our previous study suggested that Pb may impair learning and memory by disrupting cytoskeletal structure and inhibiting the expression of synaptic plasticity-related proteins in mice. However, the exact mechanism of Pb-induced cytoskeletal damage remains unclear. In this study, Neuro-2a cells and Kunming mice were used to explore the neurotoxic mechanism of Pb. The actin dynamics were observed via laser confocal microscopy. The ATP levels and ATPase activity in Neuro-2a cells was measured. In addition, the mRNA and protein expression levels of RhoA/ROCK/Cofilin signaling pathway in brain tissues and Neuro-2a cells was measured, and the mRNA expression levels of glucose metabolism rate-limiting enzymes were detected. Our results showed that Pb induces nerve cell damage and cytoskeletal abnormalities. Western blot and qRT-PCR analyses revealed that Pb activated the RhoA/ROCK/Cofilin signaling pathway. Additionally, ATPase activity significantly decreased following Pb treatment, whereas ATP levels markedly increased in the 50 μM Pb group. In addition, Pb disrupts brain glucose metabolism through affect the transcription of rate-limiting enzymes of glucose metabolism. Overall, these findings suggest that Pb activates the RhoA/ROCK/Cofilin signaling pathway, leading to cytoskeletal damage. Moreover, Pb exposure alters glucose metabolism enzyme activity and ATP production, disrupting the balance between F-actin and G-actin and ultimately affecting neuronal structure and function. These results may provide a better understanding of lead-induced nerve damage.
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Affiliation(s)
- Lingli Chen
- Postdoctoral Research Station in Biological Sciences, Henan Normal University, Xinxiang, China; College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, China
| | - Siyuan An
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, China
| | - Yuye Liu
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, China
| | - Qian Jiang
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, China
| | - Yaming Ge
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, China.
| | - Guoying Yu
- Postdoctoral Research Station in Biological Sciences, Henan Normal University, Xinxiang, China; Pingyuan Laboratory, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, State Key Laboratory of Cell Differentiation and Regulation, College of Life Science, Henan Normal University, Xinxiang, China.
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2
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Neha V, Parithathvi A, Dsouza HS. Ameliorative role of bioactive compounds against lead-induced neurotoxicity. Neuroscience 2025; 568:46-56. [PMID: 39805419 DOI: 10.1016/j.neuroscience.2025.01.018] [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: 09/25/2024] [Revised: 12/04/2024] [Accepted: 01/09/2025] [Indexed: 01/16/2025]
Abstract
Lead (Pb) is an environmental toxin ubiquitously present in the human environment due to anthropogenic activities and industrialization. Lead can enter the human body through various sources and pathways, such as inhalation, ingestion and dermal contact, leading to detrimental health effects. The majority of lead that enters the body is removed by urine or feces; however, under chronic exposure conditions, lead is not efficient, as lead is absorbed and transferred to numerous organs, such as the brain, liver, kidney, muscles, and heart, and it is ultimately stored in mineralizing tissues such as bones and teeth. The central nervous system is the most affected among all the organs and systems affected, as lead is a known neurotoxin. Lead absorption is elevated in the fasting state than in the fed state. Chelation therapy, which is used to treat lead poisoning, has various adverse effects, making this treatment detrimental because it disrupts the levels of other essential elements and redistributes lead to various tissues. One of the main mechanisms by which lead induces toxicity is through the generation of reactive oxygen species. Hence, bioactive compounds that are the source of antioxidants if consumed along with ongoing lead exposure can ameliorate the toxic effects of lead.
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Affiliation(s)
- Venkatesan Neha
- Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Aluru Parithathvi
- Department of Radiation Biology and Toxicology, Manipal School of Life Sciences,Manipal Academy of Higher Education, Manipal, Karnataka, India.
| | - Herman Sunil Dsouza
- Department of Radiation Biology and Toxicology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
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3
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Li J, Hu M, Liu Y, Lu R, Feng W. Lead exposure leads to premature neural differentiation via inhibiting Wnt signaling. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 363:125232. [PMID: 39489322 DOI: 10.1016/j.envpol.2024.125232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 10/10/2024] [Accepted: 10/31/2024] [Indexed: 11/05/2024]
Abstract
Heavy metals, such as Lead (Pb), are ubiquitous environmental pollutants that is a considerable problem worldwide. Increasing evidences suggest that Pb exposure negatively impact central nervous system. However, the exact toxic mechanism of Pb on early human brain development remain unclear due to the limitations of animal models and 2D cell models. In this study, we used human cortical organoids to reveal that Pb had specific early neurodevelopmental toxicity during the neural differentiation stage. We observed that short-term Pb exposure (10 days) is sufficient to induce premature neuronal differentiation. Mechanistically, Pb exposure downregulates the Wnt signaling in cortical organoids, and the activation of Wnt signaling reverses the neurodevelopmental phenotype. In support, Pb exposure during pregnancy lead to premature neuronal differentiation and reduced neurogenesis in mice. In conclusion, our study reveals the neuropathogenesis of Pb exposure and uncovers the potential intervention role of Wnt activation.
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Affiliation(s)
- Jun Li
- Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Meixin Hu
- Department of Child Health Care, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, 201102, China
| | - Yingying Liu
- Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Rongrong Lu
- Department of Neurosurgery, Children's Hospital of Fudan University, National Children's Medical Center (Shanghai), Shanghai, 201102, China
| | - Weijun Feng
- Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China; Fujian Key Laboratory of Neonatal Diseases, Xiamen Key Laboratory of Neonatal Diseases, Xiamen Children's Hospital, Children's Hospital of Fudan University at Xiamen, Xiamen, 361006, China.
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4
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Tota M, Karska J, Kowalski S, Piątek N, Pszczołowska M, Mazur K, Piotrowski P. Environmental pollution and extreme weather conditions: insights into the effect on mental health. Front Psychiatry 2024; 15:1389051. [PMID: 38863619 PMCID: PMC11165707 DOI: 10.3389/fpsyt.2024.1389051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 05/13/2024] [Indexed: 06/13/2024] Open
Abstract
Environmental pollution exposures, including air, soil, water, light, and noise pollution, are critical issues that may implicate adverse mental health outcomes. Extreme weather conditions, such as hurricanes, floods, wildfires, and droughts, may also cause long-term severe concerns. However, the knowledge about possible psychiatric disorders associated with these exposures is currently not well disseminated. In this review, we aim to summarize the current knowledge on the impact of environmental pollution and extreme weather conditions on mental health, focusing on anxiety spectrum disorders, autism spectrum disorders, schizophrenia, and depression. In air pollution studies, increased concentrations of PM2.5, NO2, and SO2 were the most strongly associated with the exacerbation of anxiety, schizophrenia, and depression symptoms. We provide an overview of the suggested underlying pathomechanisms involved. We highlight that the pathogenesis of environmental pollution-related diseases is multifactorial, including increased oxidative stress, systematic inflammation, disruption of the blood-brain barrier, and epigenetic dysregulation. Light pollution and noise pollution were correlated with an increased risk of neurodegenerative disorders, particularly Alzheimer's disease. Moreover, the impact of soil and water pollution is discussed. Such compounds as crude oil, heavy metals, natural gas, agro-chemicals (pesticides, herbicides, and fertilizers), polycyclic or polynuclear aromatic hydrocarbons (PAH), solvents, lead (Pb), and asbestos were associated with detrimental impact on mental health. Extreme weather conditions were linked to depression and anxiety spectrum disorders, namely PTSD. Several policy recommendations and awareness campaigns should be implemented, advocating for the advancement of high-quality urbanization, the mitigation of environmental pollution, and, consequently, the enhancement of residents' mental health.
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Affiliation(s)
- Maciej Tota
- Faculty of Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Julia Karska
- Department of Psychiatry, Wroclaw Medical University, Wroclaw, Poland
| | - Szymon Kowalski
- Faculty of Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Natalia Piątek
- Faculty of Medicine, Wroclaw Medical University, Wroclaw, Poland
| | | | - Katarzyna Mazur
- Faculty of Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Patryk Piotrowski
- Department of Psychiatry, Wroclaw Medical University, Wroclaw, Poland
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5
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Ebrahimi M, Ebrahimi M, Vergroesen JE, Aschner M, Sillanpää M. Environmental exposures to cadmium and lead as potential causes of eye diseases. J Trace Elem Med Biol 2024; 82:127358. [PMID: 38113800 DOI: 10.1016/j.jtemb.2023.127358] [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] [Received: 10/09/2023] [Revised: 12/04/2023] [Accepted: 12/06/2023] [Indexed: 12/21/2023]
Abstract
Humans are exposed to cadmium and lead in various regions of the world daily due to industrial development and climate change. Increasing numbers of preclinical and clinical studies indicate that heavy metals, such as cadmium and lead, play a role in the pathogenesis of eye diseases. Excessive exposure to heavy metals such as cadmium and lead can increase the risk of impaired vision. Therefore, it is essential to better characterize the role of these non-essential metals in disease etiology and progression. This article discusses the potential role of cadmium and lead in the development of age-related eye diseases, including age-related macular degeneration, cataracts, and glaucoma. Furthermore, we discuss how cadmium and lead affect ocular cells and provide an overview of putative pathological mechanisms associated with their propensity to damage the eye.
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Affiliation(s)
- Moein Ebrahimi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy, and Autoimmunity, Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Maryam Ebrahimi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Joëlle E Vergroesen
- Department of Ophthalmology, Erasmus MC University Medical Center, PO Box 2040, 3000 CA Rotterdam, the Netherlands; Department of Epidemiology, Erasmus MC University Medical Center, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Mika Sillanpää
- Department of Chemical Engineering, School of Mining, Metallurgy and Chemical Engineering, University of Johannesburg, P. O. Box 17011, Doornfontein 2028, South Africa; International Research Centre of Nanotechnology for Himalayan Sustainability (IRCNHS), Shoolini University, Solan 173212, Himachal Pradesh, India; Zhejiang Rongsheng Environmental Protection Paper Co. LTD, NO.588 East Zhennan Road, Pinghu Economic Development Zone, Zhejiang 314213, PR China; Department of Civil Engineering, University Centre for Research & Development, Chandigarh University, Gharuan, Mohali, Punjab, India
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6
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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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7
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Parithathvi A, Choudhari N, Dsouza HS. Prenatal and early life lead exposure induced neurotoxicity. Hum Exp Toxicol 2024; 43:9603271241285523. [PMID: 39340316 DOI: 10.1177/09603271241285523] [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] [Indexed: 09/30/2024]
Abstract
Lead (Pb) has become a major environmental contaminant. There are several ways in which lead can enter the human body and cause toxic effects on human health. This review focuses on the impact of lead toxicity at prenatal and early life stages and its effect on neurodevelopment. Lead exposure to the developing foetus targets foetal neural stem cells. Hence, it has detrimental effects on developing neural and glial cells, adversely influencing cognition and behaviour. Lead has a profound influence on the movement of calcium ions (Ca2+), which can be attributed to most of the mechanisms by which lead affects neurodevelopment. There is no known safe threshold of lead exposure for children. Lead can affect foetal neurodevelopment leading to various neurological disorders, and neurotoxic effects on behavioural and cognitive outcomes. In this review, we discuss prenatal and early-life lead exposure, its mechanism, and consequences for neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease in later stages of life. This review further highlights the importance of lead exposure during pregnancy and lactation periods as well as early development of the child in understanding the extent of lead-induced neurological damage to the foetus/children and the associated future risks.
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Affiliation(s)
- Aluru Parithathvi
- Department of Radiation Biology and Toxicology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Neha Choudhari
- Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Herman S Dsouza
- Department of Radiation Biology and Toxicology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
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8
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Arabnezhad MR, Haghani F, Ghaffarian-Bahraman A, Jafarzadeh E, Mohammadi H, Yadegari JG, Farkhondeh T, Aschner M, Darroudi M, Marouzi S, Samarghandian S. Involvement of Nrf2 Signaling in Lead-induced Toxicity. Curr Med Chem 2024; 31:3529-3549. [PMID: 37221680 DOI: 10.2174/0929867330666230522143341] [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: 12/10/2022] [Revised: 03/19/2023] [Accepted: 03/31/2023] [Indexed: 05/25/2023]
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) is used as one of the main protective factors against various pathological processes, as it regulates cells resistant to oxidation. Several studies have extensively explored the relationship between environmental exposure to heavy metals, particularly lead (Pb), and the development of various human diseases. These metals have been reported to be able to, directly and indirectly, induce the production of reactive oxygen species (ROS) and cause oxidative stress in various organs. Since Nrf2 signaling is important in maintaining redox status, it has a dual role depending on the specific biological context. On the one hand, Nrf2 provides a protective mechanism against metal-induced toxicity; on the other hand, it can induce metalinduced carcinogenesis upon prolonged exposure and activation. Therefore, the aim of this review was to summarize the latest knowledge on the functional interrelation between toxic metals, such as Pb and Nrf2 signaling.
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Affiliation(s)
- Mohammad-Reza Arabnezhad
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
| | - Fatemeh Haghani
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
| | - Ali Ghaffarian-Bahraman
- Occupational Environment Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Emad Jafarzadeh
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Hamidreza Mohammadi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Javad Ghasemian Yadegari
- Department of Pharmacognosy, Faculty of Pharmacy, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Tahereh Farkhondeh
- Department of Toxicology and Pharmacology, School of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Majid Darroudi
- Nuclear Medicine Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Somayeh Marouzi
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Saeed Samarghandian
- Healthy Ageing Research Centre, Neyshabur University of Medical Sciences, Neyshabur 9318614139, Iran
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Obafemi TO, Ekundayo BE, Adewale OB, Obafemi BA, Anadozie SO, Adu IA, Onasanya AO, Ekundayo SK. Gallic acid and neurodegenerative diseases. PHYTOMEDICINE PLUS 2023; 3:100492. [DOI: 10.1016/j.phyplu.2023.100492] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Ali Daoud Y, Tebby C, Beaudouin R, Brochot C. Development of a physiologically based toxicokinetic model for lead in pregnant women: The role of bone tissue in the maternal and fetal internal exposure. Toxicol Appl Pharmacol 2023; 476:116651. [PMID: 37549741 DOI: 10.1016/j.taap.2023.116651] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 08/01/2023] [Accepted: 08/04/2023] [Indexed: 08/09/2023]
Abstract
Epidemiological studies have shown associations between prenatal exposure to lead (Pb) and neurodevelopmental effects in young children. Prenatal exposure is generally characterized by measuring the concentration in the umbilical cord at delivery or in the maternal blood during pregnancy. To assess internal Pb exposure during prenatal life, we developed a pregnancy physiologically based pharmacokinetic (p-PBPK) model that to simulates Pb levels in blood and target tissues in the fetus, especially during critical periods for brain development. An existing Pb PBPK model was adapted to pregnant women and fetuses. Using data from literature, both the additional maternal bone remodeling, that causes Pb release into the blood, and the Pb placental transfers were estimated by Bayesian inference. Additional maternal bone remodeling was estimated to start at 21.6 weeks. Placental transfers were estimated between 4.6 and 283 L.day-1 at delivery with high interindividual variability. Once calibrated, the p-PBPK model was used to simulate fetal exposure to Pb. Internal fetal exposure greatly varies over the pregnancy with two peaks of Pb levels in blood and brain at the end of the 1st and 3rd trimesters. Sensitivity analysis shows that the fetal blood lead levels are affected by the maternal burden of bone Pb via maternal bone remodeling and by fetal bone formation at different pregnancy stages. Coupling the p-PBPK model with an effect model such as an adverse outcome pathway could help to predict the effects on children's neurodevelopment.
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Affiliation(s)
- Yourdasmine Ali Daoud
- Experimental toxicology and modeling unit (MIV/TEAM), Institut National de l'Environnement Industriel et des Risques, 60550 Verneuil-en-Halatte, France; Péritox, UMR-I 01, University of Picardie Jules Verne, 80025 Amiens, France
| | - Cleo Tebby
- Experimental toxicology and modeling unit (MIV/TEAM), Institut National de l'Environnement Industriel et des Risques, 60550 Verneuil-en-Halatte, France.
| | - Rémy Beaudouin
- Experimental toxicology and modeling unit (MIV/TEAM), Institut National de l'Environnement Industriel et des Risques, 60550 Verneuil-en-Halatte, France; Sebio, UMR-I 02, Institut National de l'Environnement Industriel et des Risques, 60550 Verneuil-en-Halatte, France
| | - Céline Brochot
- Experimental toxicology and modeling unit (MIV/TEAM), Institut National de l'Environnement Industriel et des Risques, 60550 Verneuil-en-Halatte, France; Certara UK Ltd, Simcyp Division, Sheffield, UK
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11
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Kieffer L, Sørås R, Ciesielski TM, Stawski C. Species and reproductive status influence element concentrations in bat fur. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2023; 333:122092. [PMID: 37348695 DOI: 10.1016/j.envpol.2023.122092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 06/19/2023] [Accepted: 06/20/2023] [Indexed: 06/24/2023]
Abstract
To assess the impact of increasing pollutant levels on wildlife, we measured chemical contaminant loads in bats with different habitat and dietary preferences. Samples were taken from the fur of bats (Eptesicus nilssonii, Myotis brandtii, Myotis mystacinus and Plecotus auritus) to measure concentrations of 55 elements by inductively coupled plasma mass spectrometry (ICP-MS). Variations in element concentrations between different bat groups (species, sex, reproductive status) were analysed with a focus on arsenic (As), mercury (Hg) and lead (Pb) as these are known to cause specific health concerns in wildlife. For M. brandtii we found the highest As concentrations, especially in lactating bats, with a maximum exceeding those from other studies where bats had compromised health. Whereas for M. mystacinus there was a negative correlation between body condition index (BCI) and As concentration, indicating a potential danger for bats in the study area. In M. mystacinus and M. brandtii Hg concentrations were higher for sixteen individuals than in other studies where bats suffered genotoxic effects, although median levels were still below this threshold. Lactating bats from P. auritus and M. brandtii had higher Hg concentrations than bats of other reproductive status, which could endanger offspring as Hg can be transferred through lactation. In females from M. mystacinus Pb concentrations were more than three times higher compared to males. There was also a negative correlation between Pb concentration and BCI, which could mean that Pb has an adverse effect on health. Although many other biotic and abiotic factors should be considered, some of the variations in element concentrations could be due to different behaviours (foraging, roosting, etc.) in the studied species. The high levels of chemical contamination in some of the bats in our study, particularly reproductive individuals, is of conservation concern as bats are important agents for insect control.
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Affiliation(s)
- Luc Kieffer
- Department of Biology, Norwegian University of Science and Technology, Trondheim, NO-7491, Norway
| | - Rune Sørås
- Department of Biology, Norwegian University of Science and Technology, Trondheim, NO-7491, Norway
| | - Tomasz M Ciesielski
- Department of Biology, Norwegian University of Science and Technology, Trondheim, NO-7491, Norway; Department of Arctic Technology, The University Centre in Svalbard (UNIS), P.O. Box 156, 9171, Longyearbyen, Norway
| | - Clare Stawski
- Department of Biology, Norwegian University of Science and Technology, Trondheim, NO-7491, Norway; School of Science, Technology and Engineering, University of the Sunshine Coast, Maroochydore DC, Queensland, 4558, Australia.
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12
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Srivastava A, Kumari A, Jagdale P, Ayanur A, Pant AB, Khanna VK. Potential of Quercetin to Protect Cadmium Induced Cognitive Deficits in Rats by Modulating NMDA-R Mediated Downstream Signaling and PI3K/AKT-Nrf2/ARE Signaling Pathways in Hippocampus. Neuromolecular Med 2023; 25:426-440. [PMID: 37460789 DOI: 10.1007/s12017-023-08747-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 04/14/2023] [Indexed: 09/22/2023]
Abstract
Exposure to cadmium, a heavy metal distributed in the environment is a cause of concern due to associated health effects in population around the world. Continuing with the leads demonstrating alterations in brain cholinergic signalling in cadmium induced cognitive deficits by us; the study is focussed to understand involvement of N-Methyl-D-aspartate receptor (NMDA-R) and its postsynaptic signalling and Nrf2-ARE pathways in hippocampus. Also, the protective potential of quercetin, a polyphenolic bioflavonoid, was assessed in cadmium induced alterations. Cadmium treatment (5 mg/kg, body weight, p.o., 28 days) decreased mRNA expression and protein levels of NMDA receptor subunits (NR1, NR2A) in rat hippocampus, compared to controls. Cadmium treated rats also exhibited decrease in levels of NMDA-R associated downstream signalling proteins (CaMKIIα, PSD-95, TrkB, BDNF, PI3K, AKT, Erk1/2, GSK3β, and CREB) and increase in levels of SynGap in hippocampus. Further, decrease in protein levels of Nrf2 and HO1 associated with increase in levels of Keap1 exhibits alterations in Nrf2/ARE signalling in hippocampus of cadmium treated rats. Degeneration of pyramidal neurons in hippocampus was also evident on cadmium treatment. Simultaneous treatment with quercetin (25 mg/kg body weight p.o., 28 days) was found to attenuate cadmium induced changes in hippocampus. The results provide novel evidence that cadmium exposure may disrupt integrity of NMDA receptors and its downstream signaling targets by affecting the Nrf2/ARE signaling pathway in hippocampus and these could contribute in cognitive deficits. It is further interesting that quercetin has the potential to protect cadmium induced changes by modulating Nrf2/ARE signaling which was effective to control NMDA-R and PI3K/AKT cell signaling pathways.
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Affiliation(s)
- Anugya Srivastava
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Area, CSIR- Indian Institute of Toxicology Research, Vishvigyan Bhavan, 31 Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, 201002, India
| | - Anima Kumari
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Area, CSIR- Indian Institute of Toxicology Research, Vishvigyan Bhavan, 31 Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, 201002, India
| | - Pankaj Jagdale
- Central Pathology Laboratory, Regulatory Toxicology Area, CSIR- Indian Institute of Toxicology Research, Vishvigyan Bhavan, 31 Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India
| | - Anjaneya Ayanur
- Central Pathology Laboratory, Regulatory Toxicology Area, CSIR- Indian Institute of Toxicology Research, Vishvigyan Bhavan, 31 Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India
| | - Aditya Bhushan Pant
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Area, CSIR- Indian Institute of Toxicology Research, Vishvigyan Bhavan, 31 Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, 201002, India
| | - Vinay Kumar Khanna
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Area, CSIR- Indian Institute of Toxicology Research, Vishvigyan Bhavan, 31 Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, 201002, India.
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13
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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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14
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Gladieux M, Gimness N, Rodriguez B, Liu J. Adverse Childhood Experiences (ACEs) and Environmental Exposures on Neurocognitive Outcomes in Children: Empirical Evidence, Potential Mechanisms, and Implications. TOXICS 2023; 11:259. [PMID: 36977024 PMCID: PMC10055754 DOI: 10.3390/toxics11030259] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/02/2023] [Accepted: 03/06/2023] [Indexed: 06/18/2023]
Abstract
The purpose of this article is to examine the current literature regarding the relationship between adverse childhood experiences (ACEs) and environmental exposures. Specifically, the paper will focus on how this relationship between ACEs and physical environmental factors impacts the neurocognitive development of children. With a comprehensive literary search focusing on ACEs, inclusive of socioeconomic status (SES), and environmental toxins common in urban environments, the paper explores how these factors contribute to cognitive outcomes that are associated with the environment and childhood nurturing. The relationship between ACEs and environmental exposures reveals adverse outcomes in children's neurocognitive development. These cognitive outcomes include learning disabilities, lowered IQ, memory and attention problems, and overall poor educational outcomes. Additionally, potential mechanisms of environmental exposures and children's neurocognitive outcomes are explored, referencing data from animal studies and evidence from brain imaging studies. This study further analyzes the current gaps in the literature, such as the lack of data focusing on exposure to environmental toxicants resulting from experiencing ACEs and discusses the research and social policy implications of ACEs and environmental exposure in the neurocognitive development of children.
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Affiliation(s)
| | | | | | - Jianghong Liu
- Department of Family and Community Health, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA
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15
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Sabo SL, Lahr JM, Offer M, Weekes ALA, Sceniak MP. GRIN2B-related neurodevelopmental disorder: current understanding of pathophysiological mechanisms. Front Synaptic Neurosci 2023; 14:1090865. [PMID: 36704660 PMCID: PMC9873235 DOI: 10.3389/fnsyn.2022.1090865] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 12/19/2022] [Indexed: 01/12/2023] Open
Abstract
The GRIN2B-related neurodevelopmental disorder is a rare disease caused by mutations in the GRIN2B gene, which encodes the GluN2B subunit of NMDA receptors. Most individuals with GRIN2B-related neurodevelopmental disorder present with intellectual disability and developmental delay. Motor impairments, autism spectrum disorder, and epilepsy are also common. A large number of pathogenic de novo mutations have been identified in GRIN2B. However, it is not yet known how these variants lead to the clinical symptoms of the disease. Recent research has begun to address this issue. Here, we describe key experimental approaches that have been used to better understand the pathophysiology of this disease. We discuss the impact of several distinct pathogenic GRIN2B variants on NMDA receptor properties. We then critically review pivotal studies examining the synaptic and neurodevelopmental phenotypes observed when disease-associated GluN2B variants are expressed in neurons. These data provide compelling evidence that various GluN2B mutants interfere with neuronal differentiation, dendrite morphogenesis, synaptogenesis, and synaptic plasticity. Finally, we identify important open questions and considerations for future studies aimed at understanding this complex disease. Together, the existing data provide insight into the pathophysiological mechanisms that underlie GRIN2B-related neurodevelopmental disorder and emphasize the importance of comparing the effects of individual, disease-associated variants. Understanding the molecular, cellular and circuit phenotypes produced by a wide range of GRIN2B variants should lead to the identification of core neurodevelopmental phenotypes that characterize the disease and lead to its symptoms. This information could help guide the development and application of effective therapeutic strategies for treating individuals with GRIN2B-related neurodevelopmental disorder.
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Affiliation(s)
- Shasta L. Sabo
- Department of Biology, Central Michigan University, Mount Pleasant, MI, United States,Program in Biochemistry, Cell and Molecular Biology, Central Michigan University, Mount Pleasant, MI, United States,Program in Neuroscience, Central Michigan University, Mount Pleasant, MI, United States,*Correspondence: Shasta L. Sabo
| | - Jessica M. Lahr
- Program in Biochemistry, Cell and Molecular Biology, Central Michigan University, Mount Pleasant, MI, United States
| | - Madelyn Offer
- Program in Neuroscience, Central Michigan University, Mount Pleasant, MI, United States
| | - Anika LA Weekes
- Program in Biochemistry, Cell and Molecular Biology, Central Michigan University, Mount Pleasant, MI, United States
| | - Michael P. Sceniak
- Department of Biology, Central Michigan University, Mount Pleasant, MI, United States
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16
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Schildroth S, Kordas K, Bauer JA, Wright RO, Claus Henn B. Environmental Metal Exposure, Neurodevelopment, and the Role of Iron Status: a Review. Curr Environ Health Rep 2022; 9:758-787. [PMID: 35997893 DOI: 10.1007/s40572-022-00378-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/05/2022] [Indexed: 01/31/2023]
Abstract
PURPOSE OF REVIEW Exposure to environmental metals, like lead (Pb), manganese (Mn), and methylmercury (Me-Hg), has consistently been implicated in neurodevelopmental dysfunction. Recent research has focused on identifying modifying factors of metal neurotoxicity in childhood, such as age, sex, and co-exposures. Iron (Fe) status is critical for normal cognitive development during childhood, and current mechanistic, animal, and human evidence suggests that Fe status may be a modifier or mediator of associations between environmental metals and neurodevelopment. The goals of this review are to describe the current state of the epidemiologic literature on the role of Fe status (i.e., hemoglobin, ferritin, blood Fe concentrations) and Fe supplementation in the relationship between metals and children's neurodevelopment, and to identify research gaps. RECENT FINDINGS We identified 30 studies in PubMed and EMBASE that assessed Fe status as a modifier, mediator, or co-exposure of associations of Pb, Me-Hg, Mn, copper (Cu), zinc (Zn), arsenic (As), or metal mixtures measured in early life (prenatal period through 8 years of age) with cognition in children. In experimental studies, co-supplementation of Fe and Zn was associated with better memory and cognition than supplementation with either metal alone. Several observational studies reported interactions between Fe status and Pb, Mn, Zn, or As in relation to developmental indices, memory, attention, and behavior, whereby adverse associations of metals with cognition were worse among Fe-deficient children compared to Fe-sufficient children. Only two studies quantified joint associations of complex metal mixtures that included Fe with neurodevelopment, though findings from these studies were not consistent. Findings support memory and attention as two possible cognitive domains that may be both vulnerable to Fe deficiency and a target of metals toxicity. Major gaps in the literature remain, including evaluating Fe status as a modifier or mediator of metal mixtures and cognition. Given that Fe deficiency is the most common nutritional deficiency worldwide, characterizing Fe status in studies of metals toxicity is important for informing public health interventions.
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Affiliation(s)
- Samantha Schildroth
- Department of Environmental Health, School of Public Health, Boston University, 715 Albany St., Boston, MA, 02118, USA.
| | - Katarzyna Kordas
- Department of Epidemiology and Environmental Health, The State University of New York at Buffalo, Buffalo, NY, USA
| | - Julia Anglen Bauer
- Department of Epidemiology, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA
| | - Robert O Wright
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Birgit Claus Henn
- Department of Environmental Health, School of Public Health, Boston University, 715 Albany St., Boston, MA, 02118, USA
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17
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Guan R, Wang T, Dong X, Du K, Li J, Zhao F, Xu J, Li B, Zheng G, Shen X, Cao B, Wang J, Aschner M, Liu M, Chen R. Effects of co-exposure to lead and manganese on learning and memory deficits. J Environ Sci (China) 2022; 121:65-76. [PMID: 35654517 PMCID: PMC9163452 DOI: 10.1016/j.jes.2021.09.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 09/10/2021] [Accepted: 09/13/2021] [Indexed: 06/15/2023]
Abstract
Lead (Pb) and manganese (Mn) are common neurotoxins. However, individuals are subject to co-exposures in real life, and it is therefore important to study these metals in combination. Weaning Sprague-Dawley rats were given ad libitum access to drinking water solutions containing Pb (100 mg/L), Mn (2.5 mg/mL) or a mixture, and each treatment had its own minocycline (50 mg/(kg•day)) supplement group. The results showed a significant difference in spatial memory and induction levels of hippocampal long-term potentiation (LTP) in all exposure groups when compared with controls. The combined-exposure group exhibited the most pronounced effect when compared with each of the single-metal exposure groups. Microglia displayed activation at day 3 after exposure alone or in combination, while astrocytes showed activation at day 5, accompanied by decreased expression levels of GLAST, GLT-1, and GS. Furthermore, the levels of glutamate in the synaptic cleft increased significantly. When microglial activation was inhibited by minocycline, the activation of astrocytes and the expression of GLAST, GLT-1, and GS were both reversed. In addition, upon minocycline treatment, hippocampal LTP impairment and cognitive injury were significantly alleviated in each of the exposure groups. These results suggest that combined exposure to Pb and Mn can cause greater effects on cognition and synaptic plasticity when compared to single-metal exposure groups. The reason may involve abnormal activation of microglia leading to excessive regulation of astrocytes, resulting in glutamate reuptake dysfunction in astrocytes and leading to perturbed cognition and synaptic plasticity.
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Affiliation(s)
- Ruili Guan
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China
| | - Tao Wang
- Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China
| | - Xiaoru Dong
- Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China
| | - Kejun Du
- Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China
| | - Juan Li
- Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an 710032, China
| | - Fang Zhao
- Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China
| | - Jie Xu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China
| | - Bin Li
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China
| | - Gang Zheng
- Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China
| | - Xuefeng Shen
- Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China
| | - Baohua Cao
- School of Nursing, Fourth Military Medical University, Xi'an 710032, China
| | - Jing Wang
- School of Nursing, Fourth Military Medical University, Xi'an 710032, China
| | - Michael Aschner
- School of Nursing, Fourth Military Medical University, Xi'an 710032, China; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA; IM Sechenov First Moscow State Medical University, Moscow, Russia
| | - Mingchao Liu
- Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China; School of Nursing, Fourth Military Medical University, Xi'an 710032, China.
| | - Rui Chen
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China.
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18
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Albores-Garcia D, Stansfield KH, McGlothan JL, Bursac Z, Guilarte TR. Chronic early-life lead exposure sensitizes adolescent rats to cocaine: Role of the dopaminergic system. Front Mol Neurosci 2022; 15:946726. [PMID: 36090247 PMCID: PMC9450041 DOI: 10.3389/fnmol.2022.946726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 08/03/2022] [Indexed: 11/13/2022] Open
Abstract
Exposure to heavy metals has been associated with psychiatric disorders and recent studies suggest an association between childhood lead (Pb2+) intoxication and schizophrenia (SZ). In animal models, Pb2+ exposure recapitulates key neuropathological and dopaminergic system alterations present in SZ. Given the high comorbidity of mental disorders such as SZ and substance abuse, coupled with evidence showing that Pb2+ exposure affects addiction circuits, we hypothesized that early life Pb2+ exposure could sensitize neuronal systems relevant to SZ and substance abuse. To this goal, we examined the effects of chronic developmental Pb2+ exposure on the acute locomotor response to cocaine (0, 5, and 15 mg kg–1) and behavioral sensitization. We also examined the role of the dopaminergic system in the psychostimulant effects of cocaine, and measured D1-dopamine receptor (D1R) levels in the rat brain using [3H]-SCH23390 quantitative receptor autoradiography, as well as the ability of the D1R antagonist SCH23390 to block the cocaine effects on locomotor activation. These studies were performed in male and female rats at different developmental ages consisting of juveniles (postnatal, PN14), early-adolescent (PN28), late adolescent (PN50), and adults (PN120). Our results show that chronic developmental Pb2+ exposure increases the acute locomotor response to the higher dose of cocaine in Pb2+-exposed male adolescent (PN28 and PN50) rats, and to the lower dose of cocaine in adolescent female rats. No changes in the locomotor activity were detected in adult rats. Behavioral sensitization experiments showed a sustained sensitization in early adolescent Pb2+-exposed male but not female rats. The cocaine-induced effects on locomotor activity were abrogated by injection of a D1R antagonist suggesting the involvement of this dopamine receptor subtype. Furthermore, Pb2+-induced increases D1R levels in several brain regions were prominent in juveniles and early adolescence but not in late adolescence or in adults. In summary, early chronic developmental Pb2+ exposure results in age and sex-dependent effect on the locomotor response to cocaine, suggesting differential susceptibilities to the neurotoxic effects of Pb2+ exposure. Our data provides further support to the notion that Pb2+ exposure is an environmental risk factor for psychiatric disorders and substance abuse.
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Affiliation(s)
- Damaris Albores-Garcia
- Brain, Behavior and the Environment Laboratory, Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, United States
| | | | - Jennifer L. McGlothan
- Brain, Behavior and the Environment Laboratory, Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, United States
| | - Zoran Bursac
- Department of Biostatistics, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, United States
| | - Tomás R. Guilarte
- Brain, Behavior and the Environment Laboratory, Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, United States
- *Correspondence: Tomás R. Guilarte,
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19
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Chen Y, Mao G, Zhang Z, Zhao T, Feng W, Yang L, Wu X. The protective effect of C3G against Pb-induced learning and memory impairments through cAMP-PKA-CREB signaling pathway in rat hippocampus. Process Biochem 2022. [DOI: 10.1016/j.procbio.2022.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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20
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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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21
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Mukherjee S, Chatterjee N, Sircar A, Maikap S, Singh A, Acharyya S, Paul S. A Comparative Analysis of Heavy Metal Effects on Medicinal Plants. Appl Biochem Biotechnol 2022; 195:2483-2518. [PMID: 35488955 DOI: 10.1007/s12010-022-03938-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/20/2022] [Indexed: 11/02/2022]
Abstract
Popularity of herbal drugs has always been in high demand, but recently it has been increasing all over the world, especially in India, because of the lower range of adverse health effects as compared to synthetic or man-made drugs. Not only this but their cost-effectiveness and easy availability to the poor people and the masses, particularly in developing countries, are major causes for their demand. But there lies a huge problem during the process of plant collection that affects their medicinal properties to certain degrees. This is caused by heavy metal toxicity in soil in different locations of the Indian subcontinent. This was correlated with their potential to cause health damage. Exposure of humans to heavy metals includes diverse pathways from food to water to consumption and inhalation of polluted air to permanent damage to exposed skin and even by occupational exposure at workplaces. As we can understand, the main mechanisms of heavy metal toxicity include the production of free radicals to affect the host by oxidative stress, damaging biological molecules such as enzymes, proteins, lipids, and even nucleic acids and finally damaging DNA which is the fastest way to carcinogenesis and in addition, neurotoxicity. Therefore, in this paper, we have researched how the plants/herbs are affected due to heavy metal deposition in their habitat and how it can lead to serious clinical complications.
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Affiliation(s)
- Susmita Mukherjee
- Department of Biotechnology, University of Engineering and Management, Kolkata, India
| | - Nivedita Chatterjee
- Department of Biotechnology, University of Engineering and Management, Kolkata, India
| | - Asmeeta Sircar
- Department of Biotechnology, University of Engineering and Management, Kolkata, India
| | - Shimantika Maikap
- Department of Biotechnology, University of Engineering and Management, Kolkata, India
| | - Abhilasha Singh
- Department of Biotechnology, University of Engineering and Management, Kolkata, India
| | - Sudeshna Acharyya
- Department of Biotechnology, University of Engineering and Management, Kolkata, India
| | - Sonali Paul
- Department of Biotechnology, University of Engineering and Management, Kolkata, India.
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22
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Wang Z, Zhao H, Xu Y, Zhao J, Song Z, Bi Y, Li Y, Lan X, Pan C, Foulkes NS, Zhang S. Early-life lead exposure induces long-term toxicity in the central nervous system: From zebrafish larvae to juveniles and adults. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 804:150185. [PMID: 34509844 DOI: 10.1016/j.scitotenv.2021.150185] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 09/01/2021] [Accepted: 09/02/2021] [Indexed: 06/13/2023]
Abstract
Lead induced neurotoxicity has been extensively investigated. However, the potential connections between early-life lead exposure and the frequently observed aberrant neurobehavior in juveniles and adults remain unclear. In this study, zebrafish model was used to explore the immediate and long-term effects of early-life exposure to environmental levels of lead on the central nervous system, and the cellular and molecular mechanisms underlying the consequent abnormal neurobehavior. Lead exposed zebrafish larvae exhibited neurologic damage and defective neurobehavior. Consistent with clinical studies, despite being raised in lead-free conditions, the juvenile and adult fish experienced lead exposure earlier, presented ADHD-like symptoms, and the adult fish exhibited remarkably affected vitality and shoaling behavior. Their anxiety levels were elevated, whereas their social interaction, as well as learning and memory were strongly depressed. The expression profiles of key genes involved in neurodevelopment and neurotransmitter systems were significantly modulated, in similar patterns as in the larval stage. Notably, the density of neurons was decreased and varicosities in neuronal axons were frequently observed in the lead-exposed groups. It's tempting to speculate that the disruption of early neurodevelopment as well as the prolonged modulation of neuromorphic and neurotransmitter systems contribute to the lead-induced neurobehavioral disorders observed in juveniles and adulthood.
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Affiliation(s)
- Zuo Wang
- School of Life Sciences, Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, Lanzhou University, No. 222 South Tianshui Road, Lanzhou 730000, Gansu Province, China
| | - Haiyu Zhao
- School of Life Sciences, Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, Lanzhou University, No. 222 South Tianshui Road, Lanzhou 730000, Gansu Province, China.
| | - Yanyi Xu
- School of Life Sciences, Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, Lanzhou University, No. 222 South Tianshui Road, Lanzhou 730000, Gansu Province, China
| | - Jianing Zhao
- School of Life Sciences, Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, Lanzhou University, No. 222 South Tianshui Road, Lanzhou 730000, Gansu Province, China; Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, No. 22 Xinong Road, Yangling 712100, Shaanxi Province, China
| | - Zan Song
- School of Life Sciences, Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, Lanzhou University, No. 222 South Tianshui Road, Lanzhou 730000, Gansu Province, China
| | - Yi Bi
- School of Life Sciences, Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, Lanzhou University, No. 222 South Tianshui Road, Lanzhou 730000, Gansu Province, China; Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, No. 22 Xinong Road, Yangling 712100, Shaanxi Province, China
| | - Yang Li
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, No. 22 Xinong Road, Yangling 712100, Shaanxi Province, China
| | - Xianyong Lan
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, No. 22 Xinong Road, Yangling 712100, Shaanxi Province, China
| | - Chuanying Pan
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, No. 22 Xinong Road, Yangling 712100, Shaanxi Province, China
| | - Nicholas S Foulkes
- Institute of Biological and Chemical Systems, Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
| | - Shengxiang Zhang
- School of Life Sciences, Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, Lanzhou University, No. 222 South Tianshui Road, Lanzhou 730000, Gansu Province, China
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Witkowska D, Słowik J, Chilicka K. Heavy Metals and Human Health: Possible Exposure Pathways and the Competition for Protein Binding Sites. Molecules 2021; 26:molecules26196060. [PMID: 34641604 PMCID: PMC8511997 DOI: 10.3390/molecules26196060] [Citation(s) in RCA: 179] [Impact Index Per Article: 44.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 10/03/2021] [Accepted: 10/05/2021] [Indexed: 11/16/2022] Open
Abstract
Heavy metals enter the human body through the gastrointestinal tract, skin, or via inhalation. Toxic metals have proven to be a major threat to human health, mostly because of their ability to cause membrane and DNA damage, and to perturb protein function and enzyme activity. These metals disturb native proteins’ functions by binding to free thiols or other functional groups, catalyzing the oxidation of amino acid side chains, perturbing protein folding, and/or displacing essential metal ions in enzymes. The review shows the physiological and biochemical effects of selected toxic metals interactions with proteins and enzymes. As environmental contamination by heavy metals is one of the most significant global problems, some detoxification strategies are also mentioned.
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Carmona A, Roudeau S, Ortega R. Molecular Mechanisms of Environmental Metal Neurotoxicity: A Focus on the Interactions of Metals with Synapse Structure and Function. TOXICS 2021; 9:toxics9090198. [PMID: 34564349 PMCID: PMC8471991 DOI: 10.3390/toxics9090198] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 08/25/2021] [Accepted: 08/25/2021] [Indexed: 02/07/2023]
Abstract
Environmental exposure to neurotoxic metals and metalloids such as arsenic, cadmium, lead, mercury, or manganese is a global health concern affecting millions of people worldwide. Depending on the period of exposure over a lifetime, environmental metals can alter neurodevelopment, neurobehavior, and cognition and cause neurodegeneration. There is increasing evidence linking environmental exposure to metal contaminants to the etiology of neurological diseases in early life (e.g., autism spectrum disorder) or late life (e.g., Alzheimer’s disease). The known main molecular mechanisms of metal-induced toxicity in cells are the generation of reactive oxygen species, the interaction with sulfhydryl chemical groups in proteins (e.g., cysteine), and the competition of toxic metals with binding sites of essential metals (e.g., Fe, Cu, Zn). In neurons, these molecular interactions can alter the functions of neurotransmitter receptors, the cytoskeleton and scaffolding synaptic proteins, thereby disrupting synaptic structure and function. Loss of synaptic connectivity may precede more drastic alterations such as neurodegeneration. In this article, we will review the molecular mechanisms of metal-induced synaptic neurotoxicity.
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Albores-Garcia D, McGlothan JL, Guilarte TR. Early-life lead exposure and neurodevelopmental disorders. CURRENT OPINION IN TOXICOLOGY 2021; 26:22-27. [PMID: 34013137 DOI: 10.1016/j.cotox.2021.03.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Lead (Pb2+) exposure is a global public health problem of major proportion with an alarming number of children with blood Pb2+ levels > 10 >g/dL, twice the current CDC reference level for Pb2+ exposure. Mounting evidence from population-based studies suggests an association between chronic early life Pb2+ exposure (CELLE) and psychiatric disorders, specifically schizophrenia (SZ). Preclinical studies suggest a common mechanism in the pathophysiology of CELLE and SZ, NMDA receptor hypofunction. Here we describe human and experimental animal studies providing the evidence for such an association. Further, recent preclinical studies indicate that Pb2+-induced changes in neurotransmitter receptors that mediate the action(s) of drugs of abuse are increased in brain regions associated with addiction circuits in adolescence, a period of increased susceptibility to drug use and abuse and expression of psychiatric disease in humans. In summary, the relationship between the global burden of childhood Pb2+ exposure and the latent onset of psychiatric disorders and predisposition to drug use requires further investigations in human populations.
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Affiliation(s)
- D Albores-Garcia
- Brain, Behavior & the Environment Program Department of Environmental Health Sciences Robert Stempel College of Public Health & Social Work Florida International University Miami, FL 33199, United States
| | - J L McGlothan
- Brain, Behavior & the Environment Program Department of Environmental Health Sciences Robert Stempel College of Public Health & Social Work Florida International University Miami, FL 33199, United States
| | - T R Guilarte
- Brain, Behavior & the Environment Program Department of Environmental Health Sciences Robert Stempel College of Public Health & Social Work Florida International University Miami, FL 33199, United States
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Abstract
Lead (Pb2+) is a non-essential metal with numerous industrial applications that have led to ts ubiquity in the environment. Thus, not only occupational-exposed individuals' health is compromised, but also that of the general population and in particular children. Notably, although the central nervous system is particularly susceptible to Pb2+, other systems are affected as well. The present study focuses on molecular mechanisms that underlie the effects that arise from the presence of Pb2+ in situ in the brain, and the possible toxic effects that follows. As the brain barriers represent the first target of systemic Pb2+, mechanisms of Pb2+ entry into the brain are discussed, followed by a detailed discussion on neurotoxic mechanisms, with special emphasis on theories of ion mimicry, mitochondrial dysfunction, redox imbalance, and neuroinflammation. Most importantly, the confluence and crosstalk between these events is combined into a cogent mechanism of toxicity, by intertwining recent and old evidences from humans, in vitro cell culture and experimental animals. Finally, pharmacological interventions, including chelators, antioxidants substances, anti-inflammatory drugs, or their combination are reviewed as integrated approaches to ameliorate Pb2+ harmful effects in both developing or adult organisms.
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Affiliation(s)
- Miriam B. Virgolini
- IFEC CONICET. IFEC-CONICET. Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba. Haya de la Torre y Medina Allende, Ciudad Universitaria, 5016, Córdoba, Argentina
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA and IM Sechenov First Moscow State Medical University (Sechenov University), 119146, Moscow, Russia
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Goel A, Aschner M. The Effect of Lead Exposure on Autism Development. Int J Mol Sci 2021; 22:1637. [PMID: 33561959 PMCID: PMC7915585 DOI: 10.3390/ijms22041637] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 01/31/2021] [Accepted: 02/02/2021] [Indexed: 11/17/2022] Open
Abstract
Autism Spectrum Disorder (ASD) remains one of the most detrimental neurodevelopmental conditions in society today. Common symptoms include diminished social and communication ability. Investigations on autism etiology remain largely ambiguous. Previous studies have highlighted exposure to lead (Pb) may play a role in ASD. In addition, lead has been shown to be one of the most prevalent metal exposures associated with neurological deficits. A semi-systematic review was conducted using public databases in order to evaluate the extent of lead's role in the etiology of autism. This review examines the relationship between autistic comorbid symptoms-such as deterioration in intelligence scores, memory, language ability, and social interaction-and lead exposure. Specifically, the mechanisms of action of lead exposure, including changes within the cholinergic, dopaminergic, glutamatergic, gamma aminobutyric acid (GABA)ergic systems, are discussed. The goal of this review is to help illustrate the connections between lead's mechanistic interference and the possible furthering of the comorbidities of ASD. Considerations of the current data and trends suggest a potential strong role for lead in ASD.
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Affiliation(s)
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine Bronx, New York, NY 10461, USA;
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Cognitive Impairment Induced by Lead Exposure during Lifespan: Mechanisms of Lead Neurotoxicity. TOXICS 2021; 9:toxics9020023. [PMID: 33525464 PMCID: PMC7912619 DOI: 10.3390/toxics9020023] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/19/2021] [Accepted: 01/25/2021] [Indexed: 12/25/2022]
Abstract
Lead (Pb) is considered a strong environmental toxin with human health repercussions. Due to its widespread use and the number of people potentially exposed to different sources of this heavy metal, Pb intoxication is recognized as a public health problem in many countries. Exposure to Pb can occur through ingestion, inhalation, dermal, and transplacental routes. The magnitude of its effects depends on several toxicity conditions: lead speciation, doses, time, and age of exposure, among others. It has been demonstrated that Pb exposure induces stronger effects during early life. The central nervous system is especially vulnerable to Pb toxicity; Pb exposure is linked to cognitive impairment, executive function alterations, abnormal social behavior, and fine motor control perturbations. This review aims to provide a general view of the cognitive consequences associated with Pb exposure during early life as well as during adulthood. Additionally, it describes the neurotoxic mechanisms associated with cognitive impairment induced by Pb, which include neurochemical, molecular, and morphological changes that jointly could have a synergic effect on the cognitive performance.
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Zhu G, Zhu Q, Zhang W, Hui C, Li Y, Yang M, Pang S, Li Y, Xue G, Chen H. Mitochondrial uncoupling protein 2 is regulated through heterogeneous nuclear ribonucleoprotein K in lead exposure models. JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH. PART C, TOXICOLOGY AND CARCINOGENESIS 2021; 39:1-16. [PMID: 33576715 DOI: 10.1080/26896583.2020.1854596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Synaptic plasticity plays an important role in learning and memory in the developing hippocampus. However, the precise molecular mechanism in lead exposure models remains to be studied. UCP2, an inner mitochondrial anion carrier, regulates synaptic plasticity through uncoupling neurons. And hnRNP K, an RNA binding protein, plays a role in modulating the expression of transcripts coding synaptic plasticity. We aim to investigate whether lead exposure affects UCP2 and hnRNP K expression levels. The Sprague-Dawley rats were exposed to different lead acetate concentrations (0 g/l, 0.5 g/l, 2.0 g/l) during gestational and lactational periods. PC12 cells were also exposed to different lead acetate concentrations (0 μM, 1 μM and 100 μM). We found that the expression levels of UCP2 and hnRNP K had significant declines in the lead exposure rat hippocampus and PC12 cells. Furthermore, the up-regulation of hnRNP K expression level could reverse the expression level of UCP2 in lead exposure models. In conclusion, these results suggest that lead exposure can reduce the expression level of UCP2 which is mediated by decreasing the expression level of hnRNP K.
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Affiliation(s)
- Gaochun Zhu
- Department of Anatomy, School of Medicine, Nanchang University, Nanchang, P.R. China
| | - Qian Zhu
- Department of Anatomy, School of Medicine, Nanchang University, Nanchang, P.R. China
| | - Wei Zhang
- Department of Anatomy, School of Medicine, Nanchang University, Nanchang, P.R. China
| | - Chen Hui
- Department of Anatomy, School of Medicine, Nanchang University, Nanchang, P.R. China
| | - Yuwen Li
- Queen Mary College, School of Medicine, Nanchang University, Nanchang, P.R. China
| | - Meiyuan Yang
- Department of Anatomy, School of Medicine, Nanchang University, Nanchang, P.R. China
| | - Shimin Pang
- Second Clinical College, School of Medicine, Nanchang University, Nanchang, P.R. China
| | - Yaobing Li
- Department of Anatomy, School of Medicine, Nanchang University, Nanchang, P.R. China
| | - Guoyong Xue
- Department of Anatomy, School of Medicine, Nanchang University, Nanchang, P.R. China
| | - Hongping Chen
- Department of Histology and Embryology, School of Medicine, Nanchang University, Nanchang, P.R. China
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Bo JZ, Xue L, Li S, Yin JW, Li ZY, Wang X, Wang JF, Zhang YS. D-serine reduces memory impairment and neuronal damage induced by chronic lead exposure. Neural Regen Res 2021; 16:836-841. [PMID: 33229717 PMCID: PMC8178793 DOI: 10.4103/1673-5374.297086] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Although exogenous D-serine has been applied as a neural regulatory intervention in many studies, the role played by D-serine in hippocampal injuries caused by lead exposure remains poorly understood. Rat models of chronic lead exposure were established through the administration of 0.05% lead acetate for 8 weeks. Simultaneously, rats were administered 30 or 60 mg/kg D-serine, intraperitoneally, twice a day. Our results showed that D-serine treatment shortened the escape latency from the Morris water maze, increased the number of times that mice crossed the original platform location, and alleviated the pathological damage experienced by hippocampal neurons in response to lead exposure. Although D-serine administration did not increase the expression levels of the N-methyl-D-aspartate receptor subtype 2B (NR2B) in the hippocampi of lead-exposed rats, 60 mg/kg D-serine treatment restored the expression levels of NR2A, which are reduced by lead exposure. These findings suggested that D-serine can alleviate learning and memory impairments induced by lead exposure and that the underlying mechanism is associated with the increased expression of NR2A in the hippocampus. This study was approved by the Animal Ethics Committee of North China University of Science and Technology, China (approval No. LX2018155) on December 21, 2018.
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Affiliation(s)
- Jian-Zhu Bo
- College of Public Health, North China University of Science and Technology, Tangshan, Hebei Province, China
| | - Ling Xue
- College of Public Health, North China University of Science and Technology, Tangshan, Hebei Province, China
| | - Shuang Li
- Laboratory Animal Center, North China University of Science and Technology, Tangshan, Hebei Province, China
| | - Jing-Wen Yin
- College of Public Health, North China University of Science and Technology, Tangshan, Hebei Province, China
| | - Zheng-Yao Li
- College of Public Health, North China University of Science and Technology, Tangshan, Hebei Province, China
| | - Xi Wang
- College of Public Health, North China University of Science and Technology, Tangshan, Hebei Province, China
| | - Jun-Feng Wang
- College of Public Health, North China University of Science and Technology, Tangshan, Hebei Province, China
| | - Yan-Shu Zhang
- College of Public Health; Laboratory Animal Center, North China University of Science and Technology, Tangshan, Hebei Province, China
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Wong HHW, Rannio S, Jones V, Thomazeau A, Sjöström PJ. NMDA receptors in axons: there's no coincidence. J Physiol 2020; 599:367-387. [PMID: 33141440 DOI: 10.1113/jp280059] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 10/27/2020] [Indexed: 12/16/2022] Open
Abstract
In the textbook view, N-methyl-d-aspartate (NMDA) receptors are postsynaptically located detectors of coincident activity in Hebbian learning. However, controversial presynaptically located NMDA receptors (preNMDARs) have for decades been repeatedly reported in the literature. These preNMDARs have typically been implicated in the regulation of short-term and long-term plasticity, but precisely how they signal and what their functional roles are have been poorly understood. The functional roles of preNMDARs across several brain regions and different forms of plasticity can differ vastly, with recent discoveries showing key involvement of unusual subunit composition. Increasing evidence shows preNMDAR can signal through both ionotropic action by fluxing calcium and in metabotropic mode even in the presence of magnesium blockade. We argue that these unusual properties may explain why controversy has surrounded this receptor type. In addition, the expression of preNMDARs at some synapse types but not others can underlie synapse-type-specific plasticity. Last but not least, preNMDARs are emerging therapeutic targets in disease states such as neuropathic pain. We conclude that axonally located preNMDARs are required for specific purposes and do not end up there by accident.
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Affiliation(s)
- Hovy Ho-Wai Wong
- Department of Medicine, Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Centre, Montreal General Hospital, 1650 Cedar Ave, Montreal, Quebec, H3G 1A4, Canada
| | - Sabine Rannio
- Department of Medicine, Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Centre, Montreal General Hospital, 1650 Cedar Ave, Montreal, Quebec, H3G 1A4, Canada.,Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada
| | - Victoria Jones
- Department of Medicine, Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Centre, Montreal General Hospital, 1650 Cedar Ave, Montreal, Quebec, H3G 1A4, Canada.,Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada
| | - Aurore Thomazeau
- Department of Medicine, Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Centre, Montreal General Hospital, 1650 Cedar Ave, Montreal, Quebec, H3G 1A4, Canada
| | - P Jesper Sjöström
- Department of Medicine, Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Centre, Montreal General Hospital, 1650 Cedar Ave, Montreal, Quebec, H3G 1A4, Canada
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Rangel-Barajas C, Coronel I, Zhang Y, Hernández M, Boehm Ii SL. Low-level developmental lead exposure does not predispose to adult alcohol self-administration, but does increase the risk of relapsing to alcohol seeking in mice: Contrasting role of GLT1 and xCT brain expression. Neuropharmacology 2020; 181:108339. [PMID: 33010299 DOI: 10.1016/j.neuropharm.2020.108339] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 09/22/2020] [Accepted: 09/26/2020] [Indexed: 12/27/2022]
Abstract
Lead (Pb) is a neurotoxic heavy metal pollutant. Despite the efforts to reduce Pb environmental exposure and to prevent Pb poisoning, exposure in human populations persists. Studies of adults with history of childhood lead exposure have consistently demonstrated cognitive impairments that have been associated with sustained glutamate signaling. Additionally, some clinical studies have also found correlations between Pb exposure and increased proclivity to drug addiction. Thus, here we sought to investigate if developmental Pb exposure can increase propensity to alcohol consumption and relapse using an alcohol self-administration paradigm. Because Pb exposure is associated with increased glutamatergic tone, we also studied the effects on the expression of synaptic and non-synaptic glutamate transporters in brain regions associated with drug addiction such as the nucleus accumbens (NAc), dorsomedial striatum (DMS), dorsolateral striatum (DLS), and medial prefrontal cortex (mPFC). We found that while developmental Pb exposure did not increase risk for alcohol self-administration, it did play a role in relapsing to alcohol. The effects were associated with differential expression of the glutamate transporter 1 (GLT1) and the glutamate/cystine antiporter (xCT). In the NAc and DLS the expression of GLT1 was found to be significantly reduced, while no changes were found in DMS or mPFC. Contrastingly, xCT was found to be upregulated in NAc but downregulated in DLS, with no changes in DMS or mPFC. Our data suggest that lead exposure is involved in relapse to alcohol seeking, an effect that could be associated with downregulation of GLT1 and xCT in the DLS.
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Affiliation(s)
- Claudia Rangel-Barajas
- Department of Psychology, School of Science, Indiana University-Purdue University Indianapolis, 402 N Blackford St, Indianapolis, IN, 46202, USA
| | - Israel Coronel
- Department of Psychology, School of Science, Indiana University-Purdue University Indianapolis, 402 N Blackford St, Indianapolis, IN, 46202, USA
| | - Yanping Zhang
- Department of Psychology, School of Science, Indiana University-Purdue University Indianapolis, 402 N Blackford St, Indianapolis, IN, 46202, USA
| | - Maribel Hernández
- Department of Psychology, School of Science, Indiana University-Purdue University Indianapolis, 402 N Blackford St, Indianapolis, IN, 46202, USA
| | - Stephen L Boehm Ii
- Department of Psychology, School of Science, Indiana University-Purdue University Indianapolis, 402 N Blackford St, Indianapolis, IN, 46202, USA; Indiana Alcohol Research Center, Indiana University School of Medicine, 340 W 10th St, Indianapolis, IN, 462020, USA.
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Liu CM, Tian ZK, Zhang YJ, Ming QL, Ma JQ, Ji LP. Effects of Gastrodin against Lead-Induced Brain Injury in Mice Associated with the Wnt/Nrf2 Pathway. Nutrients 2020; 12:nu12061805. [PMID: 32560430 PMCID: PMC7353406 DOI: 10.3390/nu12061805] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 06/08/2020] [Accepted: 06/16/2020] [Indexed: 12/12/2022] Open
Abstract
Gastrodin (GAS), the main phenolic glycoside extracted from Gastrodia elata Blume, exhibited potential neuroprotective properties. Here we examined the protective effects of GAS against lead(Pb)-induced nerve injury in mice, and explores its underlying mechanisms. Our research findings revealed that GAS improved behavioral deficits in Pb-exposed mice. GAS reduced the accumulation of p-tau and amyloid-beta (Aβ). GAS inhibited Pb-induced inflammation in the brain, as indicated by the decreased levels of pro-inflammatory cytokines, including tumor necrosis factor-a (TNF-α), cyclooxygenase-2 (COX-2). GAS increased the expression levels of NR2A and neurotrophin brain-derived neurotrophic factor (BDNF). GAS inhibited Pb-induced apoptosis of neurons in hippocampus tissue, as indicated by the decreased levels of pro-apoptotic proteins Bax and cleaved caspase-3. Furthermore, the neuroprotective effects of GAS were associated with inhibiting oxidative stress by modulating nuclear factor-erythroid 2-related factor 2 (Nrf2)-mediated antioxidant signaling. GAS supplement activated the Wnt/β-catenin signaling pathway and reduced the expression of Wnt inhibitor Dickkopf-1 (Dkk-1). Collectively, this study clarified that GAS exhibited neuroprotective property by anti-oxidant, anti-inflammatory and anti-apoptosis effects and its ability to regulate the Wnt/Nrf2 pathway.
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Affiliation(s)
- Chan-Min Liu
- School of Life Science, Jiangsu Normal University, No.101, Shanghai Road, Tongshan New Area, Xuzhou 221116, China; (C.-M.L.); (Z.-K.T.); (Y.-J.Z.); (Q.-L.M.)
| | - Zhi-Kai Tian
- School of Life Science, Jiangsu Normal University, No.101, Shanghai Road, Tongshan New Area, Xuzhou 221116, China; (C.-M.L.); (Z.-K.T.); (Y.-J.Z.); (Q.-L.M.)
| | - Yu-Jia Zhang
- School of Life Science, Jiangsu Normal University, No.101, Shanghai Road, Tongshan New Area, Xuzhou 221116, China; (C.-M.L.); (Z.-K.T.); (Y.-J.Z.); (Q.-L.M.)
| | - Qing-Lei Ming
- School of Life Science, Jiangsu Normal University, No.101, Shanghai Road, Tongshan New Area, Xuzhou 221116, China; (C.-M.L.); (Z.-K.T.); (Y.-J.Z.); (Q.-L.M.)
| | - Jie-Qiong Ma
- College of Chemical Engineering, Sichuan University of Science and Engineering, Xuyuan Road, Zigong 643000, China;
| | - Li-Ping Ji
- College of Physical Education, Jiangsu Normal University, No.101, Shanghai Road, Tongshan New Area, Xuzhou 221116, China
- Correspondence: ; Tel.: +86-516-83403170; Fax: +86-516-83500171
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Leão LKR, Bittencourt LO, Oliveira AC, Nascimento PC, Miranda GHN, Ferreira RO, Nabiça M, Dantas K, Dionizio A, Cartágenes S, Buzalaf MAR, Crespo-Lopez ME, Maia CSF, Lima RR. Long-Term Lead Exposure Since Adolescence Causes Proteomic and Morphological Alterations in the Cerebellum Associated with Motor Deficits in Adult Rats. Int J Mol Sci 2020; 21:ijms21103571. [PMID: 32443589 PMCID: PMC7279001 DOI: 10.3390/ijms21103571] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 03/11/2020] [Accepted: 03/16/2020] [Indexed: 11/16/2022] Open
Abstract
Lead (Pb) is an environmental contaminant that presents a high risk for human health. We aimed to investigate the possible alterations triggered by the exposure to Pb acetate for a long period in motor performance and the possible relationship with biochemical, proteomic and morphological alterations in the cerebellum of rats. Male Wistar rats were exposed for 55 days, at 50 mg/Kg of Pb acetate, and the control animals received distilled water. Open field (OF) and rotarod tests; biochemistry parameters (MDA and nitrite); staining/immunostaining of Purkinje cells (PC), mature neurons (MN), myelin sheath (MS) and synaptic vesicles (SYN) and proteomic profile were analyzed. Pb deposition on the cerebellum area and this study drove to exploratory and locomotion deficits and a decrease in the number of PC, MN, SYN and MS staining/immunostaining. The levels of MDA and nitrite remained unchanged. The proteomic profile showed alterations in proteins responsible for neurotransmitters release, as well as receptor function and second messengers signaling, and also proteins involved in the process of apoptosis. Thus, we conclude that the long-term exposure to low Pb dose promoted locomotion and histological tracings, associated with alterations in the process of cell signaling, as well as death by apoptosis.
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Affiliation(s)
- Luana Ketlen Reis Leão
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, Belém, Pará 66075-110, Brazil; (L.K.R.L.); (L.O.B.); (A.C.O.); (P.C.N.); (G.H.N.M.); (R.O.F.)
| | - Leonardo Oliveira Bittencourt
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, Belém, Pará 66075-110, Brazil; (L.K.R.L.); (L.O.B.); (A.C.O.); (P.C.N.); (G.H.N.M.); (R.O.F.)
| | - Ana Carolina Oliveira
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, Belém, Pará 66075-110, Brazil; (L.K.R.L.); (L.O.B.); (A.C.O.); (P.C.N.); (G.H.N.M.); (R.O.F.)
| | - Priscila Cunha Nascimento
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, Belém, Pará 66075-110, Brazil; (L.K.R.L.); (L.O.B.); (A.C.O.); (P.C.N.); (G.H.N.M.); (R.O.F.)
| | - Giza Hellen Nonato Miranda
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, Belém, Pará 66075-110, Brazil; (L.K.R.L.); (L.O.B.); (A.C.O.); (P.C.N.); (G.H.N.M.); (R.O.F.)
| | - Railson Oliveira Ferreira
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, Belém, Pará 66075-110, Brazil; (L.K.R.L.); (L.O.B.); (A.C.O.); (P.C.N.); (G.H.N.M.); (R.O.F.)
| | - Mariane Nabiça
- Laboratory of Applied Analytical Spectrometry, Institute of Exact and Natural Sciences, Federal University of Pará - Belém, Pará 66075-110, Brazil; (M.N.); (K.D.)
| | - Kelly Dantas
- Laboratory of Applied Analytical Spectrometry, Institute of Exact and Natural Sciences, Federal University of Pará - Belém, Pará 66075-110, Brazil; (M.N.); (K.D.)
| | - Aline Dionizio
- Department of Biological Sciences, Bauru Dental School, University of São Paulo - Bauru, São Paulo 17012-901, Brazil; (A.D.); (M.A.R.B.)
| | - Sabrina Cartágenes
- Laboratory of Inflammation and Behavior Pharmacology, Pharmacy Faculty, Institute of Health Sciences, Federal University of Pará - Belém, Pará 66075-110, Brazil; (S.C.); (C.S.F.M.)
| | - Marília Afonso Rabelo Buzalaf
- Department of Biological Sciences, Bauru Dental School, University of São Paulo - Bauru, São Paulo 17012-901, Brazil; (A.D.); (M.A.R.B.)
| | - Maria Elena Crespo-Lopez
- Laboratory of Molecular Pharmacology, Institute of Biological Sciences, Federal University of Pará - Belém, Pará 66075-110, Brazil;
| | - Cristiane S F Maia
- Laboratory of Inflammation and Behavior Pharmacology, Pharmacy Faculty, Institute of Health Sciences, Federal University of Pará - Belém, Pará 66075-110, Brazil; (S.C.); (C.S.F.M.)
| | - Rafael Rodrigues Lima
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, Belém, Pará 66075-110, Brazil; (L.K.R.L.); (L.O.B.); (A.C.O.); (P.C.N.); (G.H.N.M.); (R.O.F.)
- Correspondence: ; Tel.: +55-91-3201-7891
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da Silva DRF, Bittencourt LO, Aragão WAB, Nascimento PC, Leão LKR, Oliveira ACA, Crespo-López ME, Lima RR. Long-term exposure to lead reduces antioxidant capacity and triggers motor neurons degeneration and demyelination in spinal cord of adult rats. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2020; 194:110358. [PMID: 32151863 DOI: 10.1016/j.ecoenv.2020.110358] [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: 09/22/2019] [Revised: 02/17/2020] [Accepted: 02/18/2020] [Indexed: 06/10/2023]
Abstract
Lead is a toxic metal found in environment with great neurotoxic potential. The main effect is associated with impairments in hippocampus and cerebellum, driving to cognitive and motor dysfunctions, however, there is a lack of evidences about the effects over the spinal cord. In this way, we aimed to investigate in vivo the effects of long-term exposure to lead acetate in oxidative biochemistry and morphology of rats' spinal cord. For this, 36 male Wistar rats (Rattus norvegicus) were divided into the group exposed to 50 mg/kg of lead acetate and control group, which received only distilled water, both groups through intragastric gavage, for 55 days. After the exposure period, the animals were euthanized and the spinal cords were collected to perform the analyses of lead levels quantification, oxidative biochemistry evaluation by levels of malondialdehyde (MDA), nitrites and the antioxidant capacity against peroxyl radicals (ACAP). Besides, morphological evaluation with quantitative analysis of mature and motor neurons and reactivity to myelin basic protein (MBP). Our results showed high levels of lead in spinal cord after long-term exposure; there was a reduction on ACAP level; however, there was no difference observed in MDA and nitrite levels. Moreover, there was a reduction of mature and motor neurons in all three regions, and a reduction of immunolabeling of MBP in the thoracic and lumbar segments. Therefore, we conclude that long-term exposure to lead is able of increasing the levels of the metal in spinal cord, affecting the antioxidant capacity and inducing morphological impairments in spinal cord parenchyma. Our results also suggest that the tissue impairments triggered by lead may be resultant from others molecular mechanisms besides the oxidative stress.
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Affiliation(s)
- Dannilo Roberto Ferreira da Silva
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, Belém, State of Pará, Brazil
| | - Leonardo Oliveira Bittencourt
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, Belém, State of Pará, Brazil
| | - Walessa Alana Bragança Aragão
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, Belém, State of Pará, Brazil
| | - Priscila Cunha Nascimento
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, Belém, State of Pará, Brazil
| | - Luana Ketlen Reis Leão
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, Belém, State of Pará, Brazil
| | - Ana Carolina Alves Oliveira
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, Belém, State of Pará, Brazil
| | - Maria Elena Crespo-López
- Laboratory of Molecular Pharmacology, Institute of Biological Sciences, Federal University of Pará, Belém, State of Pará, Brazil
| | - Rafael Rodrigues Lima
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, Belém, State of Pará, Brazil.
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Sex-Dependent Effects of Developmental Lead Exposure in Wistar Rats: Evidence from Behavioral and Molecular Correlates. Int J Mol Sci 2020; 21:ijms21082664. [PMID: 32290408 PMCID: PMC7216048 DOI: 10.3390/ijms21082664] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 04/06/2020] [Accepted: 04/09/2020] [Indexed: 12/11/2022] Open
Abstract
Lead (Pb) exposure in early life affects brain development resulting in cognitive and behavioral deficits. Epidemiologic and experimental evidence of sex as an effect modifier of developmental Pb exposure is emerging. In the present study, we investigated Pb effects on behavior and mechanisms of neuroplasticity in the hippocampus and potential sex differences. To this aim, dams were exposed, from one month pre-mating to offspring weaning, to Pb via drinking water at 5 mg/kg body weight per day. In the offspring of both sexes, the longitudinal assessment of motor, emotional, and cognitive end points was performed. We also evaluated the expression and synaptic distribution of N-methyl-D-Aspartate receptor (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits at post-natal day (pnd) 23 and 70 in the hippocampus. Neonatal motor patterns and explorative behavior in offspring were affected in both sexes. Pb effects in emotional response and memory retention were observed in adult females only, preceded by increased levels of GluN2A and GluA1 subunits at the post-synapse at pnd 23. These data suggest that Pb exposure during development affects glutamatergic receptors distribution at the post-synaptic spine in females. These effects may contribute to alterations in selected behavioral domains.
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Kynurenine Pathway as a New Target of Cognitive Impairment Induced by Lead Toxicity During the Lactation. Sci Rep 2020; 10:3184. [PMID: 32081969 PMCID: PMC7035386 DOI: 10.1038/s41598-020-60159-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 02/07/2020] [Indexed: 12/31/2022] Open
Abstract
The immature brain is especially vulnerable to lead (Pb2+) toxicity, which is considered an environmental neurotoxin. Pb2+ exposure during development compromises the cognitive and behavioral attributes which persist even later in adulthood, but the mechanisms involved in this effect are still unknown. On the other hand, the kynurenine pathway metabolites are modulators of different receptors and neurotransmitters related to cognition; specifically, high kynurenic acid levels has been involved with cognitive impairment, including deficits in spatial working memory and attention process. The aim of this study was to evaluate the relationship between the neurocognitive impairment induced by Pb2+ toxicity and the kynurenine pathway. The dams were divided in control group and Pb2+ group, which were given tap water or 500 ppm of lead acetate in drinking water ad libitum, respectively, from 0 to 23 postnatal day (PND). The poison was withdrawn, and tap water was given until 60 PND of the progeny. The locomotor activity in open field, redox environment, cellular function, kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK) levels as well as kynurenine aminotransferase (KAT) and kynurenine monooxygenase (KMO) activities were evaluated at both 23 and 60 PND. Additionally, learning and memory through buried food location test and expression of KAT and KMO, and cellular damage were evaluated at 60 PND. Pb2+ group showed redox environment alterations, cellular dysfunction and KYNA and 3-HK levels increased. No changes were observed in KAT activity. KMO activity increased at 23 PND and decreased at 60 PND. No changes in KAT and KMO expression in control and Pb2+ group were observed, however the number of positive cells expressing KMO and KAT increased in relation to control, which correlated with the loss of neuronal population. Cognitive impairment was observed in Pb2+ group which was correlated with KYNA levels. These results suggest that the increase in KYNA levels could be a mechanism by which Pb2+ induces cognitive impairment in adult mice, hence the modulation of kynurenine pathway represents a potential target to improve behavioural alterations produced by this environmental toxin.
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Shvachiy L, Geraldes V, Amaro-Leal Â, Rocha I. Persistent Effects on Cardiorespiratory and Nervous Systems Induced by Long-Term Lead Exposure: Results from a Longitudinal Study. Neurotox Res 2020; 37:857-870. [PMID: 31997153 DOI: 10.1007/s12640-020-00162-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 01/06/2020] [Accepted: 01/08/2020] [Indexed: 02/06/2023]
Abstract
Long-term lead (Pb) exposure alters the normal development of the nervous system and physiology. It affects multiple organ systems, causing hypertension, cardiorespiratory dysfunction, being a well-known neurotoxin, inducing changes in neurogenesis, neurodegeneration, and glial cells. However, studies of the developmental effects of lead and its outcomes throughout life are lacking. Determine morphofunctional, behavioral, and cognitive developmental effects of long-term lead exposure at three different ages. Wistar rats were exposed to a Pb-acetate solution from fetal period until adulthood and compared to a non-exposed control group. General behavior and cognitive skills were evaluated by behavioral tests and physiological data and cardiorespiratory reflexes measured. Neurodegeneration, neuroinflammation, and synaptic activity were assessed by immunohistochemistry. Lead exposure caused long-lasting anxiety-like behavior and strong long-term memory impairment without changes in locomotor and exploratory activity. Hypertension was observed at all time points, concomitant with baroreflex impairment and increased chemoreflex sensitivity. Persistent neuroinflammation, transient synaptic overexcitation without neurodegeneration was observed. Long-term Pb exposure, since fetal period, causes long-lasting anxiety-like behavior, concomitant with hypertension, without general motor skills impairment. Synaptic overexcitation, reactive astrogliosis, and microgliosis could underlie behavioral and long-term memory changes, which might have been caused during developmental phases and consolidated during adulthood. Also, alterations observed in the cardiorespiratory reflexes can explain persistent hypertension. This longitudinal study identifies and characterizes lead toxicity nature and magnitude, important to devise and test potential interventions to attenuate the long-term harmful effects of lead on the nervous and cardiovascular systems.
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Affiliation(s)
- Liana Shvachiy
- Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina, Universidade de Lisboa, Av Prof Egas Moniz, 1649-028, Lisbon, Portugal
| | - Vera Geraldes
- Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina, Universidade de Lisboa, Av Prof Egas Moniz, 1649-028, Lisbon, Portugal.
| | - Ângela Amaro-Leal
- Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina, Universidade de Lisboa, Av Prof Egas Moniz, 1649-028, Lisbon, Portugal
| | - Isabel Rocha
- Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina, Universidade de Lisboa, Av Prof Egas Moniz, 1649-028, Lisbon, Portugal
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Alvarez-Ortega N, Caballero-Gallardo K, Olivero-Verbel J. Toxicological effects in children exposed to lead: A cross-sectional study at the Colombian Caribbean coast. ENVIRONMENT INTERNATIONAL 2019; 130:104809. [PMID: 31302530 DOI: 10.1016/j.envint.2019.05.003] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 04/28/2019] [Accepted: 05/02/2019] [Indexed: 06/10/2023]
Abstract
Lead (Pb) is an environmental pollutant with a toxicity that is a serious public health problem. The aim of this research was to evaluate the associations between Pb exposure and morphometric, hematological and biochemical parameters, mRNA expression of the P53, SOD1, ALAD, TNF and INF-γ genes, ALAD polymorphisms (db SNP ID: rs1800435) and Intelligence Quotient (IQ) in children from the Colombian Caribbean. Blood lead levels (BLL) were determined in 554 participants between the ages of 5-16 years old, from different places of the Colombian Caribbean. A health survey was given to assess risk factors. Whole blood was used for hematology and plasma employed to analyze markers of hepatic toxicity. Gene expression was quantified from blood mRNA by RT-PCR. The ALAD polymorphism was characterized by PCR-RFLP, and the Kaufman's brief intelligence test was employed to estimate the IQ. The mean BLL was 3.5 ± 0.2 μg/dL. The site of greatest exposure to Pb was Tasajera, a poor fishing community, with an average of 8.9 ± 0.8 μg/dL. Breastfeeding was associated with high BLL. Morphometric characteristics and IQ were negatively correlated with BLL. The blood platelet count and the mean corpuscular hemoglobin concentration showed positive and negative correlations with BLL, respectively. Negative relationships with BLL were observed with the ratios Neutrophils/Eosinophils and Neutrophils/Basophils, whereas for BLL and Neutrophils/Monocytes the association was positive. The associations between morphometric and some hematological parameters with BLL were age- and gender-related. The expression of ALAD, SOD1, INF-γ and P53 mRNA was down-regulated according to the BLL, whereas TNF showed an opposite trend. In short, fishing communities are at a high risk of Pb exposure. This xenobiotic can affect physical development and IQ, as well as hematological parameters, even at low concentrations. In addition, it can regulate the transcription of genes associated with inflammation, apoptosis, cell cycle, heme synthesis, and oxidative stress.
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Affiliation(s)
- Neda Alvarez-Ortega
- Environmental and Computational Chemistry Group, School of Pharmaceutical Sciences, Zaragocilla Campus, University of Cartagena, Cartagena 130015, Colombia
| | - Karina Caballero-Gallardo
- Environmental and Computational Chemistry Group, School of Pharmaceutical Sciences, Zaragocilla Campus, University of Cartagena, Cartagena 130015, Colombia
| | - Jesus Olivero-Verbel
- Environmental and Computational Chemistry Group, School of Pharmaceutical Sciences, Zaragocilla Campus, University of Cartagena, Cartagena 130015, Colombia.
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Khalid M, Abdollahi M. Epigenetic modifications associated with pathophysiological effects of lead exposure. JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH. PART C, ENVIRONMENTAL CARCINOGENESIS & ECOTOXICOLOGY REVIEWS 2019; 37:235-287. [PMID: 31402779 DOI: 10.1080/10590501.2019.1640581] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Lead (Pb) exposure during different stages of development has demonstrated dose, duration, sex, and tissue-specific pathophysiological outcomes due to altered epigenetic regulation via (a) DNA methylation, (b) histone modifications, (c) miRNAs, and (d) chromatin accessibility. Pb-induced alteration of epigenetic regulation causes neurotoxic and extra-neurotoxic pathophysiological outcomes. Neurotoxic effects of Pb include dysfunction of memory and learning, behavioral disorder, attention deficit hyperactivity disorder, autism spectrum disorder, aging, Alzheimer's disease, tauopathy, and neurodegeneration. Extra-neurotoxic effects of Pb include altered body weight, metabolic disorder, cardiovascular disorders, hematopoietic disorder, and reproductive impairment. Pb exposure either early in life or at any stage of development results in undesirable pathophysiological outcomes that tends to sustain and maintain for a lifetime.
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Affiliation(s)
- Madiha Khalid
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Mohammad Abdollahi
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences (TUMS), Tehran, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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Fjelldal MF, Hadera MG, Kongstorp M, Austdal LPE, Šulović A, Andersen JM, Paulsen RE. Opioid receptor-mediated changes in the NMDA receptor in developing rat and chicken. Int J Dev Neurosci 2019; 78:19-27. [PMID: 31351113 DOI: 10.1016/j.ijdevneu.2019.07.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 07/09/2019] [Accepted: 07/23/2019] [Indexed: 11/30/2022] Open
Abstract
The use of opioids during pregnancy has been associated with neurodevelopmental toxicity in exposed children, leading to cognitive and behavioural deficits later in life. The N-methyl-D-aspartate receptor (NMDAR) subunit GluN2B plays critical roles in cerebellar development, and methadone has been shown to possess NMDAR antagonist effect. Consequently, we wanted to explore if prenatal opioid exposure affected GluN2B subunit expression and NMDAR function in rat and chicken cerebellum. Pregnant rats were exposed to methadone (10 mg/kg/day) or buprenorphine (1 mg/kg/day) for the whole period of gestation, using an osmotic minipump. To further examine potential effects of prenatal opioid exposure in a limited time window, chicken embryos were exposed to a 20 mg/kg dose of methadone or morphine on embryonic days 13 and 14. Western blot analysis of cerebella isolated from 14 days old rat pups exposed to buprenorphine showed significantly lower level of the GluN2B subunit, while the opioid exposed chicken embryo cerebellar GluN2B expression remained unaffected at embryonic day 17. However, we observed increased NMDA/glycine-induced calcium influx in cerebellar granule neurone cultures from opioid exposed chicken embryos. We conclude that prenatal opioid exposure leads to opioid receptor-dependent reduction in the postnatal expression of GluN2B in rat cerebella, and increase in NMDA-induced calcium influx in chicken embryo cerebella.
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Affiliation(s)
- Marthe Fredheim Fjelldal
- Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Norway
| | - Mussie Ghezu Hadera
- Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Norway
| | - Mette Kongstorp
- Section for Drug Abuse Research, Department of Forensic Sciences, Oslo University Hospital, Norway
| | - Lars Peter Engeset Austdal
- Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Norway
| | - Ana Šulović
- Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Norway
| | - Jannike Mørch Andersen
- Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Norway.,Section for Drug Abuse Research, Department of Forensic Sciences, Oslo University Hospital, Norway
| | - Ragnhild Elisabeth Paulsen
- Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Norway
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Lee H, Lee M, Kim HK, Kim YO, Kwon JT, Kim HJ. Influence of clozapine on neurodevelopmental protein expression and behavioral patterns in animal model of psychiatric disorder induced by low-level of lead. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY 2019; 23:467-474. [PMID: 31680768 PMCID: PMC6819901 DOI: 10.4196/kjpp.2019.23.6.467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 08/26/2019] [Accepted: 10/08/2019] [Indexed: 11/15/2022]
Abstract
Exposure to lead during pregnancy is a risk factor for the development of psychiatric disorders in the offspring. In this study, we investigated whether exposure to low levels of lead acetate (0.2%) in drinking water during pregnancy and lactation causes behavioral impairment and affects the expression of proteins associated with neurodevelopment. Lead exposure altered several parameters in rat offspring compared with those unexposed in open-field, social interaction, and pre-pulse inhibition tests. These parameters were restored to normal levels after clozapine treatment. Western blot and immunohistochemical analyses of the hippocampus revealed that several neurodevelopmental proteins were downregulated in lead-exposed rats. The expression was normalized after clozapine treatment (5 mg/kg/day, postnatal day 35–56). These findings demonstrate that downregulation of several proteins in lead-exposed rats affected subsequent behavioral changes. Our results suggest that lead exposure in early life may induce psychiatric disorders and treatment with antipsychotics such as clozapine may reduce their incidence.
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Affiliation(s)
- Hwayoung Lee
- Department of Clinical Pharmacology, College of Medicine, Soonchunhyang University, Cheonan 31151, Korea
| | - Minyoung Lee
- Department of Clinical Pharmacology, College of Medicine, Soonchunhyang University, Cheonan 31151, Korea
| | - Hyung-Ki Kim
- Department of Clinical Pharmacology, College of Medicine, Soonchunhyang University, Cheonan 31151, Korea
| | - Young Ock Kim
- Department of Bio-Environmental Chemistry, College of Agriculture and Life Sciences, Chungnam National University, Daejeon 34134, Korea
| | - Jun-Tack Kwon
- Department of Clinical Pharmacology, College of Medicine, Soonchunhyang University, Cheonan 31151, Korea
| | - Hak-Jae Kim
- Department of Clinical Pharmacology, College of Medicine, Soonchunhyang University, Cheonan 31151, Korea
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Nam SM, Cho IS, Seo JS, Go TH, Kim JH, Nahm SS, Chang BJ, Lee JH. Ascorbic Acid Attenuates Lead-Induced Alterations in the Synapses in the Developing Rat Cerebellum. Biol Trace Elem Res 2019; 187:142-150. [PMID: 29696534 DOI: 10.1007/s12011-018-1354-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 04/17/2018] [Indexed: 11/26/2022]
Abstract
We evaluated the effect of lead (Pb) and ascorbic acid treatment of pregnant female rats on cerebellar development in pups. Pb was administered in drinking water (0.2% Pb acetate), and ascorbic acid (100 mg/kg) was administered through oral intubation. Fifteen female rats were randomly classified into control, Pb, and Pb plus ascorbic acid (PA) groups. The treatment of Pb and ascorbic acid treatments were terminated after birth to evaluate the effects on the gestational development of the cerebellum. At postnatal day 21 (PND21), pups were sacrificed, and blood Pb level was analyzed. Blood Pb levels of pups and dams were highest in the Pb group and reduced in the PA group. Immunohistochemistry and immunoblot assays were conducted to study the cerebellar expression levels of synaptic proteins. Along with a significant reduction in Purkinje cells, the reduction in presynaptic (synaptophysin) and postsynaptic (postsynaptic density protein 95, N-methyl-D-aspartate receptor subtype 1) marker proteins was observed in Pb-exposed pups. Ascorbic acid treatment significantly prevented Pb-induced impairment in the cerebellar synaptic proteins. Hypothesizing that brain-derived neurotrophic factor (BDNF) might be affected by Pb exposure given its importance in the regulation of synaptogenesis, we observed a Pb-induced decrease and ascorbic acid-mediated increase of BDNF in the cerebellum. Luxol fast blue staining and myelin basic protein analysis suggest that ascorbic acid treatment ameliorated the Pb exposure-induced reduction in the axonal fibers in the developing cerebellum. Overall, we conclude that ascorbic acid treatment during pregnancy can prevent Pb-induced impairments in the cerebellar development in rats.
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Affiliation(s)
- Sung Min Nam
- Department of Anatomy, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05030, Republic of Korea
- College of Veterinary Medicine and Veterinary Science Research Institute, Konkuk University, Seoul, 05030, Republic of Korea
| | - In-Sun Cho
- Department of Anatomy, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05030, Republic of Korea
- Korea Bio-Safety Institute Co. Ltd, Eumseong, Chungbuk, 27600, Republic of Korea
| | - Jin Seok Seo
- Department of Anatomy, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05030, Republic of Korea
| | - Tae-Hun Go
- Department of Anatomy, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05030, Republic of Korea
| | - Ji-Hye Kim
- Department of Rehabilitation Psychology, Seoul Rehabilitation Hospital, Seoul, 03428, Republic of Korea
| | - Sang-Soep Nahm
- Department of Anatomy, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05030, Republic of Korea
- College of Veterinary Medicine and Veterinary Science Research Institute, Konkuk University, Seoul, 05030, Republic of Korea
| | - Byung-Joon Chang
- Department of Anatomy, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05030, Republic of Korea.
- College of Veterinary Medicine and Veterinary Science Research Institute, Konkuk University, Seoul, 05030, Republic of Korea.
| | - Jong-Hwan Lee
- Department of Anatomy, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05030, Republic of Korea.
- College of Veterinary Medicine and Veterinary Science Research Institute, Konkuk University, Seoul, 05030, Republic of Korea.
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Liu J, Gu X, Zou R, Nan W, Yang S, Wang HL, Chen XT. Phytohormone Abscisic Acid Improves Spatial Memory and Synaptogenesis Involving NDR1/2 Kinase in Rats. Front Pharmacol 2018; 9:1141. [PMID: 30356880 PMCID: PMC6190901 DOI: 10.3389/fphar.2018.01141] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 09/19/2018] [Indexed: 11/13/2022] Open
Abstract
The abscisic acid (ABA) is a phytohormone involved in plant growth, development and environmental stress response. Recent study showed ABA can also be detected in other organisms, including mammals. And it has been reported that ABA can improve learning and memory in rats. In this study, we attempted to investigate the effects of ABA on the alternation of dendritic spine morphology of pyramidal neurons in developmental rats, which may underlie the learning and memory function. Behavior tests showed that ABA significantly improved spatial memory performance. Meanwhile, Golgi-Cox staining assay showed that ABA significantly increased the spine density and the percentage of mushroom-like spines in pyramidal neurons of hippocampus, indicating that ABA increased dendritic spine formation and maturation, which may contribute to the improvement of spatial memory. Furthermore, ABA administration increased the protein expression of NDR1/2 kinase, as well as mRNA levels of NDR2 and its substrate Rabin8. In addition, NDR1/2 shRNA prohibited the ABA-induced increases in the expression of NDR1/2 and spine density. Together, our study indicated that ABA could improve learning and memory in rats and the effect are possibly through the regulation of synaptogenesis, which is mediated via NDR1/2 kinase pathway.
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Affiliation(s)
- Juanjuan Liu
- School of Food Science and Engineering, Hefei University of Technology, Hefei, China
| | - Xiaozhen Gu
- School of Food Science and Engineering, Hefei University of Technology, Hefei, China
| | - Rongxin Zou
- School of Food Science and Engineering, Hefei University of Technology, Hefei, China
| | - Wenping Nan
- School of Pharmacy, Anhui Medical University, Hefei, China
| | - Shaohua Yang
- School of Pharmacy, Anhui Medical University, Hefei, China
| | - Hui-Li Wang
- School of Food Science and Engineering, Hefei University of Technology, Hefei, China
| | - Xiang-Tao Chen
- School of Pharmacy, Anhui Medical University, Hefei, China
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Rahman A, Rao MS, Khan KM. Intraventricular infusion of quinolinic acid impairs spatial learning and memory in young rats: a novel mechanism of lead-induced neurotoxicity. J Neuroinflammation 2018; 15:263. [PMID: 30217162 PMCID: PMC6137743 DOI: 10.1186/s12974-018-1306-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 09/04/2018] [Indexed: 12/20/2022] Open
Abstract
Background Lead (Pb), a heavy metal, and quinolinic acid (QA), a metabolite of the kynurenine pathway of tryptophan metabolism, are known neurotoxicants. Both Pb and QA impair spatial learning and memory. Pb activates astrocytes and microglia, which in turn induce the synthesis of QA. We hypothesized increased QA production in response to Pb exposure as a novel mechanism of Pb-neurotoxicity. Methods Two experimental paradigms were used. In experiment one, Wistar rat pups were exposed to Pb via their dams’ drinking water from postnatal day 1 to 21. Control group was given regular water. In the second protocol, QA (9 mM) or normal saline (as Vehicle Control) was infused into right lateral ventricle of 21-day old rats for 7 days using osmotic pumps. Learning and memory were assessed by Morris water maze test on postnatal day 30 or 45 in both Pb- and QA-exposed rats. QA levels in the Pb exposed rats were measured in blood by ELISA and in the brain by immunohistochemistry on postnatal days 45 and 60. Expression of various molecules involved in learning and memory was analyzed by Western blot. Means of control and experimental groups were compared with two-way repeated measure ANOVA (learning) and t test (all other variables). Results Pb exposure increased QA level in the blood (by ~ 58%) and increased (p < 0.05) the number of QA-immunoreactive cells in the cortex, and CA1, CA3 and dentate gyrus regions of the hippocampus, compared to control rats. In separate experiments, QA infusion impaired learning and short-term memory similar to Pb. PSD-95, PP1, and PP2A were decreased (p < 0.05) in the QA-infused rats, whereas tau phosphorylation was increased, compared to vehicle infused rats. Conclusion Putting together the results of the two experimental paradigms, we propose that increased QA production in response to Pb exposure is a novel mechanism of Pb-induced neurotoxicity.
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Affiliation(s)
- Abdur Rahman
- Department of Food Science and Nutrition, College of Life Sciences, Kuwait University, Kuwait City, Kuwait.
| | - Muddanna S Rao
- Department of Anatomy, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Khalid M Khan
- Department of Anatomy, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
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Sachana M, Rolaki A, Bal-Price A. Development of the Adverse Outcome Pathway (AOP): Chronic binding of antagonist to N-methyl-d-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities of children. Toxicol Appl Pharmacol 2018; 354:153-175. [PMID: 29524501 PMCID: PMC6095943 DOI: 10.1016/j.taap.2018.02.024] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 02/26/2018] [Accepted: 02/28/2018] [Indexed: 01/06/2023]
Abstract
The Adverse Outcome Pathways (AOPs) are designed to provide mechanistic understanding of complex biological systems and pathways of toxicity that result in adverse outcomes (AOs) relevant to regulatory endpoints. AOP concept captures in a structured way the causal relationships resulting from initial chemical interaction with biological target(s) (molecular initiating event) to an AO manifested in individual organisms and/or populations through a sequential series of key events (KEs), which are cellular, anatomical and/or functional changes in biological processes. An AOP provides the mechanistic detail required to support chemical safety assessment, the development of alternative methods and the implementation of an integrated testing strategy. An example of the AOP relevant to developmental neurotoxicity (DNT) is described here following the requirements of information defined by the OECD Users' Handbook Supplement to the Guidance Document for developing and assessing AOPs. In this AOP, the binding of an antagonist to glutamate receptor N-methyl-d-aspartate (NMDAR) receptor is defined as MIE. This MIE triggers a cascade of cellular KEs including reduction of intracellular calcium levels, reduction of brain derived neurotrophic factor release, neuronal cell death, decreased glutamate presynaptic release and aberrant dendritic morphology. At organ level, the above mentioned KEs lead to decreased synaptogenesis and decreased neuronal network formation and function causing learning and memory deficit at organism level, which is defined as the AO. There are in vitro, in vivo and epidemiological data that support the described KEs and their causative relationships rendering this AOP relevant to DNT evaluation in the context of regulatory purposes.
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Affiliation(s)
| | | | - Anna Bal-Price
- European Commission, Joint Research Centre, Ispra, Italy.
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Sachana M, Rolaki A, Bal-Price A. Development of the Adverse Outcome Pathway (AOP): Chronic binding of antagonist to N-methyl-d-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities of children. Toxicol Appl Pharmacol 2018; 354:153-175. [PMID: 29524501 DOI: 10.1787/5jlsqs5hcrmq-en] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 02/26/2018] [Accepted: 02/28/2018] [Indexed: 05/20/2023]
Abstract
The Adverse Outcome Pathways (AOPs) are designed to provide mechanistic understanding of complex biological systems and pathways of toxicity that result in adverse outcomes (AOs) relevant to regulatory endpoints. AOP concept captures in a structured way the causal relationships resulting from initial chemical interaction with biological target(s) (molecular initiating event) to an AO manifested in individual organisms and/or populations through a sequential series of key events (KEs), which are cellular, anatomical and/or functional changes in biological processes. An AOP provides the mechanistic detail required to support chemical safety assessment, the development of alternative methods and the implementation of an integrated testing strategy. An example of the AOP relevant to developmental neurotoxicity (DNT) is described here following the requirements of information defined by the OECD Users' Handbook Supplement to the Guidance Document for developing and assessing AOPs. In this AOP, the binding of an antagonist to glutamate receptor N-methyl-d-aspartate (NMDAR) receptor is defined as MIE. This MIE triggers a cascade of cellular KEs including reduction of intracellular calcium levels, reduction of brain derived neurotrophic factor release, neuronal cell death, decreased glutamate presynaptic release and aberrant dendritic morphology. At organ level, the above mentioned KEs lead to decreased synaptogenesis and decreased neuronal network formation and function causing learning and memory deficit at organism level, which is defined as the AO. There are in vitro, in vivo and epidemiological data that support the described KEs and their causative relationships rendering this AOP relevant to DNT evaluation in the context of regulatory purposes.
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Affiliation(s)
| | | | - Anna Bal-Price
- European Commission, Joint Research Centre, Ispra, Italy.
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Jakaria M, Park SY, Haque ME, Karthivashan G, Kim IS, Ganesan P, Choi DK. Neurotoxic Agent-Induced Injury in Neurodegenerative Disease Model: Focus on Involvement of Glutamate Receptors. Front Mol Neurosci 2018; 11:307. [PMID: 30210294 PMCID: PMC6123546 DOI: 10.3389/fnmol.2018.00307] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 08/13/2018] [Indexed: 12/13/2022] Open
Abstract
Glutamate receptors play a crucial role in the central nervous system and are implicated in different brain disorders. They play a significant role in the pathogenesis of neurodegenerative diseases (NDDs) such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Although many studies on NDDs have been conducted, their exact pathophysiological characteristics are still not fully understood. In in vivo and in vitro models of neurotoxic-induced NDDs, neurotoxic agents are used to induce several neuronal injuries for the purpose of correlating them with the pathological characteristics of NDDs. Moreover, therapeutic drugs might be discovered based on the studies employing these models. In NDD models, different neurotoxic agents, namely, kainic acid, domoic acid, glutamate, β-N-Methylamino-L-alanine, amyloid beta, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 1-methyl-4-phenylpyridinium, rotenone, 3-Nitropropionic acid and methamphetamine can potently impair both ionotropic and metabotropic glutamate receptors, leading to the progression of toxicity. Many other neurotoxic agents mainly affect the functions of ionotropic glutamate receptors. We discuss particular neurotoxic agents that can act upon glutamate receptors so as to effectively mimic NDDs. The correlation of neurotoxic agent-induced disease characteristics with glutamate receptors would aid the discovery and development of therapeutic drugs for NDDs.
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Affiliation(s)
- Md. Jakaria
- Department of Applied Life Sciences, Graduate School, Konkuk University, Chungju, South Korea
| | - Shin-Young Park
- Department of Applied Life Sciences, Graduate School, Konkuk University, Chungju, South Korea
| | - Md. Ezazul Haque
- Department of Applied Life Sciences, Graduate School, Konkuk University, Chungju, South Korea
| | - Govindarajan Karthivashan
- Department of Integrated Bioscience and Biotechnology, College of Biomedical and Health Sciences, Research Institute of Inflammatory Diseases (RID), Konkuk University, Chungju, South Korea
| | - In-Su Kim
- Department of Integrated Bioscience and Biotechnology, College of Biomedical and Health Sciences, Research Institute of Inflammatory Diseases (RID), Konkuk University, Chungju, South Korea
| | - Palanivel Ganesan
- Department of Integrated Bioscience and Biotechnology, College of Biomedical and Health Sciences, Research Institute of Inflammatory Diseases (RID), Konkuk University, Chungju, South Korea
- Nanotechnology Research Center, Konkuk University, Chungju, South Korea
| | - Dong-Kug Choi
- Department of Applied Life Sciences, Graduate School, Konkuk University, Chungju, South Korea
- Department of Integrated Bioscience and Biotechnology, College of Biomedical and Health Sciences, Research Institute of Inflammatory Diseases (RID), Konkuk University, Chungju, South Korea
- Nanotechnology Research Center, Konkuk University, Chungju, South Korea
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Intermittent low-level lead exposure provokes anxiety, hypertension, autonomic dysfunction and neuroinflammation. Neurotoxicology 2018; 69:307-319. [PMID: 30098355 DOI: 10.1016/j.neuro.2018.08.001] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 07/31/2018] [Accepted: 08/04/2018] [Indexed: 01/14/2023]
Abstract
BACKGROUND Exposures to lead (Pb) during developmental phases can alter the normal course of development, with lifelong health consequences. Permanent Pb exposure leads to behavioral changes, cognitive impairment, sympathoexcitation, tachycardia, hypertension and autonomic dysfunction. However, the effects of an intermittent lead exposure are not yet studied. This pattern of exposure has been recently increasing due to migrations, implementation of school exchange programs and/or residential changes. OBJECTIVE To determine and compare lead effects on mammal's behavior and physiology, using a rat model of intermittent and permanent Pb exposures. METHODS Fetuses were intermittently (PbI) or permanently (PbP) exposed to water containing lead acetate (0.2% w/v) throughout life until adulthood (28 weeks of age). A control group (CTL) without any exposure to lead was also used. Anxiety was assessed by elevated plus maze (EPM) and locomotor activity and exploration by open field test (OFT). Blood pressure (BP), electrocardiogram (ECG), heart rate (HR), respiratory frequency (RF), sympathetic and parasympathetic activity and baro- and chemoreceptor reflex profiles were evaluated. Immunohistochemistry protocol for the assessment of neuroinflammation, neuronal loss (NeuN), gliosis and synaptic alterations (Iba-1, GFAP, Syn), were performed at the hippocampus. One-way ANOVA with Tukey's multiple comparison between means were used (significance p < 0.05) for statistical analysis. RESULTS The intermittent lead exposure produced a significant increase in diastolic and mean BP values, concomitant with a tendency to sympathetic overactivity (estimated by increased low-frequency power) and without significant changes in systolic BP, HR and RF. A chemoreceptor hypersensitivity and a baroreflex impairment were also observed, however, less pronounced when compared to the permanent exposure. Regarding behavioral changes, both lead exposure profiles showed an anxiety-like behavior without changes in locomotor and exploratory activity. Increase in GFAP and Iba-1 positive cells, without changes in NeuN positive cells were found in both exposed groups. Syn staining suffered a significant decrease in PbI group and a significant increase in PbP group. CONCLUSION This study is the first to show that developmental Pb exposure since fetal period can cause lasting impairments in physiological parameters. The intermittent lead exposure causes adverse health effects, i.e, hypertension, increased respiratory frequency and chemoreflex sensitivity, baroreflex impairment, anxiety, decreased synaptic activity, neuroinflammation and reactive gliosis, in some ways similar to a permanent exposure, however some are lower-grade, due to the shorter duration of exposure. This study brings new insights on the environmental factors that influence autonomic and cardiovascular systems during development, which can help in creating public policy strategies to prevent and control the adverse effects of Pb toxicity.
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Rooney JPK, Woods NF, Martin MD, Woods JS. Genetic polymorphisms of GRIN2A and GRIN2B modify the neurobehavioral effects of low-level lead exposure in children. ENVIRONMENTAL RESEARCH 2018; 165:1-10. [PMID: 29655037 PMCID: PMC5999567 DOI: 10.1016/j.envres.2018.04.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 03/31/2018] [Accepted: 04/02/2018] [Indexed: 05/10/2023]
Abstract
Lead (Pb) is neurotoxic and children are highly susceptible to this effect, particularly within the context of continuous low-level Pb exposure. A current major challenge is identification of children who may be uniquely susceptible to Pb toxicity because of genetic predisposition. Learning and memory are among the neurobehavioral processes that are most notably affected by Pb exposure, and modification of N-methyl-D-aspartate receptors (NMDAR) that regulate these processes during development are postulated to underlie these adverse effects of Pb. We examined the hypothesis that polymorphic variants of genes encoding glutamate receptor, ionotropic, NMDAR subunits 2A and 2B, GRIN2A and GRIN2B, exacerbate the adverse effects of Pb exposure on these processes in children. Participants were subjects who participated as children in the Casa Pia Dental Amalgam Clinical Trial and for whom baseline blood Pb concentrations and annual neurobehavioral test results over the 7 year course of the clinical trial were available. Genotyping assays were performed for variants of GRIN2A (rs727605 and rs1070503) and GRIN2B (rs7301328 and rs1806201) on biological samples acquired from 330 of the original 507 trial participants. Regression modeling strategies were employed to evaluate the association between genotype status, Pb exposure, and neurobehavioral test outcomes. Numerous significant adverse interaction effects between variants of both GRIN2A and GRIN2B, individually and in combination, and Pb exposure were observed particularly among boys, preferentially within the domains of Learning & Memory and Executive Function. In contrast, very few interaction effects were observed among similarly genotyped girls with comparable Pb exposure. These findings support observations of an essential role of GRIN2A and GRIN2B on developmental processes underlying learning and memory as well as other neurological functions in children and demonstrate, further, modification of Pb effects on these processes by specific variants of both GRIN2A and GRIN2B genes. These observations highlight the importance of genetic factors in defining susceptibility to Pb neurotoxicity and may have important public health implications for future strategies aimed at protecting children and adolescents from potential health risks associated with low-level Pb exposure.
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Affiliation(s)
- James P K Rooney
- Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland.
| | - Nancy F Woods
- Department of Biobehavioral Nursing and Health Informatics, University of Washington, Seattle, WA, USA
| | - Michael D Martin
- Departments of Oral Medicine and Epidemiology, University of Washington, Seattle, WA, USA
| | - James S Woods
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA
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