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Wu J, Yin Q, Wang Y, Wang R, Gong W, Chen Y, Zhang M, Liu Y, Ji Y. Integrated transcriptome and metabolomic analyses uncover the mechanism of cadmium-caused mouse spermatogonia apoptosis via inducing endoplasmic reticulum stress. Reprod Toxicol 2024; 129:108664. [PMID: 39038763 DOI: 10.1016/j.reprotox.2024.108664] [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: 04/18/2024] [Revised: 07/04/2024] [Accepted: 07/07/2024] [Indexed: 07/24/2024]
Abstract
Cadmium (Cd) is a well-recognized male reproductive toxicant that can cause testicular germ cell apoptosis. However, the underlying mechanism needs investigation. CG-1 mouse spermatogonia (spg) cells were treated with 20 μM cadmium chloride (CdCl2) for 24 h. Cell apoptosis was measured, and the expressions of key genes and protein biomarkers involved in endoplasmic reticulum (ER) stress were detected, respectively. Untargeted metabolomics was performed to identify different metabolites, and transcriptome analysis was conducted to screen differentially expressed genes (DEGs). Our results indicated that CdCl2 exposure caused cell apoptosis, and DEGs were involved in several apoptosis-related pathways. Moreover, CdCl2 exposure apparently increased the mRNA and protein expressions levels of both GRP78 and ATF6α, disrupting the expression of various metabolites, particularly amino acids. Conclusively, our study reveals the pathway of CdCl2 toxicity on mouse spg, providing a deep understanding of CdCl2-induced testicular toxicity.
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Affiliation(s)
- Jie Wu
- Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Qizi Yin
- Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Yi Wang
- Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Rong Wang
- Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Wenjing Gong
- Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Yihang Chen
- Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Mingming Zhang
- Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Yehao Liu
- Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China.
| | - Yanli Ji
- Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China.
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Ling Q, Zhang YF, Chang W, Liu ST, Zhu HL, Wang H. NBR1-dependent autophagy activation protects against environmental cadmium-evoked placental trophoblast senescence. CHEMOSPHERE 2024; 358:142138. [PMID: 38670504 DOI: 10.1016/j.chemosphere.2024.142138] [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: 01/03/2024] [Revised: 03/27/2024] [Accepted: 04/23/2024] [Indexed: 04/28/2024]
Abstract
Cadmium (Cd), a well-established developmental toxicant, accumulates in the placentae and disrupts its structure and function. Population study found adverse pregnancy outcomes caused by environmental Cd exposure associated with cell senescence. However, the role of autophagy activation in Cd-induced placental cell senescence and its reciprocal mechanisms are unknown. In this study, we employed animal experiments, cell culture, and case-control study to investigate the above mentioned. We have demonstrated that exposure to Cd during gestation induces placental senescence and activates autophagy. Pharmacological and genetic interventions further exacerbated placental senescence induced by Cd through the suppression of autophagy. Conversely, activation of autophagy ameliorated Cd-induced placental senescence. Knockdown of NBR1 exacerbated senescence in human placental trophoblast cells. Further investigations revealed that NBR1 facilitated the degradation of p21 via LC3B. Our case-control study has demonstrated a positive correlation between placental senescence and autophagy activation in all-cause fetal growth restriction (FGR). These findings offer a novel perspective for mitigating placental aging and placental-origin developmental diseases induced by environmental toxicants.
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Affiliation(s)
- Qing Ling
- Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China
| | - Yu-Feng Zhang
- Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China; Teaching and Research Section of Nuclear Medicine, School of Basic Medical Sciences, Anhui Medica University, China
| | - Wei Chang
- Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China
| | - Si-Ting Liu
- Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China
| | - Hua-Long Zhu
- Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, China
| | - Hua Wang
- Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, China.
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Wang R, Li M, Wu Z, Gong W, Zhang M, Liu Y, Yao Y, Ji Y. PBA alleviates cadmium-induced mouse spermatogonia apoptosis by suppressing endoplasmic reticulum stress. Toxicol In Vitro 2024; 96:105784. [PMID: 38242296 DOI: 10.1016/j.tiv.2024.105784] [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: 08/17/2023] [Revised: 09/17/2023] [Accepted: 01/16/2024] [Indexed: 01/21/2024]
Abstract
OBJECTIVE Endoplasmic reticulum (ER) stress mediates Cd-caused germ cell apoptosis in testis. The effects of 4-phenylbutyric acid (PBA), a classical chaperone, were investigated on Cd-induced apoptosis in mouse GC-1 spermatogonia cells. METHODS The cells were pretreated with PBA before Cd exposure. TUNEL and flow cytometry assays were applied to determine apoptosis. Some key biomarkers of ER stress were analyzed using RT-PCR and western blot. RESULTS as expected, the apoptotic cells exposed to Cd apparently increased. The mRNA and protein expression levels of GRP78 and ATF6α, were elevated in the Cd groups. Additional experiments displayed that Cd notably increased IRE1α and JNK phosphorylation, and upregulated XBP-1 mRNA and protein expression. Moreover, p-eIF2α and CHOP expressions were clearly elevated in the Cd groups. Interestingly, PBA almost completely inhibited ER stress and protected spermatogonia against apoptosis induced by Cd. CONCLUSION PBA alleviated Cd-induced ER stress and spermatogonia apoptosis, and may have the therapeutic role in Cd-induced male reproductive toxicity.
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Affiliation(s)
- Rong Wang
- Department of health inspection and quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Department of Histology and Embryology, Anhui Medical University, Hefei, China
| | - Mengyuan Li
- Department of health inspection and quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Zhen Wu
- Department of health inspection and quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China; The People's Hospital of Bozhou, Anhui, China
| | - Wenjing Gong
- Department of health inspection and quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Mingming Zhang
- Department of health inspection and quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Yehao Liu
- Department of health inspection and quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Anhui Provincial Key Laboratory of Population Health and Aristogenics / Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University; Hefei Anhui, China
| | - Yuyou Yao
- Department of health inspection and quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Anhui Provincial Key Laboratory of Population Health and Aristogenics / Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University; Hefei Anhui, China.
| | - Yanli Ji
- Department of health inspection and quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Anhui Provincial Key Laboratory of Population Health and Aristogenics / Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University; Hefei Anhui, China.
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Li Y, Yang L, Su P, Chen N. Curcumin protects against cadmium-induced germ cell death in the testis of rats. Toxicol Res (Camb) 2024; 13:tfae082. [PMID: 38841432 PMCID: PMC11149375 DOI: 10.1093/toxres/tfae082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 03/26/2024] [Accepted: 05/10/2024] [Indexed: 06/07/2024] Open
Abstract
Introduction Cadmium (Cd) has been shown to disrupt the reproductive system. In this study, we evaluated the protective effects of Curcumin (Cur) against Cd-induced reproductive toxicity. Methods Exploring the role of Cur in Cd-treated rat models. Results The study demonstrated that Cd treatment impaired the seminiferous epithelium, leading to increased apoptosis of germ cells. Interestingly, pretreatment with Cur ameliorated the histological damage and decreased the germ cell apoptosis induced by Cd. Furthermore, after Cd exposure, B-cell lymphoma-2 expression was significantly decreased while Bax expression was increased. Pretreatment of rats with Cur protected against germ cell apoptosis by improving the expression of B-cell lymphoma-2 and reducing Bax. Additionally, Cd treatment increased reactive oxygen species, resulting in a decrease in antioxidant enzymes. However, pretreatment of rats with Cur followed by Cd administration led to a substantial decrease in reactive oxygen species levels and increased activities of antioxidant enzymes. Ultrastructural investigations revealed that damage to the mitochondrial structure was significantly ameliorated by Cur pretreatment in Cd-treated rats. Notably, Cur significantly activated the peroxisome proliferator-activated receptor gamma coactivator 1a/Sirtuins-3 signaling pathway. Conclusions Overall, our data suggest that Cd induces germ cell apoptosis through mitochondrial-induced oxidative stress, but Cur pretreatment offers strong protection against Cd-induced reproductive toxicity.
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Affiliation(s)
- Yamin Li
- Department of Woman's Health Care, Maternal and Child Health Hospital of Hubei Province, 745 Luoyu Avenue, Wuhan, Hubei 430071, P. R. China
| | - Lu Yang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, P. R. China
| | - Ping Su
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, 13 HangkongAvenue, Wuhan 430030, P. R. China
| | - Na Chen
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, P. R. China
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Cirovic A, Satarug S. Toxicity Tolerance in the Carcinogenesis of Environmental Cadmium. Int J Mol Sci 2024; 25:1851. [PMID: 38339129 PMCID: PMC10855822 DOI: 10.3390/ijms25031851] [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: 01/13/2024] [Revised: 01/31/2024] [Accepted: 02/01/2024] [Indexed: 02/12/2024] Open
Abstract
Cadmium (Cd) is an environmental toxicant of worldwide public health significance. Diet is the main non-workplace Cd exposure source other than passive and active smoking. The intestinal absorption of Cd involves transporters for essential metals, notably iron and zinc. These transporters determine the Cd body burden because only a minuscule amount of Cd can be excreted each day. The International Agency for Research on Cancer listed Cd as a human lung carcinogen, but the current evidence suggests that the effects of Cd on cancer risk extend beyond the lung. A two-year bioassay demonstrated that Cd caused neoplasms in multiple tissues of mice. Also, several non-tumorigenic human cells transformed to malignant cells when they were exposed to a sublethal dose of Cd for a prolonged time. Cd does not directly damage DNA, but it influences gene expression through interactions with essential metals and various proteins. The present review highlights the epidemiological studies that connect an enhanced risk of various neoplastic diseases to chronic exposure to environmental Cd. Special emphasis is given to the impact of body iron stores on the absorption of Cd, and its implications for breast cancer prevention in highly susceptible groups of women. Resistance to cell death and other cancer phenotypes acquired during Cd-induced cancer cell transformation, under in vitro conditions, are briefly discussed. The potential role for the ZnT1 efflux transporter in the cellular acquisition of tolerance to Cd cytotoxicity is highlighted.
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Affiliation(s)
- Aleksandar Cirovic
- Institute of Anatomy, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Soisungwan Satarug
- Kidney Disease Research Collaborative, Translational Research Institute, Woolloongabba, Brisbane, QLD 4102, Australia
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Zhang R, Walker L, Wen X, Doherty C, Gorczyca L, Buckley B, Barrett ES, Aleksunes LM. Placental BCRP transporter reduces cadmium accumulation and toxicity in immortalized human trophoblasts. Reprod Toxicol 2023; 121:108466. [PMID: 37660740 PMCID: PMC10591833 DOI: 10.1016/j.reprotox.2023.108466] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/20/2023] [Accepted: 08/28/2023] [Indexed: 09/05/2023]
Abstract
Cadmium (Cd) is a ubiquitous environmental metal detectable in most pregnant women. Animal and human studies demonstrate that in utero exposure to Cd reduces birth weight and impairs perinatal growth due to placental toxicity. BCRP is a prominent transporter that can efflux xenobiotics from the placenta. This study sought to investigate Cd transport and toxicity in cultured human BeWo trophoblasts with reduced expression and function of the placental barrier transporter BCRP. Knockdown (KD) of BCRP protein expression and function in BeWo trophoblasts increased the intracellular accumulation of Cd by 100% following treatment with 1 μM CdCl2. No change in the expression of Cd uptake transporters was observed between control and BCRP-KD cells. Reduced BCRP expression impaired viability of BeWo cells exposed to CdCl2 for 48 hr (BCRP-KD IC50: 11 μM, control cells IC50: 18 μM). Moreover, BCRP-KD cells were more sensitive to CdCl2-induced cytotoxicity compared to control BeWo cells. CdCl2 treatment strongly induced the expression of the metal-binding protein metallothionein (MT) in both control and BCRP-KD cells, with significantly greater MT upregulation in Cd-treated BCRP-KD cells. These data suggest that the BCRP transporter reduces Cd accumulation in syncytiotrophoblasts, which may be one mechanism to reduce subsequent toxicity to the placenta and developing fetus.
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Affiliation(s)
- Ranran Zhang
- Department of Biostatistics and Epidemiology, Rutgers University, Piscataway, NJ 08854, USA
| | - Lauren Walker
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA
| | - Xia Wen
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA; Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA
| | - Cathleen Doherty
- Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA
| | - Ludwik Gorczyca
- Joint Graduate Program in Toxicology, Rutgers University, Piscataway, NJ 08854, USA
| | - Brian Buckley
- Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA
| | - Emily S Barrett
- Department of Biostatistics and Epidemiology, Rutgers University, Piscataway, NJ 08854, USA; Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA
| | - Lauren M Aleksunes
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA; Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA.
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7
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Kozlosky D, Lu A, Doherty C, Buckley B, Goedken MJ, Miller RK, Barrett ES, Aleksunes LM. Cadmium reduces growth of male fetuses by impairing development of the placental vasculature and reducing expression of nutrient transporters. Toxicol Appl Pharmacol 2023; 475:116636. [PMID: 37487938 PMCID: PMC10528997 DOI: 10.1016/j.taap.2023.116636] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 07/12/2023] [Accepted: 07/21/2023] [Indexed: 07/26/2023]
Abstract
In utero exposure to the toxic metal cadmium (Cd) alters fetoplacental growth in rodents and has been inversely associated with birth weight and infant size in some birth cohorts. Moreover, studies suggest that Cd may have differential effects on growth and development according to offspring sex. The purpose of the current study was to evaluate changes in male and female fetoplacental development following a single injection of saline (5 ml/kg ip) or cadmium chloride (CdCl2, 2.5, 5 mg/kg, ip) on gestational day (GD) 9. By GD18, no changes in fetal or placental weights were observed after treatment with 2.5 mg/kg CdCl2. By comparison, the weight and length of male fetuses and their placentas were reduced following treatment with 5 mg/kg CdCl2 whereas no change was observed in females. In addition, the area of maternal and fetal blood vessels as well as the expression of the glucose transporters, Glut1 and Glut3, and the endothelial marker, CD34, were reduced in the placentas of CdCl2-treated male offspring compared to females. Interestingly, the placentas of females accumulated 80% more Cd than males after CdCl2 (5 mg/kg) administration. Female placentas also had higher concentrations of zinc and the zinc transporter Znt1 compared to males which may explain the limited changes in fetal growth observed following CdCl2 treatment. Taken together, disruption of vasculature development and reduced expression of glucose transporters in the placenta provide potential mechanisms underlying reduced fetal growth in male offspring despite the greater accumulation of Cd in female placentas.
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Affiliation(s)
- Danielle Kozlosky
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, NJ 08854, USA
| | - Alexander Lu
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, NJ 08854, USA
| | - Cathleen Doherty
- Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA..
| | - Brian Buckley
- Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA..
| | - Michael J Goedken
- Research Pathology Services, Rutgers University, Piscataway, NJ 08854, USA..
| | - Richard K Miller
- School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY 14642, USA..
| | - Emily S Barrett
- Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA.; School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY 14642, USA.; Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, NJ 08854, USA..
| | - Lauren M Aleksunes
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, NJ 08854, USA.; Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA..
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Lu H, Ke Z, Feng L, Liu B. Voltammetric sensing of Cd(II) at ZIF-8/GO modified electrode: Optimization and field measurements. CHEMOSPHERE 2023; 329:138710. [PMID: 37068613 DOI: 10.1016/j.chemosphere.2023.138710] [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: 01/13/2023] [Revised: 03/31/2023] [Accepted: 04/14/2023] [Indexed: 05/03/2023]
Abstract
In this work, a metal-organic framework/graphene oxide (MOF(ZIF-8)/GO) nanocomposite was utilized for the electroanalysis of trace level of Cd(II) after modification of a cheap graphite rod electrode (GRE). After closed circuit process on the modified electrode, the differential pulse anodic stripping voltammetry (DPASV) technique was used for measuring of Cd(II). In optimal conditions, the sensor showed a linear dependence of current with concentration range 0.1-30 ppb for Cd(II). Moreover, limit of detection 0.03 ppb were obtained. Besides good selectivity, the sensor also indicated good reproducibility (below 5%). Moreover, the sensor showed satisfactory sensing performance in river, dam and wastewater samples with recovery ranging from 97.2% to 102.4%. Additionally, possible interfering cations were examined, but no significant interference was found. For the detection of trace Cd(II) in real matrices, this sensor illustrated other good merits like high stability, rapidity and simplicity.
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Affiliation(s)
- Haitao Lu
- School of Civil and Transportation Engineering, Guangdong University of Technology, Guangzhou, 510006, Guangdong, China
| | - Zijie Ke
- School of Civil and Transportation Engineering, Guangdong University of Technology, Guangzhou, 510006, Guangdong, China
| | - Li Feng
- School of Civil and Transportation Engineering, Guangdong University of Technology, Guangzhou, 510006, Guangdong, China.
| | - Bingzhi Liu
- School of Civil and Transportation Engineering, Guangdong University of Technology, Guangzhou, 510006, Guangdong, China
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Obaid AA, Almasmoum H, Almaimani RA, El-Boshy M, Aslam A, Idris S, Ghaith MM, El-Readi MZ, Ahmad J, Farrash WF, Mujalli A, Eid SY, Elzubier ME, Refaat B. Vitamin D and calcium co-therapy mitigates pre-established cadmium nephropathy by regulating renal calcium homeostatic molecules and improving anti-oxidative and anti-inflammatory activities in rat. J Trace Elem Med Biol 2023; 79:127221. [PMID: 37244046 DOI: 10.1016/j.jtemb.2023.127221] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 05/21/2023] [Accepted: 05/22/2023] [Indexed: 05/29/2023]
Abstract
BACKGROUND Cadmium (Cd) is a major environmental pollutant and chronic toxicity could induce nephropathy by increasing renal oxidative stress and inflammation. Although vitamin D (VD) and calcium (Ca) prophylactic treatments attenuated Cd-induced cell injury, none of the prior studies measure their renoprotective effects against pre-established Cd-nephropathy. AIMS To measure the alleviating effects of VD and/or Ca single and dual therapies against pre-established nephrotoxicity induced by chronic Cd toxicity prior to treatment initiation. METHODS Forty male adult rats were allocated into: negative controls (NC), positive controls (PC), Ca, VD and VC groups. The study lasted for eight weeks and all animals, except the NC, received CdCl2 in drinking water (44 mg/L) throughout the study. Ca (100 mg/kg) and/or VD (350 IU/kg) were given (five times/week) during the last four weeks to the designated groups. Subsequently, the expression of transforming growth factor-β (TGF-β1), inducible nitric oxide synthase (iNOS), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), VD synthesising (Cyp27b1) and catabolizing (Cyp24a1) enzymes with VD receptor (VDR) and binding protein (VDBP) was measured in renal tissues. Similarly, renal expression of Ca voltage-dependent channels (CaV1.1/CaV3.1), store-operated channels (RyR1/ITPR1), and binding proteins (CAM/CAMKIIA/S100A1/S100B) were measured. Serum markers of renal function alongside several markers of oxidative stress (MDA/H2O2/GSH/GPx/CAT) and inflammation (IL-6/TNF-α/IL-10) together with renal cell apoptosis and expression of caspase-3 were also measured. RESULTS The PC group exhibited hypovitaminosis D, hypocalcaemia, hypercalciuria, proteinuria, reduced creatinine clearance, and increased renal apoptosis/necrosis with higher caspase-3 expression. Markers of renal tissue damage (TGF-β1/iNOS/NGAL/KIM-1), oxidative stress (MDA/H2O2), and inflammation (TNF-α/IL-1β/IL-6) increased, whilst the antioxidants (GSH/GPx/CAT) and IL-10 decreased, in the PC group. The PC renal tissues also showed abnormal expression of Cyp27b1, Cyp24a1, VDR, and VDBP, alongside Ca-membranous (CaV1.1/CaV3.1) and store-operated channels (RyR1/ITPR1) and cytosolic Ca-binding proteins (CAM/CAMKIIA/S100A1/S100B). Although VD was superior to Ca monotherapy, their combination revealed the best mitigation effects by attenuating serum and renal tissue Cd concentrations, inflammation and oxidative stress, alongside modulating the expression of VD/Ca-molecules. CONCLUSIONS This study is the first to show improved alleviations against Cd-nephropathy by co-supplementing VD and Ca, possibly by better regulation of Ca-dependent anti-oxidative and anti-inflammatory actions.
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Affiliation(s)
- Ahmad A Obaid
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | - Hussain Almasmoum
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | - Riyad A Almaimani
- Biochemistry Department, Faculty of Medicine, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | - Mohamed El-Boshy
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia; Clinical Pathology Department, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Akhmed Aslam
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | - Shakir Idris
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | - Mazen M Ghaith
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | - Mahmoud Z El-Readi
- Biochemistry Department, Faculty of Medicine, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia; Biochemistry Department, Faculty of Pharmacy, Al-Azhar University, Assuit 71524, Egypt
| | - Jawwad Ahmad
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | - Wesam F Farrash
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | - Abdulrahman Mujalli
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | - Safaa Y Eid
- Biochemistry Department, Faculty of Medicine, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | - Mohamed E Elzubier
- Biochemistry Department, Faculty of Medicine, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | - Bassem Refaat
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia.
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Li N, Yi BJ, Saleem MAU, Li XN, Li JL. Autophagy protects against Cd-induced cell damage in primary chicken hepatocytes via mitigation of oxidative stress and endoplasmic reticulum stress. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 259:115056. [PMID: 37229871 DOI: 10.1016/j.ecoenv.2023.115056] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 05/17/2023] [Accepted: 05/21/2023] [Indexed: 05/27/2023]
Abstract
Cadmium (Cd) is widespread globally in the environment as a toxic metal. Although it is well known to induce hepatotoxicity in the cells, defense mechanisms against the detrimental effects of Cd are still unknown. We examined the role of autophagy (a cellular defense mechanism) on Cd-induced cytotoxicity in bird hepatocytes. Primary chicken hepatocytes were cultured with different concentrations (0, 1, 2.5, 5, and 10 μM) of cadmium chloride (CdCl2) for 12 h. We assessed the effects of CdCl2 on the cell viability, antioxidant status, reactive oxygen species (ROS) generation, autophagy response and endoplasmic reticulum (ER) stress. Further, it is also evaluated that insight into underling molecular mechanisms involved in the study. In this study, CdCl2-induce hepatotoxicity was caused by drastically increased ROS generation as well as a reduction level of antioxidant enzymes. It was also demonstrated that marked activation of ER stress markers (GRP78, IRE1, PERK, ATF4, ATF6 and XBP-1 s) was observed. Simultaneously, increased activation of autophagy in low-dose CdCl2 (1 μM) exposed group was observed, but high-dose CdCl2 (10 μM) inhibited autophagy and significantly promoted apoptosis, as indicated by the expression of the autophagy related genes for P62, Beclin-1, ATG3, ATG5, ATG9, and the detection of autophagic vacuoles. Pretreatment with autophagy agonist Rapamycin (RAP) has successfully reduced ROS production, attenuated ER stress and enhanced hepatocytes viability, while the autophagy inhibitor 3-Methyladenine (3-MA) had the opposite effect. Hence, these findings stipulate that Cd could inhibit viability of hepatocytes in a dose-dependent manner. Autophagy relieves hepatotoxicity of Cd via reducing ROS generation and regulating ER stress. We identified autophagy as a novel protective mechanism involved in Cd-mediated chicken hepatotoxicity.
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Affiliation(s)
- Nan Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; National Research Institute for Family Planning, Beijing 100081, PR China
| | - Bao-Jin Yi
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | | | - Xue-Nan Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin 150030, PR China; Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Northeast Agricultural University, Harbin 150030, PR China.
| | - Jin-Long Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin 150030, PR China.
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11
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Wang Y, Wu J, Zhang M, OuYang H, Li M, Jia D, Wang R, Zhou W, Liu H, Hu Y, Yao Y, Liu Y, Ji Y. Cadmium exposure during puberty damages testicular development and spermatogenesis via ferroptosis caused by intracellular iron overload and oxidative stress in mice. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2023; 325:121434. [PMID: 36907243 DOI: 10.1016/j.envpol.2023.121434] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 02/27/2023] [Accepted: 03/09/2023] [Indexed: 06/18/2023]
Abstract
Cadmium (Cd) is a widespread environmental pollutant and a reproductive toxicant. It has been proved that Cd can reduce male fertility, however, the molecular mechanisms remain unveiled. This study aims to explore the effects and mechanisms of pubertal Cd exposure on testicular development and spermatogenesis. The results showed that Cd exposure during puberty could cause pathological damage to testes and reduce sperm counts in mice in adulthood. Moreover, Cd exposure during puberty reduced GSH content, induced iron overload and ROS production in testes, suggesting that Cd exposure during puberty may induce testicular ferroptosis. The results in vitro experiments further strengthened that Cd caused iron overload and oxidative stress, and decreased MMP in GC-1 spg cells. In addition, Cd disturbed intracellular iron homeostasis and peroxidation signal pathway based on transcriptomics analysis. Interestingly, these changes induced by Cd could be partially suppressed by pretreated with ferroptotic inhibitors, Ferrostatin-1 and Deferoxamine mesylate. In conclusion, the study demonstrated that Cd exposure during puberty maybe disrupted intracellular iron metabolism and peroxidation signal pathway, triggered ferroptosis in spermatogonia, and ultimately damaged testicular development and spermatogenesis in mice in adulthood.
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Affiliation(s)
- Yi Wang
- Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Jie Wu
- Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Mingming Zhang
- Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Huijuan OuYang
- Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Mengyuan Li
- Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Didi Jia
- Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Rong Wang
- Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Weiyi Zhou
- Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Hao Liu
- Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Yuan Hu
- Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Yuyou Yao
- Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Yehao Liu
- Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - YanLi Ji
- Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China.
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12
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Smereczański NM, Brzóska MM. Current Levels of Environmental Exposure to Cadmium in Industrialized Countries as a Risk Factor for Kidney Damage in the General Population: A Comprehensive Review of Available Data. Int J Mol Sci 2023; 24:ijms24098413. [PMID: 37176121 PMCID: PMC10179615 DOI: 10.3390/ijms24098413] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/01/2023] [Accepted: 05/03/2023] [Indexed: 05/15/2023] Open
Abstract
The growing number of reports indicating unfavorable outcomes for human health upon environmental exposure to cadmium (Cd) have focused attention on the threat to the general population posed by this heavy metal. The kidney is a target organ during chronic Cd intoxication. The aim of this article was to critically review the available literature on the impact of the current levels of environmental exposure to this xenobiotic in industrialized countries on the kidney, and to evaluate the associated risk of organ damage, including chronic kidney disease (CKD). Based on a comprehensive review of the available data, we recognized that the observed adverse effect levels (NOAELs) of Cd concentration in the blood and urine for clinically relevant kidney damage (glomerular dysfunction) are 0.18 μg/L and 0.27 μg/g creatinine, respectively, whereas the lowest observed adverse effect levels (LOAELs) are >0.18 μg/L and >0.27 μg/g creatinine, respectively, which are within the lower range of concentrations noted in inhabitants of industrialized countries. In conclusion, the current levels of environmental exposure to Cd may increase the risk of clinically relevant kidney damage, resulting in, or at least contributing to, the development of CKD.
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Affiliation(s)
- Nazar M Smereczański
- Department of Toxicology, Medical University of Bialystok, Adama Mickiewicza 2C Street, 15-222 Bialystok, Poland
| | - Małgorzata M Brzóska
- Department of Toxicology, Medical University of Bialystok, Adama Mickiewicza 2C Street, 15-222 Bialystok, Poland
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13
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Kim J, Song H, Lee J, Kim YJ, Chung HS, Yu JM, Jang G, Park R, Chung W, Oh CM, Moon S. Smoking and passive smoking increases mortality through mediation effect of cadmium exposure in the United States. Sci Rep 2023; 13:3878. [PMID: 36890267 PMCID: PMC9995499 DOI: 10.1038/s41598-023-30988-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 03/03/2023] [Indexed: 03/10/2023] Open
Abstract
Cigarette smoking is one of the leading causes of preventable and premature death worldwide. Even worse, many people are generally exposed to passive smoking, which leads to several respiratory diseases and related mortalities. Considering, more than 7000 compounds are included in cigarettes, their combustion results intoxicants that have deleterious effects on health. However, there is a lack of research analyzing the effects of smoking and passive smoking on all-cause and disease-specific mortality through its chemical compounds including heavy metals. Thus, this study aimed to evaluate the effect of smoking and passive smoking on all-cause and disease-specific mortality mediated by cadmium, one of the representative smoking-related heavy metals using data from the National Health and Nutrition Examination Survey (NHANES) 1999-2018 in the United States. We found that current smoking and passive smoking was related to increased risk of all-cause, CVD-related, and cancer-related mortality. Notably, passive smoking showed a synergistic effect with smoking status on the risk of mortality. In particular, current smokers with passive smoking had the highest risk of all-cause and disease-specific deaths. In addition, the accumulation of cadmium in the blood due to smoking and passive smoking mediates the increased risk of all-cause mortality. Further studies are needed to monitor and treat cadmium toxicity to improve smoking-related mortality rates.
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Affiliation(s)
- Joon Kim
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Hangyul Song
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Junghoon Lee
- Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Yoon Jung Kim
- Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Hye Soo Chung
- Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Jae Myung Yu
- Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Gyuho Jang
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Raekil Park
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Wankyo Chung
- Department of Public Health Science, Graduate School of Public Health, Seoul National University, Seoul, Korea
| | - Chang-Myung Oh
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea.
| | - Shinje Moon
- Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea.
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14
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Liu C, Li H, Duan W, Duan Y, Yu Q, Zhang T, Sun Y, Li Y, Liu Y, Xu S. MCU Upregulation Overactivates Mitophagy by Promoting VDAC1 Dimerization and Ubiquitination in the Hepatotoxicity of Cadmium. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2203869. [PMID: 36642847 PMCID: PMC9982555 DOI: 10.1002/advs.202203869] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 12/09/2022] [Indexed: 06/17/2023]
Abstract
Cadmium (Cd) is a high-risk pathogenic toxin for hepatic diseases. Excessive mitophagy is a hallmark in Cd-induced hepatotoxicity. However, the underlying mechanism remains obscure. Mitochondrial calcium uniporter (MCU) is a key regulator for mitochondrial and cellular homeostasis. Here, Cd exposure upregulated MCU expression and increased mitochondrial Ca2+ uptake are found. MCU inhibition through siRNA or by Ru360 significantly attenuates Cd-induced excessive mitophagy, thereby rescues mitochondrial dysfunction and increases hepatocyte viability. Heterozygous MCU knockout mice exhibit improved liver function, ameliorated pathological damage, less mitochondrial fragmentation, and mitophagy after Cd exposure. Mechanistically, Cd upregulates MCU expression through phosphorylation activation of cAMP-response element binding protein at Ser133(CREBS133 ) and subsequent binding of MCU promoter at the TGAGGTCT, ACGTCA, and CTCCGTGATGTA regions, leading to increased MCU gene transcription. The upregulated MCU intensively interacts with voltage-dependent anion-selective channel protein 1 (VDAC1), enhances its dimerization and ubiquitination, resulting in excessive mitophagy. This study reveals a novel mechanism, through which Cd upregulates MCU to enhance mitophagy and hepatotoxicity.
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Affiliation(s)
- Cong Liu
- Chongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and PoisoningChongqing400060P. R. China
- National Emergency Response Team for Sudden Poisoningthe First Affiliated Hospital of Chongqing Medical and Pharmaceutical CollegeChongqing400060P. R. China
| | - Hui‐Juan Li
- Institute of Rocket Force MedicineState Key Laboratory of TraumaBurns and Combined InjuryThird Military Medical UniversityChongqing400038P. R. China
| | - Wei‐Xia Duan
- Chongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and PoisoningChongqing400060P. R. China
- National Emergency Response Team for Sudden Poisoningthe First Affiliated Hospital of Chongqing Medical and Pharmaceutical CollegeChongqing400060P. R. China
| | - Yu Duan
- Chongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and PoisoningChongqing400060P. R. China
- National Emergency Response Team for Sudden Poisoningthe First Affiliated Hospital of Chongqing Medical and Pharmaceutical CollegeChongqing400060P. R. China
| | - Qin Yu
- Chongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and PoisoningChongqing400060P. R. China
- National Emergency Response Team for Sudden Poisoningthe First Affiliated Hospital of Chongqing Medical and Pharmaceutical CollegeChongqing400060P. R. China
| | - Tian Zhang
- Chongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and PoisoningChongqing400060P. R. China
- Bioengineering College of Chongqing UniversityChongqing400044P. R. China
| | - Ya‐Pei Sun
- Chongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and PoisoningChongqing400060P. R. China
- School of Public HealthNanjing Medical University211166NanjingP. R. China
| | - Yuan‐Yuan Li
- Chongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and PoisoningChongqing400060P. R. China
- National Emergency Response Team for Sudden Poisoningthe First Affiliated Hospital of Chongqing Medical and Pharmaceutical CollegeChongqing400060P. R. China
| | - Yong‐Sheng Liu
- Chongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and PoisoningChongqing400060P. R. China
- National Emergency Response Team for Sudden Poisoningthe First Affiliated Hospital of Chongqing Medical and Pharmaceutical CollegeChongqing400060P. R. China
| | - Shang‐Cheng Xu
- Chongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and PoisoningChongqing400060P. R. China
- National Emergency Response Team for Sudden Poisoningthe First Affiliated Hospital of Chongqing Medical and Pharmaceutical CollegeChongqing400060P. R. China
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15
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Niture S, Gadi S, Lin M, Qi Q, Niture SS, Moore JT, Bodnar W, Fernando RA, Levine KE, Kumar D. Cadmium modulates steatosis, fibrosis, and oncogenic signaling in liver cancer cells by activating notch and AKT/mTOR pathways. ENVIRONMENTAL TOXICOLOGY 2023; 38:783-797. [PMID: 36602393 DOI: 10.1002/tox.23731] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 12/17/2022] [Accepted: 12/23/2022] [Indexed: 06/17/2023]
Abstract
Cadmium (Cd) is an environmental pollutant that increases hepatotoxicity and the risk of liver diseases. In the current study, we investigated the effect of a physiologically relevant, low concentration of Cd on the regulation of liver cancer cell proliferation, steatosis, and fibrogenic/oncogenic signaling. Exposure to low concentrations of Cd increased endogenous reactive oxygen species (ROS) production and enhanced cell proliferation in a human bipotent progenitor cell line HepaRG and hepatocellular carcinoma (HCC) cell lines. Acute exposure of Cd increased Jagged-1 expression and activated Notch signaling in HepaRG and HCC cells HepG2 and SK-Hep1. Cd activated AKT/mTOR signaling by increasing phosphorylation of AKT-S473 and mTOR-S-4448 residues. Moreover, a low concentration of Cd also promoted cell steatosis and induced fibrogenic signaling in HCC cells. Chronic exposure to low concentrations of Cd-activated Notch and AKT/mTOR signaling induced the expression of pro-inflammatory cytokines tumor necrosis factor-alpha (TNFα) and its downstream target TNF-α-Induced Protein 8 (TNFAIP8). RNA-Seq data revealed that chronic exposure to low concentrations of Cd modulated the expression of several fatty liver disease-related genes involved in cell steatosis/fibrosis in HepaRG and HepG2 cells. Collectively, our data suggest that low concentrations of Cd modulate steatosis along with fibrogenic and oncogenic signaling in HCC cells by activating Notch and AKT/mTOR pathways.
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Affiliation(s)
- Suryakant Niture
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University Durham, North Carolina, USA
- NCCU-RTI Center for Applied Research in Environmental Sciences (CARES), RTI International, Durham, North Carolina, USA
| | - Sashi Gadi
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University Durham, North Carolina, USA
| | - Minghui Lin
- The Fourth People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, China
| | - Qi Qi
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University Durham, North Carolina, USA
| | - Samiksha S Niture
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University Durham, North Carolina, USA
| | - John T Moore
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University Durham, North Carolina, USA
| | - Wanda Bodnar
- NCCU-RTI Center for Applied Research in Environmental Sciences (CARES), RTI International, Durham, North Carolina, USA
| | - Reshan A Fernando
- NCCU-RTI Center for Applied Research in Environmental Sciences (CARES), RTI International, Durham, North Carolina, USA
| | - Keith E Levine
- NCCU-RTI Center for Applied Research in Environmental Sciences (CARES), RTI International, Durham, North Carolina, USA
| | - Deepak Kumar
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University Durham, North Carolina, USA
- NCCU-RTI Center for Applied Research in Environmental Sciences (CARES), RTI International, Durham, North Carolina, USA
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16
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Gannouni A, Louis H, Roisnel T, Isang BB, Benjamin I, Kefi R. X-Ray Crystallography, Spectral Analysis, DFT Studies, and Molecular Docking of (C 9H 15N 3)[CdCl 4] Hybrid Material against Methicillin-Resistant Staphylococcus aureus (MRSA). Polycycl Aromat Compd 2023. [DOI: 10.1080/10406638.2023.2169721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Affiliation(s)
- Afef Gannouni
- Faculté Des Sciences De Bizerte, Laboratoire de Chimie Des Matériaux, Zarzouna, Tunisie
| | - Hitler Louis
- Computational and Bio-Simulation Research Group, University of Calabar, Calabar, Nigeria
- Department of Pure and Applied Chemistry, Faculty of Physical Sciences, University of Calabar, Calabar, Nigeria
| | - Thierry Roisnel
- Centre de Diffractométrie X, UMR 6226 CNRS, Institut Sciences Chimiques De Rennes, Université De Rennes I, Rennes, France
| | - Bartholomew B. Isang
- Computational and Bio-Simulation Research Group, University of Calabar, Calabar, Nigeria
- Department of Mathematics, Faculty of Physical Sciences, University of Calabar, Calabar, Nigeria
| | - Innocent Benjamin
- Computational and Bio-Simulation Research Group, University of Calabar, Calabar, Nigeria
- Department of Microbiology, Faculty of Biological Sciences, University of Calabar, Calabar, Nigeria
| | - Riadh Kefi
- Faculté Des Sciences De Bizerte, Laboratoire de Chimie Des Matériaux, Zarzouna, Tunisie
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17
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Deng P, Zhang H, Wang L, Jie S, Zhao Q, Chen F, Yue Y, Wang H, Tian L, Xie J, Chen M, Luo Y, Yu Z, Pi H, Zhou Z. Long-term cadmium exposure impairs cognitive function by activating lnc-Gm10532/m6A/FIS1 axis-mediated mitochondrial fission and dysfunction. THE SCIENCE OF THE TOTAL ENVIRONMENT 2023; 858:159950. [PMID: 36336035 DOI: 10.1016/j.scitotenv.2022.159950] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 10/31/2022] [Accepted: 10/31/2022] [Indexed: 06/16/2023]
Abstract
Cadmium (Cd), a ubiquitous environmental contaminant, is deemed a possible aetiological cause of cognitive disorders in humans. Nevertheless, the exact mechanism by which chronic exposure to Cd causes neurotoxicity is not fully understood. In this study, mouse neuroblastoma cells (Neuro-2a cells) and primary hippocampal neurons were exposed to low-dose (1, 2, and 4 μM for Neuro-2a cells or 0.5, 1, and 1.5 μM for hippocampal neurons) cadmium chloride (CdCl2) for 72 h (h), and male mice (C57BL/6J, 8 weeks) were orally administered CdCl2 (0.6 mg/L, approximately equal to 2.58 μg/kg·bw/d) for 6 months to investigate the effects and mechanism of chronic Cd-induced neurotoxicity. Here, chronic exposure to Cd impaired mitochondrial function by promoting excess reactive oxygen species (ROS) production, altering mitochondrial membrane potential (Δψm) and reducing adenosine triphosphate (ATP) content, contributing to neuronal cell death. Specifically, microarray analysis revealed that the long noncoding RNA Gm10532 (lnc-Gm10532) was most highly expressed in Neuro-2a cells exposed to 4 μM CdCl2 for 72 h compared with controls, and inhibition of lnc-Gm10532 significantly antagonized CdCl2-induced mitochondrial dysfunction and neurotoxicity. Mechanistically, lnc-Gm10532 increased Fission 1 (FIS1) expression and mitochondrial fission by recruiting the m6A writer methyltransferase-like 14 (METTL14) and enhancing m6A modification of Fis1 mRNA. Moreover, lnc-Gm10532 was also required for chronic Cd-induced mitochondrial dysfunction and memory deficits in a rodent model. Therefore, data of this study reveal a new epigenetic mechanism of chronic Cd neurotoxicity.
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Affiliation(s)
- Ping Deng
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Third Military Medical University, Chongqing 400038, China
| | - Huadong Zhang
- Chongqing Center for Disease Control and Prevention, Chongqing 400042, China
| | - Liting Wang
- Biomedical Analysis Center, Third Military Medical University, Chongqing 400038, China
| | - Sheng Jie
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Third Military Medical University, Chongqing 400038, China
| | - Qi Zhao
- Chongqing Center for Disease Control and Prevention, Chongqing 400042, China
| | - Fengqiong Chen
- Chongqing Center for Disease Control and Prevention, Chongqing 400042, China
| | - Yang Yue
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Third Military Medical University, Chongqing 400038, China
| | - Hui Wang
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Third Military Medical University, Chongqing 400038, China
| | - Li Tian
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Third Military Medical University, Chongqing 400038, China
| | - Jia Xie
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Third Military Medical University, Chongqing 400038, China
| | - Mengyan Chen
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Third Military Medical University, Chongqing 400038, China
| | - Yan Luo
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Third Military Medical University, Chongqing 400038, China
| | - Zhengping Yu
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Third Military Medical University, Chongqing 400038, China
| | - Huifeng Pi
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Third Military Medical University, Chongqing 400038, China.
| | - Zhou Zhou
- Center for Neurointelligence, School of Medicine, Chongqing University, Chongqing 400030, China; Department of Environmental Medicine, School of Public Health, and Department of Emergency Medicine, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China.
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18
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Cadmium-Induced Proteinuria: Mechanistic Insights from Dose-Effect Analyses. Int J Mol Sci 2023; 24:ijms24031893. [PMID: 36768208 PMCID: PMC9915107 DOI: 10.3390/ijms24031893] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 01/16/2023] [Accepted: 01/17/2023] [Indexed: 01/21/2023] Open
Abstract
Cadmium (Cd) is a toxic metal that accumulates in kidneys, especially in the proximal tubular epithelial cells, where virtually all proteins in the glomerular ultrafiltrate are reabsorbed. Here, we analyzed archived data on the estimated glomerular filtration rate (eGFR) and excretion rates of Cd (ECd), total protein (EProt), albumin (Ealb), β2-microglobulin (Eβ2M), and α1-microglobulin (Eα1M), which were recorded for residents of a Cd contamination area and a low-exposure control area of Thailand. Excretion of Cd and all proteins were normalized to creatinine clearance (Ccr) as ECd/Ccr and EProt/Ccr to correct for differences among subjects in the number of surviving nephrons. Low eGFR was defined as eGFR ≤ 60 mL/min/1.73 m2, while proteinuria was indicted by EPro/Ccr ≥ 20 mg/L of filtrate. EProt/Ccr varied directly with ECd/Ccr (β = 0.263, p < 0.001) and age (β = 0.252, p < 0.001). In contrast, eGFR values were inversely associated with ECd/Ccr (β = -0.266, p < 0.001) and age (β = -0.558, p < 0.001). At ECd/Ccr > 8.28 ng/L of filtrate, the prevalence odds ratios for proteinuria and low eGFR were increased 4.6- and 5.1-fold, respectively (p < 0.001 for both parameters). Thus, the eGFR and tubular protein retrieval were both simultaneously diminished by Cd exposure. Of interest, ECd/Ccr was more closely correlated with EProt/Ccr (r = 0.507), Eβ2M (r = 0.430), and Eα1M/Ccr (r = 0.364) than with EAlb/Ccr (r = 0.152). These data suggest that Cd may differentially reduce the ability of tubular epithelial cells to reclaim proteins, resulting in preferential reabsorption of albumin.
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19
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Tavakoli Pirzaman A, Ebrahimi P, Niknezhad S, Vahidi T, Hosseinzadeh D, Akrami S, Ashrafi AM, Moeen Velayatimehr M, Hosseinzadeh R, Kazemi S. Toxic mechanisms of cadmium and exposure as a risk factor for oral and gastrointestinal carcinomas. Hum Exp Toxicol 2023; 42:9603271231210262. [PMID: 37870872 DOI: 10.1177/09603271231210262] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2023]
Abstract
Incidence and mortality rates of gastrointestinal (GI) and oral cancers are among the highest in the world, compared to other cancers. GI cancers include esophageal, gastric, colon, rectal, liver, and pancreatic cancers, with colorectal cancer being the most common. Oral cancer, which is included in the head and neck cancers category, is one of the most important causes of death in India. Cadmium (Cd) is a toxic element affecting humans and the environment, which has both natural and anthropogenic sources. Generally, water, soil, air, and food supplies are reported as some sources of Cd. It accumulates in organs, particularly in the kidneys and liver. Exposure to cadmium is associated with different types of health risks such as kidney dysfunction, cardiovascular disease, reproductive dysfunction, diabetes, cerebral infarction, and neurotoxic effects (Parkinson's disease (PD) and Alzheimer's disease (AD)). Exposure to Cd is also associated with various cancers, including lung, kidney, liver, stomach, hematopoietic system, gynecologic and breast cancer. In the present study, we have provided and summarized the association of Cd exposure with oral and GI cancers.
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Affiliation(s)
| | - Pouyan Ebrahimi
- Student Research Committee, Babol University of Medical Science, Babol, Iran
| | - Shokat Niknezhad
- Student Research Committee, Babol University of Medical Science, Babol, Iran
| | - Turan Vahidi
- Student Research Committee, Babol University of Medical Science, Babol, Iran
| | | | - Sousan Akrami
- Students' Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran
- Department of Microbiology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Arash M Ashrafi
- Student Research Committee, Babol University of Medical Science, Babol, Iran
| | | | - Rezvan Hosseinzadeh
- Student Research Committee, Babol University of Medical Science, Babol, Iran
| | - Sohrab Kazemi
- Cellular and Molecular Biology Research Center, Health Research Center, Babol University of Medical Science, Babol, Iran
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20
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Li ZZ, Zhou XW, Chen LJ. Transcriptomic analysis of cadmium toxicity and molecular response in the spiderling of Pirata subpiraticus. Comp Biochem Physiol C Toxicol Pharmacol 2022; 261:109441. [PMID: 35981662 DOI: 10.1016/j.cbpc.2022.109441] [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: 07/01/2022] [Revised: 07/29/2022] [Accepted: 08/12/2022] [Indexed: 11/16/2022]
Abstract
Cadmium (Cd) is a kind of toxic heavy metal widely distributed in the environment, posing life-threatening challenges to organisms. The paddy field spider is a natural enemy of pests and an essential component of rice biodiversity. Nonetheless, the effects of Cd stress on the postembryonic development of spiders and its detailed mechanism remain to be investigated. In the present study, we found that Cd stress posed adverse impacts on the growth indicators (e.g., carapace length, development duration, and survival rate) and increased the levels of three antioxidants (i.e., superoxide dismutase, glutathione S-transferase, and glutathione peroxidase) in the spiderlings of Pirata subpiraticus. An in-depth transcriptome analysis was employed in the study, and the results displayed that differentially expressed genes (DEGs) involved in postembryonic morphogenesis, development involved in symbiotic interaction, postembryonic development, and growth were distinctively altered under Cd stress. Further enrichment analysis showed that Cd exposure could activate the apoptosis pathway in the spider via the up-regulation of several key factors, including caspase-10, α-tubulin, actin, etc. In addition, we demonstrated that the increased level of glutathione-related enzymes in spiderlings was caused by the activation of glutathione metabolic pathway. The altered hedgehog signaling pathway might affect cell proliferation, tissue patterning, and development of spiderlings. Further protein interaction network displayed that Cd stress could affect multiple biological processes in spiderlings, particularly cellular response to stimulus and system development. To sum up, this study can provide multi-level perspectives to understand the toxicity of Cd on the growth and development of spiders.
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Affiliation(s)
- Zhe-Zhi Li
- College of Urban and Rural Construction, Shaoyang University, 422099 Shaoyang, China
| | - Xuan-Wei Zhou
- School of Life Sciences, Southwest University, 400715, Beibei, Chongqing, China
| | - Li-Jun Chen
- College of Urban and Rural Construction, Shaoyang University, 422099 Shaoyang, China.
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21
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The mechanism of the cadmium-induced toxicity and cellular response in the liver. Toxicology 2022; 480:153339. [PMID: 36167199 DOI: 10.1016/j.tox.2022.153339] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 09/22/2022] [Accepted: 09/23/2022] [Indexed: 01/22/2023]
Abstract
Cadmium is a toxic element to which man can be exposed at work or in the environment. Cd's most salient toxicological property is its exceptionally long half-life in the human body. Once absorbed, Cd accumulates in the human body, particularly in the liver. The cellular actions of Cd are extensively documented, but the molecular mechanisms underlying these actions are still not resolved. The liver manages the cadmium to eliminate it by a diverse mechanism of action. Still, many cellular and physiological responses are executed in the task, leading to worse liver damage, ranging from steatosis, steatohepatitis, and eventually hepatocellular carcinoma. The progression of cadmium-induced liver damage is complex, and it is well-known the cellular response that depends on the time in which the metal is present, ranging from oxidative stress, apoptosis, adipogenesis, and failures in autophagy. In the present work, we aim to present a review of the current knowledge of cadmium toxicity and the cellular response in the liver.
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22
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Akbulut S, Isik B, Mehdi Uremis M, Dogan UG, Sahin TT, Sarici KB, Koc C, Demyati K, Dirican A, Turkoz Y, Yilmaz S. Tissue Heavy Metals in Liver Diseases. Transplant Proc 2022; 54:1859-1864. [PMID: 35985878 DOI: 10.1016/j.transproceed.2022.05.029] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 05/03/2022] [Accepted: 05/22/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Our objective was to determine the levels of heavy metals, oxidants, and antioxidants in liver tissue of patients with chronic liver disease (CLD) compared with healthy living liver donors (LLDs). METHODS We obtained liver specimens from patients undergoing liver transplant for CLD. Samples were also obtained from LLDs. Biochemical analyses were performed on all samples, and the levels of liver tissue, heavy metal, and oxidant-antioxidants biomarker levels in patients with CLD were compared with those measured in LLDs. RESULTS One hundred and eighteen individuals were included for analyses. Fifty-nine were patients with CLD, and 59 were LLDs. The median levels of liver tissue of superoxide dismutase (P = .009), glutathione peroxidase (P = .042), total oxidant status (P = .006), oxidative stress index (P < .001), and copper (P = .035) were prominently more elevated in CLD than LLDs. On the other hand, the median levels of liver tissue of cadmium (P < .001), selenium (P = .042), and zinc (P < .001) levels were more elevated in the LLDs than patients with CLD. The 2 groups were similar in terms of total antioxidant status, manganese, arsenic, and lead levels. CONCLUSIONS Superoxide accumulation in the liver was higher in patients with CLD. Concerning heavy metals, only the median tissue copper was elevated in patients with CLD with higher Cu/Zn ratio. Cadmium, selenium, and zinc were significantly higher in the healthy LLDs.
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Affiliation(s)
- Sami Akbulut
- Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya, Turkey.
| | - Burak Isik
- Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya, Turkey
| | - Muhammed Mehdi Uremis
- Department of Medical Biochemistry, Inonu University Faculty of Medicine, Malatya, Turkey
| | - Ufuk Gunay Dogan
- Fuel-Oil Analysis Laboratory, Inonu University Rectorate, Malatya, Turkey
| | - Tevfik Tolga Sahin
- Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya, Turkey
| | - Kemal Baris Sarici
- Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya, Turkey
| | - Cemalettin Koc
- Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya, Turkey
| | - Khaled Demyati
- Department of Surgery, An-Najah National University Hospital, An-Najah National University, Nablus, Palestine
| | - Abuzer Dirican
- Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya, Turkey
| | - Yusuf Turkoz
- Department of Medical Biochemistry, Inonu University Faculty of Medicine, Malatya, Turkey
| | - Sezai Yilmaz
- Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya, Turkey
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23
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Zhou J, Zhang Y, Zeng L, Wang X, Mu H, Wang M, Pan H, Su P. Paternal cadmium exposure affects testosterone synthesis by reducing the testicular cholesterol pool in offspring mice. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 242:113947. [PMID: 35999762 DOI: 10.1016/j.ecoenv.2022.113947] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 07/12/2022] [Accepted: 08/01/2022] [Indexed: 06/15/2023]
Abstract
Cadmium（Cd） is a heavy metal that is harmful to human health. Early studies have shown that cadmium can damage testicular structure, affecting testosterone synthesis and spermatogenesis. However, the effect of paternal Cd exposure on the reproductive system of offspring remains unclear. In this study, male 8-week C57BL/6 J mice were used as research objects, and Cd was injected intraperitoneally every other day at a dose of 1 mg/kg for 5 weeks, after which the effect on the reproductive system of offspring male mice was studied. Our results showed that the body weight of the offspring male mice increased faster, with increases of the testicular and epididymis indices under Cd exposure. At the same time, the serum testosterone and free cholesterol decreased, total cholesterol increased, and the sperm concentration decreased. Further qRT-PCR and western blot analyses showed that the expressions of StAR, P450scc, 3β-HSD and 17β-HSD, which are related to testosterone synthesis, was significantly downregulated. Additionally, ATGL, LDLR and SR-BI, which are related to the intracellular cholesterol pool were downregulated, leading to the reduction of the cholesterol pool and the accumulation of lipid droplets. Oil red O and BODIPY staining revealed an increase in the abundance of lipid droplets in testicular tissue of newborn and adult mice. Prediction of tsRNA target genes in the sperm of parents and testicular transcriptome of newborn mice showed that the differentially expressed genes were associated with catabolism of fatty acids, cholesterol and ion channels, while the mitochondrial and lysosome functions of testicular tissue of adult offspring mice were decreased. Overall, our results suggest that paternal Cd exposure reduced the intracellular cholesterol pool of testicular of offspring, affected testosterone synthesis and reproductive system development.
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Affiliation(s)
- Jinzhao Zhou
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Yanwei Zhang
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Ling Zeng
- Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province, Wuhan, China.
| | - Xiaofei Wang
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Hongbei Mu
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Mei Wang
- Reproductive Medicine Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
| | - Hao Pan
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and echnology, Wuhan, China.
| | - Ping Su
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Wuhan Tongji Reproductive Medicine Hospital, Wuhan, China.
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24
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Vidal AC, Moylan CA, Wilder J, Grant DJ, Murphy SK, Hoyo C. Racial disparities in liver cancer: Evidence for a role of environmental contaminants and the epigenome. Front Oncol 2022; 12:959852. [PMID: 36072796 PMCID: PMC9441658 DOI: 10.3389/fonc.2022.959852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 07/21/2022] [Indexed: 01/09/2023] Open
Abstract
Liver cancer incidence has tripled since the early 1980s, making this disease one of the fastest rising types of cancer and the third leading cause of cancer-related deaths worldwide. In the US, incidence varies by geographic location and race, with the highest incidence in the southwestern and southeastern states and among racial minorities such as Hispanic and Black individuals. Prognosis is also poorer among these populations. The observed ethnic disparities do not fully reflect differences in the prevalence of risk factors, e.g., for cirrhosis that may progress to liver cancer or from genetic predisposition. Likely substantial contributors to risk are environmental factors, including chemical and non-chemical stressors; yet, the paucity of mechanistic insights impedes prevention efforts. Here, we review the current literature and evaluate challenges to reducing liver cancer disparities. We also discuss the hypothesis that epigenetic mediators may provide biomarkers for early detection to support interventions that reduce disparities.
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Affiliation(s)
- Adriana C. Vidal
- Department of Biological Sciences, Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, United States
| | - Cynthia A. Moylan
- Department of Medicine, Division of Gastroenterology and Hepatology, School of Medicine, Duke University, Durham, NC, United States
| | - Julius Wilder
- Department of Medicine, Division of Gastroenterology and Hepatology, School of Medicine, Duke University, Durham, NC, United States
| | - Delores J. Grant
- Department of Biomedical and Biological Sciences, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, United States
| | - Susan K. Murphy
- Department of Obstetrics and Gynecology, Division of Research, School of Medicine, Duke University, Durham, NC, United States
| | - Cathrine Hoyo
- Department of Biological Sciences, Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, United States
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25
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Bao QJ, Zhao K, Guo Y, Wu XT, Yang JC, Yang MF. Environmental toxic metal contaminants and risk of stroke: a systematic review and meta-analysis. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:32545-32565. [PMID: 35190994 DOI: 10.1007/s11356-022-18866-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 01/21/2022] [Indexed: 06/14/2023]
Abstract
The relationship between toxic metals in the environment and clinical stroke risk remains unclear, although their role as immunotoxicants and carcinogens has been well established. We conducted a systematic review of the relationship between five metals (arsenic, mercury, copper, cadmium, and lead) and stroke. First, we comprehensively searched 3 databases (Pubmed, EMBASE, and Cochrane) from inception until June 2021. Random-effects meta-analyses, pooled relative risks (RR) and 95% confidence intervals (CI) were applied to evaluate the effect value. We finally identified 38 studies involving 642,014 non-overlapping participants. Comparing the highest vs. lowest baseline levels, chronic exposure to lead (RR = 1.07; 95%CI,1.00-1.14), cadmium (RR = 1.30; 95%CI,1.13-1.48), and copper (RR = 1.19; 95%CI,1.04-1.36) were significantly associated with stroke risks. However, the other two metals (arsenic and mercury) had less effect on stroke risk. Further analysis indicated that the association was likely in a metal dose-dependent manner. The results may further support the possibility that environmental toxic metal contaminants in recent years are associated with the increased risk of stroke.
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Affiliation(s)
- Qiang-Ji Bao
- Graduate School, Qinghai University, Xining, 810016, Qinghai, China
| | - Kai Zhao
- Graduate School, Qinghai University, Xining, 810016, Qinghai, China
| | - Yu Guo
- Graduate School, Qinghai University, Xining, 810016, Qinghai, China
| | - Xin-Ting Wu
- Graduate School, Qinghai University, Xining, 810016, Qinghai, China
| | - Jin-Cai Yang
- Graduate School, Qinghai University, Xining, 810016, Qinghai, China
| | - Ming-Fei Yang
- Department of Neurosurgery, Qinghai Provincial People's Hospital, Xining, 810007, Qinghai, China.
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26
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Wei Y, Yi K, Shen C, Chen X, Iqbal T, Cao M, Chen T, Luo Y, Li J, Zhou X, Li C, Chen L. Whole Transcriptome Profiling of the Effects of Cadmium on the Liver of the Xiangxi Yellow Heifer. Front Vet Sci 2022; 9:846662. [PMID: 35498726 PMCID: PMC9047687 DOI: 10.3389/fvets.2022.846662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 03/07/2022] [Indexed: 11/21/2022] Open
Abstract
Cadmium (Cd) is a major heavy metal toxicant found in industrial zones. Humans and animals are exposed to it through their diet, which results in various physiological problems. In the current study, the toxic effects of Cd on the liver were investigated by whole-transcriptome sequencing (RNA-seq) of the livers of Xiangxi heifers fed a diet with excess Cd. We randomly divided six healthy heifers into two groups. The first group received a control diet, whereas the second group received Cd-exceeding diets for 100 days. After 100 days, the livers were collected. A total of 551 differentially expressed mRNAs, 24 differentially expressed miRNAs, and 169 differentially expressed lncRNAs were identified (p < 0.05, |log2FC| >1). Differentially expressed genes (DEGs) were analyzed by gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. We found that under Cd exposure, DEGs were enriched in the adenosine 5'-monophosphate-activated protein kinase pathway, which is involved in autophagy regulation, and the peroxisome proliferator-activated receptor pathway, which is involved in lipid metabolism. In addition, the apolipoprotein A4 gene, which has anti-inflammatory and antioxidant effects, the anti-apoptotic gene ATPase H+/K+ transporting the nongastric alpha2 subunit, and the cholesterol metabolism-associated gene endothelial lipase gene were significantly downregulated. C-X-C motif chemokine ligand 3, cholesterol 7α-hydroxylase, and stearoyl-CoA desaturase, which are involved in the development of fatty liver, were significantly upregulated. These genes revealed the main effects of Cd on the liver of Xiangxi yellow heifers. The current study provides insightful information regarding the DEGs involved in autophagy regulation, apoptosis, lipid metabolism, anti-inflammation, and antioxidant enzyme activity. These may serve as useful biomarkers for predicting and treating Cd-related diseases in the future.
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Affiliation(s)
- Yameng Wei
- College of Animal Sciences, Jilin University, Changchun, China
| | - Kangle Yi
- Grassland and Herbivore Research Laboratory, Hunan Animal Husbandry and Veterinary Research Institute, Changsha, China
| | - Caomeihui Shen
- College of Animal Sciences, Jilin University, Changchun, China
| | - Xue Chen
- College of Animal Sciences, Jilin University, Changchun, China
| | - Tariq Iqbal
- College of Animal Sciences, Jilin University, Changchun, China
| | - Maosheng Cao
- College of Animal Sciences, Jilin University, Changchun, China
| | - Tong Chen
- College of Animal Sciences, Jilin University, Changchun, China
| | - Yang Luo
- Grassland and Herbivore Research Laboratory, Hunan Animal Husbandry and Veterinary Research Institute, Changsha, China
| | - Jianbo Li
- Grassland and Herbivore Research Laboratory, Hunan Animal Husbandry and Veterinary Research Institute, Changsha, China
| | - Xu Zhou
- College of Animal Sciences, Jilin University, Changchun, China
| | - Chunjin Li
- College of Animal Sciences, Jilin University, Changchun, China
| | - Lu Chen
- College of Animal Sciences, Jilin University, Changchun, China
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27
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Xu H, Jia Y, Sun Z, Su J, Liu QS, Zhou Q, Jiang G. Environmental pollution, a hidden culprit for health issues. ECO-ENVIRONMENT & HEALTH (ONLINE) 2022; 1:31-45. [PMID: 38078200 PMCID: PMC10702928 DOI: 10.1016/j.eehl.2022.04.003] [Citation(s) in RCA: 88] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 03/26/2022] [Accepted: 04/23/2022] [Indexed: 12/12/2023]
Abstract
The environmental and health impacts from the massive discharge of chemicals and subsequent pollution have been gaining increasing public concern. The unintended exposure to different pollutants, such as heavy metals, air pollutants and organic chemicals, may cause diverse deleterious effects on human bodies, resulting in the incidence and progression of different diseases. The article reviewed the outbreak of environmental pollution-related public health emergencies, the epidemiological evidence on certain pollution-correlated health effects, and the pathological studies on specific pollutant exposure. By recalling the notable historical life-threatening disasters incurred by local chemical pollution, the damning evidence was presented to criminate certain pollutants as the main culprit for the given health issues. The epidemiological data on the prevalence of some common diseases revealed a variety of environmental pollutants to blame, such as endocrine-disrupting chemicals (EDCs), fine particulate matters (PMs) and heavy metals. The retrospection of toxicological studies provided illustrative clues for evaluating ambient pollutant-induced health risks. Overall, environmental pollution, as the hidden culprit, should answer for the increasing public health burden, and more efforts are highly encouraged to strive to explore the cause-and-effect relationships through extensive epidemiological and pathological studies.
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Affiliation(s)
- Hanqing Xu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China
- National and Local Joint Engineering Research Center of Ecological Treatment Technology for Urban Water Pollution, and Zhejiang Provincial Key Lab for Subtropical Water Environment and Marine Biological Resources Protection, Wenzhou University, Wenzhou, 325035, China
| | - Yang Jia
- National and Local Joint Engineering Research Center of Ecological Treatment Technology for Urban Water Pollution, and Zhejiang Provincial Key Lab for Subtropical Water Environment and Marine Biological Resources Protection, Wenzhou University, Wenzhou, 325035, China
| | - Zhendong Sun
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China
- School of Environment, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310000, China
| | - Jiahui Su
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Qian S. Liu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China
| | - Qunfang Zhou
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China
- School of Environment, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310000, China
- Institute of Environment and Health, Jianghan University, Wuhan, 430056, China
| | - Guibin Jiang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China
- School of Environment, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310000, China
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28
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Nguyen J, Patel A, Gensburg A, Bokhari R, Lamar P, Edwards J. Diabetogenic and Obesogenic Effects of Cadmium in Db/Db Mice and Rats at a Clinically Relevant Level of Exposure. TOXICS 2022; 10:toxics10030107. [PMID: 35324731 PMCID: PMC8949435 DOI: 10.3390/toxics10030107] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 02/11/2022] [Accepted: 02/21/2022] [Indexed: 12/16/2022]
Abstract
Studies show an association between cadmium (Cd) exposure and prediabetes or type II diabetes mellitus. We have previously reported that Cd causes decreased levels of serum leptin in rats following 12 weeks of daily Cd dosing (0.6 mg/kg/b.w./day). Since leptin plays an important role in metabolism, we examined the effects of Cd on rats and db/db mice, which are deficient in leptin receptor activity. We gave rats and mice daily subcutaneous injections of saline (control) or CdCl2 at a dose of 0.6 mg/kg of Cd for 2 weeks, followed by 2 weeks of no dosing. At the end of the 4-week study, exposure to Cd resulted in a more rapid increase in blood glucose levels following an oral glucose tolerance test in db/db vs. lean mice. During the two weeks of no Cd dosing, individual rat bodyweight gain was greater (p ≤ 0.05) in Cd-treated animals. At this time point, the combined epididymal and retroperitoneal fat pad weight was significantly greater (p ≤ 0.05) in the Cd-treated lean mice compared to saline-treated controls. Although this pilot study had relatively low N values (4 per treatment group for mice and 6 for rats) the results show that clinically relevant levels of Cd exposure resulted in diabetogenic as well as obesogenic effects.
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Affiliation(s)
- Jessica Nguyen
- Chicago College of Pharmacy, Midwestern University, Downers Grove, IL 60515, USA;
| | - Arjun Patel
- Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ 85308, USA;
| | - Andrew Gensburg
- Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL 60515, USA; (A.G.); (R.B.)
| | - Rehman Bokhari
- Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL 60515, USA; (A.G.); (R.B.)
| | - Peter Lamar
- College of Graduate Studies, Midwestern University, Downers Grove, IL 60515, USA;
| | - Joshua Edwards
- College of Graduate Studies, Midwestern University, Downers Grove, IL 60515, USA;
- Correspondence: ; Tel.: +1-(630)-515-7417
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29
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Cadmium Exposure in Young Adulthood Is Associated with Risk of Nonalcoholic Fatty Liver Disease in Midlife. Dig Dis Sci 2022; 67:689-696. [PMID: 33630217 PMCID: PMC8843233 DOI: 10.1007/s10620-021-06869-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 01/20/2021] [Indexed: 02/03/2023]
Abstract
BACKGROUND Studies have suggested that cadmium (Cd) may be involved in the etiology of nonalcoholic fatty liver disease (NAFLD), but available data in human is sparse. AIMS We aimed to examine Cd exposure in young adulthood in relation to prevalent NAFLD in midlife among American adults. METHODS This study included 2446 participants from the Coronary Artery Risk Development in Young Adults study with toenail Cd measurement at exam year 2 (baseline) and computed tomography quantification of liver fat at exam year 25. Toenail Cd concentrations were considered as a reliable marker of long-term exposure. NAFLD was defined if liver attenuation < 51 Hounsfield units after excluding other possible causes of liver fat. Multivariable-adjusted logistic regression models were used to estimate the odds ratio of NAFLD by Cd exposure. RESULTS Median toenail Cd concentration was 8.2 ppb (inter-quartile range 4.3-18.6 ppb). After 23 years from baseline, 580 participants with prevalent NAFLD (24% prevalence) in midlife were identified. Compared with individuals in the lowest quartile, those in the highest quartile of toenail Cd had a significantly higher odds of NAFLD (OR: 1.43, 95% CI: 1.02, 1.99, P for trend: 0.04) after adjustment for demographics, socioeconomics, major lifestyle factors, and baseline levels of body mass index, lipids, and fasting insulin. The association was not significantly modified by race, sex, BMI, or smoking status at baseline. CONCLUSIONS Toenail Cd concentration was associated with a higher odds of prevalent NAFLD23 years later in life in this cohort of US general population.
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Nie Y, Huang B, Hu AL, Xu YY, Zou Y, Liu Y, Liu J. Antitumor effects of cadmium against diethylnitrosamine-induced liver tumors in mice. Oncol Lett 2021; 23:33. [PMID: 34966449 PMCID: PMC8669683 DOI: 10.3892/ol.2021.13151] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 11/02/2021] [Indexed: 11/15/2022] Open
Abstract
Cadmium (Cd) has been reported to exhibit antitumor effects against chemically induced liver tumors. However, the antitumor effects of Cd are not completely understood. Metallotherapy, the use of a toxic metal to attack liver tumors, could be a viable strategy. In the present study, 8-week old, male, C57BL/6 mice were administered injections of diethylnitrosamine (DEN) (90 mg/kg, and then 50 mg/kg 2 weeks later), followed by liver tumor promotion with carbon tetrachloride. Cadmium chloride was administered in the drinking water (1000 ppm) from 21–40 weeks after DEN initiation. Body weights were recorded and liver tumor formation was monitored via ultrasound. At the end of experiments, livers were removed, weighed, and the tumor incidence, tumor numbers and tumor size scores were recorded. Liver histology and metallothionein (MT) immunostaining were performed. After DEN injection, animal body weight decreased, and then slowly recovered with time. Cd treatment did not affect animal body weight gain. Ultrasound analysis detected liver tumors 35 weeks after DEN injection, and the mice were necropsied at 40 weeks. Liver/body weight ratios increased in the DEN and DEN + Cd groups. Cd treatment decreased the tumor incidence (71 vs. 17%), tumor numbers (15 vs. 2) and tumor scores (22 vs. 3) when compared with the DEN only group. Histopathology showed hepatocyte degeneration in all groups, and immunohistochemistry showed MT-deficiency in the liver tumors, while MT staining was intensified in the surrounding tissues. Reverse transcription-quantitative PCR showed increases in α-fetoprotein level in DEN-treated livers, and increases in MT-2 and tumor necrosis factor α (TNFα) levels in Cd-treated livers. Thus, it was concluded that Cd is effective in the suppression of DEN-induced liver tumors, and that the mechanisms may be related to MT-deficiency in tumors and the induction of TNFα to kill tumor cells.
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Affiliation(s)
- Yu Nie
- Key Lab for Basic Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Bo Huang
- Key Lab for Basic Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - An-Ling Hu
- Key Lab for Basic Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Yun-Yan Xu
- Key Lab for Basic Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Yan Zou
- School of Public Health, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Yun Liu
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Jie Liu
- Key Lab for Basic Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
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Zhang X, Guan L, Tian H, Zeng Z, Chen J, Huang D, Sun J, Guo J, Cui H, Li Y. Risk Factors and Prevention of Viral Hepatitis-Related Hepatocellular Carcinoma. Front Oncol 2021; 11:686962. [PMID: 34568017 PMCID: PMC8458967 DOI: 10.3389/fonc.2021.686962] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 08/20/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a common cancer in the world, and its incidence is increasing yearly. Hepatitis B virus (HBV) infection and hepatitis C virus (HCV) infection are important causes of HCC. Liver cirrhosis, age, sex, smoking and drinking, and metabolic risk factors will increase the risk of cancer in HBV/HCV patients. And viral load, APRI, FIB-4, and liver stiffness can all predict the risk of HCC in patients with viral infection. In addition, effective prevention strategies are essential in reducing the risk of HCC. The prevention of HCC involves mainly tertiary prevention strategies, while the primary prevention is based on standardized vaccine injections to prevent the occurrence of HBV/HCV. Eliminating the route of transmission and vaccination will lead to a decrease in the incidence of HCC. Secondary prevention involves effective antiviral treatment of HBV/HCV to prevent the disease from progressing to HCC, and tertiary prevention is actively treating HCC to prevent its recurrence.
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Affiliation(s)
- Xinhe Zhang
- Gastroenterology Department, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Lin Guan
- Gastroenterology Department, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Haoyu Tian
- The 3rd Clinical Department of China Medical University, Shenyang, China
| | - Zilu Zeng
- Gastroenterology Department, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Jiayu Chen
- Gastroenterology Department, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Die Huang
- Gastroenterology Department, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Ji Sun
- Gastroenterology Department, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Jiaqi Guo
- Gastroenterology Department, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Huipeng Cui
- Gastroenterology Department, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yiling Li
- Gastroenterology Department, The First Affiliated Hospital of China Medical University, Shenyang, China
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Xu Y, Mu W, Li J, Ba Q, Wang H. Chronic cadmium exposure at environmental-relevant level accelerates the development of hepatotoxicity to hepatocarcinogenesis. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 783:146958. [PMID: 33866181 DOI: 10.1016/j.scitotenv.2021.146958] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 03/31/2021] [Accepted: 03/31/2021] [Indexed: 06/12/2023]
Abstract
Cadmium (Cd) is an environmental heavy metal with long biological half-time and adverse health effects. The long-term toxicity of Cd at low levels remains to be elucidated. Here, we investigated the impact of dietary Cd intake at environmental doses in the full disease cycle from liver injury, fibrosis, inflammation to cancer progression in mouse models and in vitro. We found that chronic low-dose Cd exposure promoted the hepatotoxicity and hepato-pathogenesis in normal and CCl4 mouse models. Cd enhanced liver injury and accelerated liver fibrosis, a key risk factor for cirrhosis and liver cancer, featured as up-regulation of fibrosis-related markers (TGF-β1, collagen-1, and TIMP1) and activation of hepatic stellate cells. Consistently, Cd increased the inflammation and the infiltration of macrophages and dendritic cells in liver. At late stage, the angiogenetic factors, VEGF and CD34, were elevated, indicating abnormal angiogenesis. At the end of treatment, Cd promoted CCl4-induced liver cancer formation, including incidence, tumor number and size. These effects were more pronounced in male mice than that in females. The promoting-effects of Cd on fibrosis and angiogenesis were further validated in hepatic stellate cells and liver sinusoidal endothelial cells. PPAR and ERBB signaling pathways were identified as the potential pathways to promote the toxicity of chronic Cd exposure. These findings provide a better understanding about the long-term influence of environmental Cd spanning the entire precancerous lesions-to-cancer formation cycle.
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Affiliation(s)
- Yajie Xu
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Wei Mu
- State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jingquan Li
- State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qian Ba
- State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Hui Wang
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China; State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Jackson TW, Ryherd GL, Scheibly CM, Sasser AL, Guillette TC, Belcher SM. Gestational Cd Exposure in the CD-1 Mouse Induces Sex-Specific Hepatic Insulin Insensitivity, Obesity, and Metabolic Syndrome in Adult Female Offspring. Toxicol Sci 2021; 178:264-280. [PMID: 33259630 DOI: 10.1093/toxsci/kfaa154] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
There is compelling evidence that developmental exposure to toxic metals increases risk for obesity and obesity-related morbidity including cardiovascular disease and type 2 diabetes. To explore the hypothesis that developmental Cd exposure increases risk of obesity later in life, male, and female CD-1 mice were maternally exposed to 500 ppb CdCl2 in drinking water during a human gestational equivalent period (gestational day 0-postnatal day 10 [GD0-PND10]). Hallmark indicators of metabolic disruption, hepatic steatosis, and metabolic syndrome were evaluated prior to birth through adulthood. Maternal blood Cd levels were similar to those observed in human pregnancy cohorts, and Cd was undetected in adult offspring. There were no observed impacts of exposure on dams or pregnancy-related outcomes. Results of glucose and insulin tolerance testing revealed that Cd exposure impaired offspring glucose homeostasis on PND42. Exposure-related increases in circulating triglycerides and hepatic steatosis were apparent only in females. By PND120, Cd-exposed females were 30% heavier with 700% more perigonadal fat than unexposed control females. There was no evidence of dyslipidemia, steatosis, increased weight gain, nor increased adiposity in Cd-exposed male offspring. Hepatic transcriptome analysis on PND1, PND21, and PND42 revealed evidence for female-specific increases in oxidative stress and mitochondrial dysfunction with significant early disruption of retinoic acid signaling and altered insulin receptor signaling consistent with hepatic insulin sensitivity in adult females. The observed steatosis and metabolic syndrome-like phenotypes resulting from exposure to 500 ppb CdCl2 during the pre- and perinatal period of development equivalent to human gestation indicate that Cd acts developmentally as a sex-specific delayed obesogen.
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Affiliation(s)
- Thomas W Jackson
- Department of Biological Sciences, Center for Human Health and the Environment, North Carolina State University, Raleigh, North Carolina 27695
| | - Garret L Ryherd
- Department of Biological Sciences, Center for Human Health and the Environment, North Carolina State University, Raleigh, North Carolina 27695
| | - Chris M Scheibly
- Department of Biological Sciences, Center for Human Health and the Environment, North Carolina State University, Raleigh, North Carolina 27695
| | - Aubrey L Sasser
- Department of Biological Sciences, Center for Human Health and the Environment, North Carolina State University, Raleigh, North Carolina 27695
| | - T C Guillette
- Department of Biological Sciences, Center for Human Health and the Environment, North Carolina State University, Raleigh, North Carolina 27695
| | - Scott M Belcher
- Department of Biological Sciences, Center for Human Health and the Environment, North Carolina State University, Raleigh, North Carolina 27695
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Niture S, Lin M, Qi Q, Moore JT, Levine KE, Fernando RA, Kumar D. Role of Autophagy in Cadmium-Induced Hepatotoxicity and Liver Diseases. J Toxicol 2021; 2021:9564297. [PMID: 34422041 PMCID: PMC8371627 DOI: 10.1155/2021/9564297] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 07/12/2021] [Accepted: 08/03/2021] [Indexed: 12/12/2022] Open
Abstract
Cadmium (Cd) is a toxic pollutant that is associated with several severe human diseases. Cd can be easily absorbed in significant quantities from air contamination/industrial pollution, cigarette smoke, food, and water and primarily affects the liver, kidney, and lungs. Toxic effects of Cd include hepatotoxicity, nephrotoxicity, pulmonary toxicity, and the development of various human cancers. Cd is also involved in the development and progression of fatty liver diseases and hepatocellular carcinoma. Cd affects liver function via modulation of cell survival/proliferation, differentiation, and apoptosis. Moreover, Cd dysregulates hepatic autophagy, an endogenous catabolic process that detoxifies damaged cell organelles or dysfunctional cytosolic proteins through vacuole-mediated sequestration and lysosomal degradation. In this article, we review recent developments and findings regarding the role of Cd in the modulation of hepatotoxicity, autophagic function, and liver diseases at the molecular level.
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Affiliation(s)
- Suryakant Niture
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA
| | - Minghui Lin
- The Fourth People's Hospital of Ningxia Hui Autonomous Region, Yinchuan 750021, China
| | - Qi Qi
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA
| | - John T. Moore
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA
| | - Keith E. Levine
- RTI International, Research Triangle Park, Durham, NC 27709, USA
| | | | - Deepak Kumar
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA
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Yeh H, Chiang CC, Yen TH. Hepatocellular carcinoma in patients with renal dysfunction: Pathophysiology, prognosis, and treatment challenges. World J Gastroenterol 2021; 27:4104-4142. [PMID: 34326614 PMCID: PMC8311541 DOI: 10.3748/wjg.v27.i26.4104] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/17/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
The population of patients with hepatocellular carcinoma (HCC) overlaps to a high degree with those for chronic kidney disease (CKD) and end-stage renal disease (ESRD). The degrees of renal dysfunction vary, from the various stages of CKD to dialysis-dependent ESRD, which often affects the prognosis and treatment choice of patients with HCC. In addition, renal dysfunction makes treatment more difficult and may negatively affect treatment outcomes. This study summarized the possible causes of the high comorbidity of HCC and renal dysfunction. The possible mechanisms of CKD causing HCC involve uremia itself, long-term dialysis status, immunosuppressive agents for postrenal transplant status, and miscellaneous factors such as hormone alterations and dysbiosis. The possible mechanisms of HCC affecting renal function include direct tumor invasion and hepatorenal syndrome. Finally, we categorized the risk factors that could lead to both HCC and CKD into four categories: Environmental toxins, viral hepatitis, metabolic syndrome, and vasoactive factors. Both CKD and ESRD have been reported to negatively affect HCC prognosis, but more research is warranted to confirm this. Furthermore, ESRD status itself ought not to prevent patients receiving aggressive treatments. This study then adopted the well-known Barcelona Clinic Liver Cancer guidelines as a framework to discuss the indicators for each stage of HCC treatment, treatment-related adverse renal effects, and concerns that are specific to patients with pre-existing renal dysfunction when undergoing aggressive treatments against CKD and ESRD. Such aggressive treatments include liver resection, simultaneous liver kidney transplantation, radiofrequency ablation, and transarterial chemoembolization. Finally, focusing on patients unable to receive active treatment, this study compiled information on the latest systemic pharmacological therapies, including targeted and immunotherapeutic drugs. Based on available clinical studies and Food and Drug Administration labels, this study details the drug indications, side effects, and dose adjustments for patients with renal dysfunction. It also provides a comprehensive review of information on HCC patients with renal dysfunction from disease onset to treatment.
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Affiliation(s)
- Hsuan Yeh
- Department of Nephrology, Chang Gung Memorial Hospital and Chang Gung University, Taipei 105, Taiwan
| | - Chun-Cheng Chiang
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Tzung-Hai Yen
- Department of Nephrology, Chang Gung Memorial Hospital and Chang Gung University, Taipei 105, Taiwan
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36
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Cui ZG, Ahmed K, Zaidi SF, Muhammad JS. Ins and outs of cadmium-induced carcinogenesis: Mechanism and prevention. Cancer Treat Res Commun 2021; 27:100372. [PMID: 33865114 DOI: 10.1016/j.ctarc.2021.100372] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 04/03/2021] [Accepted: 04/06/2021] [Indexed: 11/16/2022]
Abstract
Cadmium (Cd) is a heavy metal and a highly toxic pollutant that is released into the environment as a byproduct of most modern factories and industries. Cd enters our body in significant quantities from contaminated water, cigarette smoke, or food product to many detrimental health hazards. Based on causal association all the Cd-related or derived compounds have been classified as carcinogens. In this study, we present an overview of the published literature to understand the molecular mechanisms for Cd-induced carcinogenesis and its prevention. In acute Cd poisoning production of reactive oxygen species is a key factor. However, chronic Cd exposure can transform cells to become more resistant to oxidative stress. Also, as an epigenetic mechanism Cd acts indirectly on DNA repair mechanisms via alteration of reactions upstream. Those transformed cells acquire resistance to apoptosis and deregulation of calcium homeostasis. Leading to uncontrolled carcinogenic cell proliferation and inherent DNA lesions. Flavonoids commonly found in plant foods have been shown to have a protective effect against Cd-induced carcinogenicity. A wide variety of tumorigenic mechanisms involved in chronic Cd exposure and the beneficial effects of flavonoids against Cd-induced carcinogenicity necessitate further investigations.
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Affiliation(s)
- Zheng-Guo Cui
- Graduate School of Medicine, Henan Polytechnic University, Jiaozuo 454000, China; Department of Environmental Health, University of Fukui School of Medical Science, 23-3 Matsuoka Shimoaizuki, Eiheiji, Fukui 910-1193 Japan
| | - Kanwal Ahmed
- Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University of Health Sciences, Jeddah, Saudi Arabia
| | - Syed Faisal Zaidi
- Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University of Health Sciences, Jeddah, Saudi Arabia
| | - Jibran Sualeh Muhammad
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates.
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Man RJ, Jeelani N, Zhou C, Yang YS. Recent Progress in the Development of Quinoline Derivatives for the Exploitation of Anti-Cancer Agents. Anticancer Agents Med Chem 2021; 21:825-838. [PMID: 32416703 DOI: 10.2174/1871520620666200516150345] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 01/23/2020] [Accepted: 02/10/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Along with the progress in medicine and therapies, the exploitation of anti-cancer agents focused more on the vital signaling pathways and key biological macromolecules. With rational design and advanced synthesis, quinoline derivatives have been utilized frequently in medicinal chemistry, especially in developing anti-cancer drugs or candidates. METHODS Using DOI searching, articles published before 2020 all over the world have been reviewed as comprehensively as possible. RESULTS In this review, we selected the representative quinoline derivate drugs in market or clinical trials, classified them into five major categories with detailed targets according to their main mechanisms, discussed the relationship within the same mechanism, and generated a summative discussion with prospective expectations. For each mechanism, the introduction of the target was presented, with the typical examples of quinoline derivate drugs. CONCLUSION This review has highlighted the quinoline drugs or candidates, suited them into corresponding targets in their pathways, summarized and discussed. We hope that this review may help the researchers who are interested in discovering quinoline derivate anti-cancer agents obtain considerable understanding of this specific topic. Through the flourishing period and the vigorous strategies in clinical trials, quinoline drugs would be potential but facing new challenges in the future.
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Affiliation(s)
- Ruo-Jun Man
- College of Chemistry and Chemical Engineering, Guangxi University for Nationalities, Nanning, China
| | - Nasreen Jeelani
- Institute of Chemistry and BioMedical Sciences, School of Life Sciences, Nanjing University, Nanjing 210023, China
| | - Chongchen Zhou
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, 450018, China
| | - Yu-Shun Yang
- Institute of Chemistry and BioMedical Sciences, School of Life Sciences, Nanjing University, Nanjing 210023, China
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38
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Park E, Kim J, Kim B, Park EY. Association between environmental exposure to cadmium and risk of suspected non-alcoholic fatty liver disease. CHEMOSPHERE 2021; 266:128947. [PMID: 33220986 DOI: 10.1016/j.chemosphere.2020.128947] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 10/23/2020] [Accepted: 11/08/2020] [Indexed: 05/21/2023]
Abstract
AIM We evaluated the associations between blood Cadmium (Cd) concentrations and risk of suspected NAFLD using nationally representative data from the Korea National Health and Nutrition Examination Survey (KNHANES) 2008-2013, 2016 and 2017. METHODS This cross-sectional study included 12,099 adults for the serum alanine aminotransferase (ALT) and hepatic steatosis index (HSI) analyses and 2,904 adults for the serum gamma-glutamyl transferase (GGT) and fatty liver index (FLI) analyses, without significant alcohol consumption. Blood Cd concentrations were measured by graphite furnace atomic absorption spectrometry. Data were analyzed using survey logistic regression models. RESULTS Odds ratios (ORs) of suspected NAFLD increased significantly per unit of natural log-transformed blood Cd concentration (OR [95% (CI)], for ALT, overall: 1.50 [1.34, 1.68], men: 1.64 [1.40, 2.10] and women: 1.29 [1.08, 1.47]; for GGT, overall: 1.77 [1.33, 2.35], men: 2.28 [1.53, 3.41] and women: 1.27 [0.82, 1.97]; for FLI, overall: 1.84 [1.32, 2.57], men: 1.91 [1.24, 2.94] and women: 1.58 [0.87, 2.86]; for HSI, overall: 1.19 [1.07, 1.32], men: 1.17 [1.01, 1.37] and women: 1.14 [0.99, 1.32]). The blood Cd concentrations associated with risk of suspected NAFLD were lower than those previously reported (for ALT, > 0.64 μg/L, for GGT, > 1.41 μg/L, for FLI, > 0.96 μg/L, and for HSI, > 1.41 μg/L). CONCLUSIONS This study suggests that the reference level of blood Cd should probably be lower than the previously recommended value to prevent adverse health effects due to Cd exposure.
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Affiliation(s)
- Eunjung Park
- Division of Cancer Prevention & Early Detection, National Cancer Control Institute, National Cancer Center, Goyang, Republic of Korea
| | - Jinsun Kim
- Division of TB and HIV/AIDS Control, Center for Disease Prevention, Korea Centers for Disease Control & Prevention, Cheongju-si, Republic of Korea
| | - Byungmi Kim
- Division of Cancer Prevention & Early Detection, National Cancer Control Institute, National Cancer Center, Goyang, Republic of Korea
| | - Eun Young Park
- Division of Cancer Prevention & Early Detection, National Cancer Control Institute, National Cancer Center, Goyang, Republic of Korea.
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Saintilnord WN, Tenlep SYN, Preston JD, Duregon E, DeRouchey JE, Unrine JM, de Cabo R, Pearson KJ, Fondufe-Mittendorf YN. Chronic Exposure to Cadmium Induces Differential Methylation in Mice Spermatozoa. Toxicol Sci 2021; 180:262-276. [PMID: 33483743 PMCID: PMC8041459 DOI: 10.1093/toxsci/kfab002] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Cadmium exposure is ubiquitous and has been linked to diseases including cancers and reproductive defects. Since cadmium is nonmutagenic, it is thought to exert its gene dysregulatory effects through epigenetic reprogramming. Several studies have implicated germline exposure to cadmium in developmental reprogramming. However, most of these studies have focused on maternal exposure, while the impact on sperm fertility and disease susceptibility has received less attention. In this study, we used reduced representation bisulfite sequencing to comprehensively investigate the impact of chronic cadmium exposure on mouse spermatozoa DNA methylation. Adult male C57BL/J6 mice were provided water with or without cadmium chloride for 9 weeks. Sperm, testes, liver, and kidney tissues were collected at the end of the treatment period. Cadmium exposure was confirmed through gene expression analysis of metallothionein-1 and 2, 2 well-known cadmium-induced genes. Analysis of sperm DNA methylation changes revealed 1788 differentially methylated sites present at regulatory regions in sperm of mice exposed to cadmium compared with vehicle (control) mice. Furthermore, most of these differential methylation changes positively correlated with changes in gene expression at both the transcription initiation stage as well as the splicing levels. Interestingly, the genes targeted by cadmium exposure are involved in several critical developmental processes. Our results present a comprehensive analysis of the sperm methylome in response to chronic cadmium exposure. These data, therefore, highlight a foundational framework to study gene expression patterns that may affect fertility in the exposed individual as well as their offspring, through paternal inheritance.
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Affiliation(s)
- Wesley N Saintilnord
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536-0509, USA
| | - Sara Y N Tenlep
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40536-0509, USA
| | - Joshua D Preston
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40536-0509, USA,Emory University School of Medicine, Atlanta, Georgia 30322, USA
| | - Eleonora Duregon
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 20892, USA
| | - Jason E DeRouchey
- Department of Chemistry, University of Kentucky, Lexington, Kentucky 40536-0509, USA
| | - Jason M Unrine
- Department of Plant and Soil Sciences, University of Kentucky, Lexington, Kentucky 40536-0509, USA
| | - Rafael de Cabo
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 20892, USA
| | - Kevin J Pearson
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40536-0509, USA,To whom correspondence should be addressed at Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536-0509, USA. E-mail: ; Department of Molecular and Cellular Biochemistry, University of Kentucky, 800 Rose Street, 273 BBSRB, Lexington, KY 40536-0509, USA. E-mail:
| | - Yvonne N Fondufe-Mittendorf
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536-0509, USA,To whom correspondence should be addressed at Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536-0509, USA. E-mail: ; Department of Molecular and Cellular Biochemistry, University of Kentucky, 800 Rose Street, 273 BBSRB, Lexington, KY 40536-0509, USA. E-mail:
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Rehman AU, Nazir S, Irshad R, Tahir K, ur Rehman K, Islam RU, Wahab Z. Toxicity of heavy metals in plants and animals and their uptake by magnetic iron oxide nanoparticles. J Mol Liq 2021. [DOI: 10.1016/j.molliq.2020.114455] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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41
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Tian J, Hu J, Liu D, Yin J, Chen M, Zhou L, Yin H. Cadmium chloride-induced transgenerational neurotoxicity in zebrafish development. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2021; 81:103545. [PMID: 33171223 DOI: 10.1016/j.etap.2020.103545] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 10/12/2020] [Accepted: 11/04/2020] [Indexed: 06/11/2023]
Abstract
As an important environmental pollutant, the heavy metal cadmium has a significant negative impact on the stability of the ecological environment and on organismal health. Previous studies have shown that cadmium chloride can damage the nervous, skeletal, endocrine, and reproductive systems, but to our knowledge, the effects of cadmium on the behavior, neurotransmitter levels, and neuronal development in the offspring of exposed animals have not been reported. In the present study, sexually-mature zebrafish were exposed to cadmium chloride at different concentrations for 60 days, and in this background, behavior, neurotransmitters level, neuro-development and neurotransmitter metabolism was investigated in the F1 offspring. The results showed that exposure of the parental zebrafish to cadmium chloride resulted swimming speed and distance of F1 offspring significantly reduced; the levels of neurotransmitters, such as dopamine, serotonin, and acetylcholine is disrupted. neuro-development and neurotransmitter metabolism related genes expression pattern was altered, which cause zebrafish F1 offspring developmental neurotoxicity. These findings provide further insights into the harm posed by cadmium chloride to the aquatic ecosystems.
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Affiliation(s)
- Jingjing Tian
- Academy for Engineering & Technology, Fudan University, Shanghai 200433, PR China; CAS Key Lab of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, Jiangsu 215163, PR China
| | - Jia Hu
- School of Biology & Basic Medical Sciences, Medical College, Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Di Liu
- CAS Key Lab of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, Jiangsu 215163, PR China
| | - Jian Yin
- CAS Key Lab of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, Jiangsu 215163, PR China
| | - Mingli Chen
- CAS Key Lab of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, Jiangsu 215163, PR China
| | - Lianqun Zhou
- Academy for Engineering & Technology, Fudan University, Shanghai 200433, PR China; CAS Key Lab of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, Jiangsu 215163, PR China.
| | - Huancai Yin
- CAS Key Lab of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, Jiangsu 215163, PR China.
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Cheng Y, Bao Y, Chen X, Yao Q, Wang C, Chai S, Zeng J, Fan X, Kang H, Sha L, Zhang H, Zhou Y, Wang Y. Different nitrogen forms differentially affect Cd uptake and accumulation in dwarf Polish wheat (Triticum polonicum L.) seedlings. JOURNAL OF HAZARDOUS MATERIALS 2020; 400:123209. [PMID: 32947742 DOI: 10.1016/j.jhazmat.2020.123209] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 06/08/2020] [Accepted: 06/11/2020] [Indexed: 05/22/2023]
Abstract
This study investigated the effects of different nitrogen (N) forms on Cadmium (Cd) uptake and accumulation in dwarf Polish wheat (DPW) seedlings, which were grown under Cd stress with N-Null, NH4+-N, NO3--N and NH4+-N + NO3--N. We measured plant growth and determined Cd uptake, translocation, accumulation, subcellular distribution and chemical forms in the roots and shoots of DPW seedlings. We also analyzed saccharide concentrations, and the transcript levels of genes encoding metal transporters in the roots of DPW seedlings. In the absence of NO3--N, addition of NH4+-N reduced roots Cd concentration, FCW (Cd in cell wall), FS (Cd in soluble fraction) and FE (inorganic Cd) concentrations, and induced the expression of four genes encoding metal transporters in roots, while it promoted Cd translocation to shoots. In the presence of NO3--N, addition of NH4+-N increased roots Cd concentration, FCW and FW concentrations, and induced the expression of 22 genes encoding metal transporters in roots. Regardless of NH4+-N level, addition of NO3--N increased roots Cd concentration, FCW, FS, FW (water-soluble Cd), FNaCl (pectates and protein Cd), FHAc (undissolved Cd phosphate) and lactose concentrations, and also induced the expression of genes encoding metal transporters in roots. Overall, NH4+-N differently regulated Cd uptake and accumulation in DPW seedlings in the absence or presence of NO3--N, while NO3--N greatly increased Cd uptake and accumulation in the presence of NH4+-N compared to the absence of NH4+-N. These patterns of Cd alteration likely arose due to different N forms altering Cd subcellular distribution and chemical forms, lactose concentration and the expression of metal transporter genes.
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Affiliation(s)
- Yiran Cheng
- Triticeae Research Institute, Sichuan Agricultural University, Wenjiang, 611130, Sichuan, China
| | - Yunjing Bao
- Triticeae Research Institute, Sichuan Agricultural University, Wenjiang, 611130, Sichuan, China
| | - Xing Chen
- Triticeae Research Institute, Sichuan Agricultural University, Wenjiang, 611130, Sichuan, China
| | - Qin Yao
- Triticeae Research Institute, Sichuan Agricultural University, Wenjiang, 611130, Sichuan, China
| | - Chao Wang
- Triticeae Research Institute, Sichuan Agricultural University, Wenjiang, 611130, Sichuan, China
| | - Songyue Chai
- Triticeae Research Institute, Sichuan Agricultural University, Wenjiang, 611130, Sichuan, China
| | - Jian Zeng
- College of Resources, Sichuan Agricultural University, Wenjiang, 611130, Sichuan, China
| | - Xing Fan
- Triticeae Research Institute, Sichuan Agricultural University, Wenjiang, 611130, Sichuan, China; Joint International Research Laboratory of Crop Resources and Genetic Improvement, Sichuan Agricultural University, Wenjiang, 611130, Sichuan, China
| | - Houyang Kang
- Triticeae Research Institute, Sichuan Agricultural University, Wenjiang, 611130, Sichuan, China; Joint International Research Laboratory of Crop Resources and Genetic Improvement, Sichuan Agricultural University, Wenjiang, 611130, Sichuan, China
| | - Lina Sha
- Triticeae Research Institute, Sichuan Agricultural University, Wenjiang, 611130, Sichuan, China; Joint International Research Laboratory of Crop Resources and Genetic Improvement, Sichuan Agricultural University, Wenjiang, 611130, Sichuan, China
| | - Haiqin Zhang
- Triticeae Research Institute, Sichuan Agricultural University, Wenjiang, 611130, Sichuan, China; Joint International Research Laboratory of Crop Resources and Genetic Improvement, Sichuan Agricultural University, Wenjiang, 611130, Sichuan, China
| | - Yonghong Zhou
- Triticeae Research Institute, Sichuan Agricultural University, Wenjiang, 611130, Sichuan, China; Joint International Research Laboratory of Crop Resources and Genetic Improvement, Sichuan Agricultural University, Wenjiang, 611130, Sichuan, China.
| | - Yi Wang
- Triticeae Research Institute, Sichuan Agricultural University, Wenjiang, 611130, Sichuan, China; Joint International Research Laboratory of Crop Resources and Genetic Improvement, Sichuan Agricultural University, Wenjiang, 611130, Sichuan, China.
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Cadmium and Lead Exposure, Nephrotoxicity, and Mortality. TOXICS 2020; 8:toxics8040086. [PMID: 33066165 PMCID: PMC7711868 DOI: 10.3390/toxics8040086] [Citation(s) in RCA: 112] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 10/07/2020] [Accepted: 10/11/2020] [Indexed: 12/11/2022]
Abstract
The present review aims to provide an update on health risks associated with the low-to-moderate levels of environmental cadmium (Cd) and lead (Pb) to which most populations are exposed. Epidemiological studies examining the adverse effects of coexposure to Cd and Pb have shown that Pb may enhance the nephrotoxicity of Cd and vice versa. Herein, the existing tolerable intake levels of Cd and Pb are discussed together with the conventional urinary Cd threshold limit of 5.24 μg/g creatinine. Dietary sources of Cd and Pb and the intake levels reported for average consumers in the U.S., Spain, Korea, Germany and China are summarized. The utility of urine, whole blood, plasma/serum, and erythrocytes to quantify exposure levels of Cd and Pb are discussed. Epidemiological studies that linked one of these measurements to risks of chronic kidney disease (CKD) and mortality from common ailments are reviewed. A Cd intake level of 23.2 μg/day, which is less than half the safe intake stated by the guidelines, may increase the risk of CKD by 73%, and urinary Cd levels one-tenth of the threshold limit, defined by excessive ß2-microglobulin excretion, were associated with increased risk of CKD, mortality from heart disease, cancer of any site and Alzheimer's disease. These findings indicate that the current tolerable intake of Cd and the conventional urinary Cd threshold limit do not provide adequate health protection. Any excessive Cd excretion is probably indicative of tubular injury. In light of the evolving realization of the interaction between Cd and Pb, actions to minimize environmental exposure to these toxic metals are imperative.
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Xu MY, Sun YJ, Wang P, Yang L, Wu YJ. Metabolomic biomarkers in urine of rats following long-term low-dose exposure of cadmium and/or chlorpyrifos. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2020; 195:110467. [PMID: 32182532 DOI: 10.1016/j.ecoenv.2020.110467] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 03/05/2020] [Accepted: 03/09/2020] [Indexed: 06/10/2023]
Abstract
Heavy metals and pesticides can be easily enriched in food chains and accumulated in organisms, thus pose significant threat to human health. However, their combined effects for long-term exposure at low dose has not been thoroughly investigated; especially there was no biofluid biomarker available to noninvasively diagnose the toxicosis of the combined exposure of the two chemicals at their low levels. In this study, we investigated the change of urine metabolites of rats with 90-day exposure to heavy metal cadmium (Cd) and/or organophosphorus pesticide chlorpyrifos (CPF) using gas chromatography-mass spectrometry (GC-MS)-based metabolomics approach. Our results showed that the interaction of Cd and CPF mainly displayed an antagonistic effect. We identified the panels of metabolite biomarkers in urine: benzoic acid and mannose were unique biomarkers for Cd exposure; creatinine and N-phenylacetyl glycine were unique biomarkers for CPF exposure; anthranilic acid, ribitol, and glucose were unique biomarkers for Cd plus CPF exposure. Our results suggest that 90-day exposure to Cd and/or CPF could cause a disturbance in energy and amino acid metabolism. And urine metabolomics analysis can help understand the toxicity of low dose exposure to mixed environmental chemicals.
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Affiliation(s)
- Ming-Yuan Xu
- Laboratory of Molecular Toxicology, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, PR China
| | - Ying-Jian Sun
- Department of Veterinary Medicine and Animal Science, Beijing University of Agriculture, Beijing, 102206, PR China
| | - Pan Wang
- Laboratory of Molecular Toxicology, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, PR China
| | - Lin Yang
- Laboratory of Molecular Toxicology, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, PR China
| | - Yi-Jun Wu
- Laboratory of Molecular Toxicology, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, PR China.
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Zhang C, Ge J, Lv M, Zhang Q, Talukder M, Li JL. Selenium prevent cadmium-induced hepatotoxicity through modulation of endoplasmic reticulum-resident selenoproteins and attenuation of endoplasmic reticulum stress. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2020; 260:113873. [PMID: 32369892 DOI: 10.1016/j.envpol.2019.113873] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 12/20/2019] [Accepted: 12/22/2019] [Indexed: 06/11/2023]
Abstract
Cadmium (Cd), a heavy metal contaminant, exists in humans and animals throughout life and closely associate with severe hepatotoxicity. Selenium (Se) has been recognized as an effective chemo-protectant of Cd, but the underlying mechanisms remain unclear. The objective of the present study is to illustrate the antagonistic effect of Se against Cd-induced hepatotoxicity. Primary hepatocytes were cultured in the presence of 5 μM Cd, 1 μM Se and the mixture of 1 μM Se and 5 μM Cd for 24 h. Cell viability and morphology, antioxidant status, endoplasmic reticulum (ER) stress response and selenotranscriptome were assessed. It was observed that Se treatment dramatically alleviated Cd-induced hepatocytes death and morphological change. Simultaneously, Se mitigated Cd-induced oxidative stress by reducing ROS production, increasing reduced glutathione (GSH) level and increasing selenoenzyme (glutathione peroxidase, GPX) activity. Cd induced hepatotoxicity via disordering ER-resident selenoproteins transcription and triggering ER stress and unfolded protein response. Supplementary Se evidently relieved hepatocytes injury via modulating ER-resident selenoproteins transcription to inhibit ER stress. Collectively, our findings showed a potential protection of Se against Cd-induced hepatotoxicity via suppressing ER stress response.
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Affiliation(s)
- Cong Zhang
- College of Veterinary Medicine, PR China.
| | - Jing Ge
- College of Veterinary Medicine, PR China.
| | - Meiwei Lv
- College of Veterinary Medicine, PR China.
| | - Qi Zhang
- College of Veterinary Medicine, PR China.
| | - Milton Talukder
- College of Veterinary Medicine, PR China; Department of Physiology and Pharmacology, Faculty of Animal Science and Veterinary Medicine, Patuakhali Science and Technology University, Barishal, 8210, Bangladesh.
| | - Jin-Long Li
- College of Veterinary Medicine, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin, 150030, PR China.
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Chen J, Liu J, Lei Y, Liu M. Potential ameliorative effects of epigallocatechin-3-gallate against cigarette smoke exposure induced renal and hepatic deficits. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2020; 191:110202. [PMID: 31945511 DOI: 10.1016/j.ecoenv.2020.110202] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 01/08/2020] [Accepted: 01/10/2020] [Indexed: 06/10/2023]
Abstract
The environmental pollution caused by cigarette smoke (CS) seriously endangers people's health. Epigallocatechin-3-gallate (EGCG) is the most abundant catechin in green tea. In this study, rats were exposed to CS for 90 days. Kidney function was evaluated by detecting the levels of serum creatinine and blood urea nitrogen. Liver function was evaluated by detecting the activities of alanine aminotransferase and aspartate transaminase. The renal and hepatic oxidative stress and inflammation were assessed by detecting the levels of malondialdehyde, reduced glutathione, antioxidant enzymes (superoxide dismutase and glutathione peroxidase) and proinflammatory cytokines. Organ fibrosis was evaluated by observing collagen deposition via masson staining, by examining the hydroxyproline level, by measuring the mRNA levels of fibrosis-associated genes collagen (Col)-1A1 and Col-3A1, as well as by assessing the activity of profibrotic TGF-β1 pathway. Additionally, renal and hepatic epithelial-mesenchymal transition (EMT) were evaluated. It was observed that EGCG ameliorated the renal and hepatic oxidative stress, inflammation, EMT, as well as inhibited the activation of TGF-β1 signaling pathway induced by CS. These results showed that EGCG could attenuate CS-induced renal and hepatic fibrosis.
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Affiliation(s)
- Jinglou Chen
- The Gerontology Research Center of Jianghan University, The Sixth Hospital of Wuhan (Affiliated Hospital of Jianghan University), Jianghan University, Wuhan, China; Medical College, Jianghan University, Wuhan, China.
| | - Jianhua Liu
- The Gerontology Research Center of Jianghan University, The Sixth Hospital of Wuhan (Affiliated Hospital of Jianghan University), Jianghan University, Wuhan, China; Medical College, Jianghan University, Wuhan, China
| | - Yongfang Lei
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Min Liu
- The Gerontology Research Center of Jianghan University, The Sixth Hospital of Wuhan (Affiliated Hospital of Jianghan University), Jianghan University, Wuhan, China.
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El-Boshy M, Refaat B, Almaimani RA, Abdelghany AH, Ahmad J, Idris S, Almasmoum H, Mahbub AA, Ghaith MM, BaSalamah MA. Vitamin D 3 and calcium cosupplementation alleviates cadmium hepatotoxicity in the rat: Enhanced antioxidative and anti-inflammatory actions by remodeling cellular calcium pathways. J Biochem Mol Toxicol 2020; 34:e22440. [PMID: 31926057 DOI: 10.1002/jbt.22440] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Revised: 12/10/2019] [Accepted: 12/17/2019] [Indexed: 12/13/2022]
Abstract
Although vitamin D (VD) and calcium (Ca) attenuate cadmium (Cd) metabolism, their combined antioxidant and anti-inflammatory actions against Cd toxicity have not been previously explored. Hence, this study measured the protective effects of VD ± Ca supplements against Cd hepatotoxicity. Forty adult male rats were distributed to: negative controls (NCs), positive controls (PCs), VD, Ca, and VD3 and Ca (VDC) groups. All groups, except NC, received CdCl2 in drinking water (44 mg/L) for 4 weeks individually or concurrently with intramuscular VD3 (600 IU/kg; three times per week) and/or oral Ca (100 mg/kg; five times per week). The PC group showed abnormal hepatic biochemical parameters and increase in cellular cytochrome C, caspase-9, and caspase-3 alongside the apoptotic/necrotic cell numbers by terminal deoxynucleotidyl transferase dUTP nick end labeling technique. The PC hepatic tissue also had substantially elevated pro-oxidants (malondialdehyde [MDA]/H2 O2 /protein carbonyls) and inflammatory cytokines (interleukin 1β [IL-1β]/IL-6/IL17A/tumor necrosis factor-α), whereas the anti-inflammatory (IL-10/IL-22) and antioxidants (glutathione [GSH]/GPx/catalase enzyme [CAT]) markers declined. Hypovitaminosis D, low hepatic tissue Ca, aberrant hepatic expression of VD-metabolizing enzymes (Cyp2R1/Cyp27a1/cyp24a1), receptor and binding protein alongside Ca-membrane (CaV 1.1/CaV 3.1), and store-operated (RyR1/ITPR1) channels, and Ca-binding proteins (CAM/CAMKIIA/S100A1/S100B) were observed in the PC group. Both monotherapies decreased serum, but not tissue Cd levels, restored the targeted hepatic VD/Ca molecules' expression. However, these effects were more prominent in the VD group than the Ca group. The VDC group, contrariwise, disclosed the greatest alleviations on serum and tissue Cd, inflammatory and oxidative markers, the VD/Ca molecules and tissue integrity. In conclusion, this report is the first to reveal boosted protection for cosupplementing VD and Ca against Cd hepatotoxicity that could be due to enhanced antioxidative, anti-inflammatory, and modulation of the Ca pathways.
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Affiliation(s)
- Mohamed El-Boshy
- Faculty of Applied Medical Sciences, Department of Laboratory Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.,Faculty of Veterinary Medicine, Department of Clinical Pathology, Mansoura University, Mansoura, Egypt
| | - Bassem Refaat
- Faculty of Applied Medical Sciences, Department of Laboratory Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Riyad A Almaimani
- Faculty of Medicine, Department of Biochemistry, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Abdelghany H Abdelghany
- Faculty of Applied Medical Sciences, Department of Laboratory Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.,Faculty of Medicine, Department of Anatomy, Alexandria University, Alexandria, Egypt
| | - Jawwad Ahmad
- Faculty of Applied Medical Sciences, Department of Laboratory Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Shakir Idris
- Faculty of Applied Medical Sciences, Department of Laboratory Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Hussain Almasmoum
- Faculty of Applied Medical Sciences, Department of Laboratory Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Amani A Mahbub
- Faculty of Applied Medical Sciences, Department of Laboratory Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Mazen M Ghaith
- Faculty of Applied Medical Sciences, Department of Laboratory Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Mohammad A BaSalamah
- Faculty of Medicine, Department of Pathology, Umm Al-Qura University, Makkah, Saudi Arabia
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He X, Gao J, Hou H, Qi Z, Chen H, Zhang XX. Inhibition of Mitochondrial Fatty Acid Oxidation Contributes to Development of Nonalcoholic Fatty Liver Disease Induced by Environmental Cadmium Exposure. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2019; 53:13992-14000. [PMID: 31682409 DOI: 10.1021/acs.est.9b05131] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Cadmium (Cd) is one of the most prevalent toxic metal pollutants widely distributed in water and soil environments. Epidemiological studies have shown that exposure to Cd is implicated in the prevalence of nonalcoholic fatty liver disease (NAFLD) in middle-aged human population, but biological evidence is lacking and its toxicological mechanism remains unclear for the disease predisposition from environmental Cd exposure. In this study, we established a chronic Cd-exposure mouse model mimicking the liver Cd deposition in middle-aged human population to determine whether the environmental Cd exposure can induce NAFLD. Results showed that hepatic Cd burden at levels of 0.95 and 6.04 μg/g wet weight resulting from 20-week Cd exposure at different doses induced NAFLD and nonalcoholic steatohepatitis-like phenotypes in mice, respectively. The Cd exposure caused marked hepatic mitochondrial dysfunction and fatty acid oxidation deficiency, along with significant suppression of sirtuin 1 (SIRT1) signaling pathway in the liver. In vitro study confirmed that Cd evidently inhibited the mitochondrial fatty acid oxidation in hepatocytes and that SIRT1 signaling was potentially involved in the process. Our findings suggest that exposure to environmental Cd is a tangible risk factor for NAFLD, and the induced public health risks deserve greater attention.
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Seong JB, Bae YC, Lee HS, Huh JW, Lee SR, Lee HJ, Lee DS. Increasing ERK phosphorylation by inhibition of p38 activity protects against cadmium-induced apoptotic cell death through ERK/Drp1/p38 signaling axis in spermatocyte-derived GC-2spd cells. Toxicol Appl Pharmacol 2019; 384:114797. [PMID: 31676320 DOI: 10.1016/j.taap.2019.114797] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 10/24/2019] [Accepted: 10/26/2019] [Indexed: 01/30/2023]
Abstract
Many studies report that cadmium chloride (CdCl2)-induces oxidative stress is associated with male reproductive damage in the testes. CdCl2 also induces mitochondrial fission by increasing dynamin-related protein 1 (Drp1) expression as well as the mitochondria-dependent apoptosis pathway by extracellular signal-regulated kinase (ERK) activation. However, it remains unclear whether mechanisms linked to the mitochondrial damage signal via CdCl2-induced mitogen-activated protein kinases (MAPK) cause damage to spermatocytes. In this study, increased intracellular and mitochondrial reactive oxygen species (ROS) levels, mitochondrial membrane potential (∆Ψm) depolarization, and mitochondrial fragmentation and swelling were observed at 5 μM of CdCl2 exposure, resulting in increased apoptotic cell death. Moreover, CdCl2-induced cell death is closely associated with the ERK/Drp1/p38 signaling axis. Interestingly, SB203580, a p38 inhibitor, effectively prevented CdCl2-induced apoptotic cell death by reducing ∆Ψm depolarization and intracellular and mitochondrial ROS levels. Knockdown of Drp1 expression diminished CdCl2-induced mitochondrial deformation and ROS generation and protected GC-2spd cells from apoptotic cell death. In addition, electron microscopy showed that p38 inhibition reduced CdCl2-induced mitochondrial interior damage more effectively than N-acetyl-L-cysteine (NAC), an ROS scavenger; ERK inhibition; or Drp1 knockdown. Therefore, these results demonstrate that inhibition of p38 activity prevents CdCl2-induced apoptotic GC-2spd cell death by reducing depolarization of mitochondrial membrane potential and mitochondrial ROS levels via ERK phosphorylation in a signal pathway different from the CdCl2-induced ERK/Drp1/p38 axis and suggest a therapeutic strategy for CdCl2-induced male infertility.
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Affiliation(s)
- Jung Bae Seong
- School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea; School of Life Sciences & Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - Yong Chul Bae
- Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu, Republic of Korea
| | - Hyun-Shik Lee
- School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea; School of Life Sciences & Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - Jae-Won Huh
- National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Republic of Korea
| | - Sang-Rae Lee
- National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Republic of Korea
| | - Hong Jun Lee
- College of Medicine, Chungbuk National University, Chungbuk, Republic of Korea; Department of Radiology, Chungbuk National University Hospital, Chungbuk, Republic of Korea; Research Institute, e-biogen Inc., Seoul, Republic of Korea
| | - Dong-Seok Lee
- School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea; School of Life Sciences & Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea.
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50
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Ma G, Zhang J, Zhang L, Huang C, Chen L, Wang G, Liu X, Lu C. Elements characterization of Chinese tea with different fermentation degrees and its use for geographical origins by liner discriminant analysis. J Food Compost Anal 2019. [DOI: 10.1016/j.jfca.2019.103246] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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