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Mukherjee AG, Gopalakrishnan AV. Arsenic-induced prostate cancer: an enigma. Med Oncol 2024; 41:50. [PMID: 38184511 DOI: 10.1007/s12032-023-02266-5] [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: 10/25/2023] [Accepted: 11/21/2023] [Indexed: 01/08/2024]
Abstract
Arsenic exhibits varying degrees of toxicity depending on its many chemical forms. The carcinogenic properties of arsenic have already been established. However, the precise processes underlying the development of diseases following acute or chronic exposure to arsenic remain poorly known. Most of the existing investigation has focused on studying the occurrence of cancer following significant exposure to elevated levels of arsenic. Nevertheless, multiple investigations have documented diverse health consequences from prolonged exposure to low levels of arsenic. Inorganic arsenic commonly causes lung, bladder, and skin cancer. Some investigations have shown an association between arsenic in drinking water and prostate cancer, but few investigations have focused on exploring this connection. There is currently a lack of relevant animal models demonstrating a clear link between inorganic arsenic exposure and the development of prostate cancer. Nevertheless, studies using cellular model systems have demonstrated that arsenic can potentially promote the malignant transformation of human prostate epithelial cells in vitro. The administration of elevated levels of arsenic has been demonstrated to elicit cell death in instances of acute experimental exposure. Conversely, in cases of chronic exposure, arsenic prompts cellular proliferation and sustains cellular viability, thereby circumventing the constraints imposed by telomere shortening and apoptosis. Furthermore, cells consistently exposed to the stimulus exhibit an augmented ability to invade surrounding tissues and an enhanced potential to form tumors. This review aims to portray mechanistic insights into arsenic-induced prostate cancer.
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Affiliation(s)
- Anirban Goutam Mukherjee
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.
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EFSA Panel on Contaminants in the Food Chain (CONTAM), Schrenk D, Bignami M, Bodin L, Chipman JK, del Mazo J, Grasl‐Kraupp B, Hogstrand C, Hoogenboom L(R, Leblanc J, Nebbia CS, Nielsen E, Ntzani E, Petersen A, Sand S, Vleminckx C, Wallace H, Barregård L, Benford D, Broberg K, Dogliotti E, Fletcher T, Rylander L, Abrahantes JC, Gómez Ruiz JÁ, Steinkellner H, Tauriainen T, Schwerdtle T. Update of the risk assessment of inorganic arsenic in food. EFSA J 2024; 22:e8488. [PMID: 38239496 PMCID: PMC10794945 DOI: 10.2903/j.efsa.2024.8488] [Citation(s) in RCA: 36] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2024] Open
Abstract
The European Commission asked EFSA to update its 2009 risk assessment on arsenic in food carrying out a hazard assessment of inorganic arsenic (iAs) and using the revised exposure assessment issued by EFSA in 2021. Epidemiological studies show that the chronic intake of iAs via diet and/or drinking water is associated with increased risk of several adverse outcomes including cancers of the skin, bladder and lung. The CONTAM Panel used the benchmark dose lower confidence limit based on a benchmark response (BMR) of 5% (relative increase of the background incidence after adjustment for confounders, BMDL05) of 0.06 μg iAs/kg bw per day obtained from a study on skin cancer as a Reference Point (RP). Inorganic As is a genotoxic carcinogen with additional epigenetic effects and the CONTAM Panel applied a margin of exposure (MOE) approach for the risk characterisation. In adults, the MOEs are low (range between 2 and 0.4 for mean consumers and between 0.9 and 0.2 at the 95th percentile exposure, respectively) and as such raise a health concern despite the uncertainties.
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Baghery F, Lau LDW, Mohamadi M, Vazirinejad R, Ahmadi Z, Javedani H, Eslami H, Nazari A. Risk of urinary tract cancers following arsenic exposure and tobacco smoking: a review. ENVIRONMENTAL GEOCHEMISTRY AND HEALTH 2023; 45:5579-5598. [PMID: 37248359 DOI: 10.1007/s10653-023-01627-3] [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: 02/28/2023] [Accepted: 05/18/2023] [Indexed: 05/31/2023]
Abstract
Bladder cancer, prostate cancer, and kidney cancer, due to their high morbidity and mortality rates, result in significant economic and health care costs. Arsenic exposure affects the drinking water of millions of people worldwide. Long-term exposure to arsenic, even in low concentrations, increases the risk of developing various cancers. Smoking is also one of the leading causes of bladder, prostate and kidney cancers. Accordingly, this research reviews the relationship between arsenic exposure and smoking with three kinds of urinary tract cancers (bladder cancer, prostate cancer, and kidney cancer) due to their widespread concern for their negative impact on public health globally. In this review, we have gathered the most current information from scientific databases [PubMed, Scopus, Google Scholar, ISI web of science] regarding the relationship between arsenic exposure and tobacco smoking with the risk of bladder, prostate, and kidney cancer. In several studies, a significant relationship was determined between the incidence and mortality rate of the above-mentioned cancers in humans with arsenic exposure and tobacco smoking. The decrease or cessation of smoking and consumption of arsenic-free water significantly declined the incidence of bladder, prostate, and kidney cancers.
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Affiliation(s)
- Fatemeh Baghery
- Pistachio Safety Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | | | - Maryam Mohamadi
- Occupational Safety and Health Research Center, NICICO, WorldSafety Organization and Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Reza Vazirinejad
- Social Determinants of Health Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Zahra Ahmadi
- Pistachio Safety Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Hossein Javedani
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Hadi Eslami
- Occupational Safety and Health Research Center, NICICO, WorldSafety Organization and Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Alireza Nazari
- Social Determinants of Health Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
- Department of Surgery, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
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Kurşunoğlu NE, Sarer Yurekli BP. Endocrine disruptor chemicals as obesogen and diabetogen: Clinical and mechanistic evidence. World J Clin Cases 2022; 10:11226-11239. [PMID: 36387809 PMCID: PMC9649566 DOI: 10.12998/wjcc.v10.i31.11226] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/19/2022] [Accepted: 09/27/2022] [Indexed: 02/05/2023] Open
Abstract
Obesity is becoming an inevitable pandemic all over the world. The World Obesity Federation predicts in the 2022 World Obesity Atlas that one billion people worldwide, including 1 in 5 women and 1 in 7 men, will be living with obesity by 2030. Moreover, the prevalence of diabetes is increasing worldwide, and diabetes is becoming more of a public health problem. Increased insulin resistance due to obesity and deficiency in insulin secretion are the two main causes of type 2 diabetes mellitus (T2DM). An exogenous chemical or mixture of chemicals that interferes with any aspect of hormone action was defined as endocrine-disrupting chemicals (EDCs). Bisphenol A (BPA), the first known EDC, was synthesized and was considered to be estrogenic. Global production of BPA has increased progressively from 5 to 8 million tons (MT) between 2010 and 2016. Furthermore, researchers estimated that the production should reach 10.2 MT by 2022. The human population is exposed to EDCs in daily life in such forms as pesticides/herbicides, industrial and household products, plastics, detergents, and personal care products. The term obesogen was used for chemicals that promote weight gain and obesity by increasing the number of adipocytes and fat storage in existing adipocytes, changing the energy balance, and finally regulating appetite and satiety. Besides the obesogenic effect, EDCs can cause T2DM through alteration in ß cell function and morphology and insulin resistance. In this review, we provide clinical and mechanistic evidence regarding EDCs as obesogen and diabetogen. However, those studies are not enough methodologically to indicate causality. In this respect, randomized clinical trials are needed to investigate the association between obesogen, diabetogen and the related metabolic clinical picture.
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Yang Y, McDonald AC, Wang X, Pan Y, Wang M. Arsenic exposures and prostate cancer risk: A multilevel meta-analysis. J Trace Elem Med Biol 2022; 72:126992. [PMID: 35550984 DOI: 10.1016/j.jtemb.2022.126992] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 03/14/2022] [Accepted: 05/03/2022] [Indexed: 01/08/2023]
Abstract
OBJECTIVE Previous studies found that arsenic exposures have been linked to prostate cancer risk. However, this finding has been inconsistent. The purpose of this paper was to estimate the effects of arsenic exposures on prostate cancer risk. METHOD We conducted a meta-analysis of epidemiologic studies of arsenic exposures and prostate cancer risk. We searched for both arsenic exposure and prostate cancer studies published until January 2021 from the following electronic databases: PubMed, Scopus, and Web of Science. Multilevel meta-analysis via random-effects modeling was used to examine the association between arsenic exposures and prostate cancer risk. RESULTS There were 12 studies included with an effect size of 23. Arsenic exposure was determined from water and soil (n = 8), urinary measurements (n = 2), or self-reported questionnaire (n = 2). Overall, arsenic exposure was found to be statistically significantly associated with prostate cancer risk (Relative risk [RR] = 1.18, 95% confidence interval [CI]: 1.06 - 1.30). In the sub-analysis, arsenic exposure from water and soil was found to be statistically significantly associated with prostate cancer risk (RR= 1.22, 95% CI: 1.05 - 1.41). CONCLUSION Data suggest that arsenic exposures may play a role in increasing prostate cancer risk. Further prospective studies are warranted to verify the association between arsenic exposure and prostate cancer risk.
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Affiliation(s)
- Yanxu Yang
- Department of Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, PA, United States
| | - Alicia C McDonald
- Department of Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, PA, United States; Penn State Cancer Institute, Hershey, PA, United States
| | - Xingyan Wang
- Department of Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, PA, United States
| | - Yunqi Pan
- Department of Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, PA, United States
| | - Ming Wang
- Department of Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, PA, United States; Penn State Cancer Institute, Hershey, PA, United States.
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Lin MH, Li CY, Cheng YY, Guo HR. Arsenic in Drinking Water and Incidences of Leukemia and Lymphoma: Implication for Its Dual Effects in Carcinogenicity. Front Public Health 2022; 10:863882. [PMID: 35570949 PMCID: PMC9099091 DOI: 10.3389/fpubh.2022.863882] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 04/08/2022] [Indexed: 01/11/2023] Open
Abstract
Arsenic in drinking water has been recognized as carcinogenic to humans and can cause solid cancers of lung, urinary bladder, and skin. Positive associations have also been reported between arsenic ingestion and cancers of kidney, liver and prostate. Nevertheless, arsenic trioxide has been used successfully in the treatment of acute promyelocytic leukemia. Therefore, arsenic might play different roles in the carcinogenesis of solid cancers and hematologic malignancies. The relationship between arsenic in drinking water and the incidences of hematologic malignancies has not been fully investigated. We established a cohort of Taiwanese population and assorted 319 townships of Taiwan into two exposure categories using 0.05 mg/L as the cutoff. Then, we linked these data to the Taiwan Cancer Registry and computed standardized incidence ratios (SIRs) of lymphoma and leukemia by sex, exposure category and time period. The trend of changes in the SIRs over time was assessed, from 1981-1990 to 1991-2000 and then to 2001-2010. We found that in both lymphoma and leukemia, the higher exposure category was associated with lower SIRs in both men and women. In terms of time trends, the SIRs in both lymphoma and leukemia showed increasing trends in both sexes, while exposure to arsenic in drinking water decreased over time. The arsenic level in drinking water was negatively associated with the incidences of lymphoma and leukemia in both men and women. This study supports the dual effects of arsenic on carcinogenesis, with a potential protective effect against hematologic malignancies.
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Affiliation(s)
- Ming-Hsien Lin
- Division of Hematology and Oncology, Department of Internal Medicine, An Nan Hospital, China Medical University, Tainan, Taiwan,Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chung-Yi Li
- Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ya-Yun Cheng
- Department of Environmental Health, T.H. Chan School of Public Health, Harvard University, Boston, MA, United States
| | - How-Ran Guo
- Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan,Department of Occupational and Environmental Medicine, National Cheng Kung University Hospital, Tainan, Taiwan,*Correspondence: How-Ran Guo
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Saran U, Tyagi A, Chandrasekaran B, Ankem MK, Damodaran C. The role of autophagy in metal-induced urogenital carcinogenesis. Semin Cancer Biol 2021; 76:247-257. [PMID: 33798723 DOI: 10.1016/j.semcancer.2021.03.022] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 03/18/2021] [Accepted: 03/22/2021] [Indexed: 12/13/2022]
Abstract
Environmental and/or occupational exposure to metals such as Arsenic (As), Cadmium (Cd), and Chromium (Cr) have been shown to induce carcinogenesis in various organs, including the urogenital system. However, the mechanisms responsible for metal-induced carcinogenesis remain elusive. We and others have shown that metals are potent inducers of autophagy, which has been suggested to be an adaptive stress response to allow metal-exposed cells to survive in hostile environments. Albeit few, recent experimental studies have shown that As and Cd promote tumorigenesis via autophagy and that inhibition of autophagic signaling suppressed metal-induced carcinogenesis. In light of the newly emerging role of autophagic involvement in metal-induced carcinogenesis, the present review focuses explicitly on the mechanistic role of autophagy and potential signaling pathways involved in As-, Cd-, and Cr-induced urogenital carcinogenesis.
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Affiliation(s)
- Uttara Saran
- Department of Urology, University of Louisville, Louisville, KY, United States
| | - Ashish Tyagi
- Department of Urology, University of Louisville, Louisville, KY, United States
| | | | - Murali K Ankem
- Department of Urology, University of Louisville, Louisville, KY, United States
| | - Chendil Damodaran
- Department of Urology, University of Louisville, Louisville, KY, United States; College of Pharmacy, Department of Pharmaceutical Sciences, Texas A&M, College Station, TX, United States.
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Merrick BA, Phadke DP, Bostrom MA, Shah RR, Wright GM, Wang X, Gordon O, Pelch KE, Auerbach SS, Paules RS, DeVito MJ, Waalkes MP, Tokar EJ. KRAS-retroviral fusion transcripts and gene amplification in arsenic-transformed, human prostate CAsE-PE cancer cells. Toxicol Appl Pharmacol 2020; 397:115017. [PMID: 32344290 PMCID: PMC7606314 DOI: 10.1016/j.taap.2020.115017] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/16/2020] [Accepted: 04/19/2020] [Indexed: 01/03/2023]
Abstract
CAsE-PE cells are an arsenic-transformed, human prostate epithelial line containing oncogenic mutations in KRAS compared to immortalized, normal KRAS parent cells, RWPE-1. We previously reported increased copy number of mutated KRAS in CAsE-PE cells, suggesting gene amplification. Here, KRAS flanking genomic and transcriptomic regions were sequenced in CAsE-PE cells for insight into KRAS amplification. Comparison of DNA-Seq and RNA-Seq showed increased reads from background aligning to all KRAS exons in CAsE-PE cells, while a uniform DNA-Seq read distribution occurred in RWPE-1 cells with normal transcript expression. We searched for KRAS fusions in DNA and RNA sequencing data finding a portion of reads aligning to KRAS and viral sequence. After generation of cDNA from total RNA, short and long KRAS probes were generated to hybridize cDNA and KRAS enriched fragments were PacBio sequenced. More KRAS reads were captured from CAsE-PE cDNA versus RWPE-1 by each probe set. Only CAsE-PE cDNA showed KRAS viral fusion transcripts, primarily mapping to LTR and endogenous retrovirus sequences on either 5'- or 3'-ends of KRAS. Most KRAS viral fusion transcripts contained 4 to 6 exons but some PacBio sequences were in unusual orientations, suggesting viral insertions within the gene body. Additionally, conditioned media was extracted for potential retroviral particles. RNA-Seq of culture media isolates identified KRAS retroviral fusion transcripts in CAsE-PE media only. Truncated KRAS transcripts suggested multiple retroviral integration sites occurred within the KRAS gene producing KRAS retroviral fusions of various lengths. Findings suggest activation of endogenous retroviruses in arsenic carcinogenesis should be explored.
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Affiliation(s)
- B Alex Merrick
- Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States.
| | - Dhiral P Phadke
- Sciome, LLC, Research Triangle Park, North Carolina, United States
| | - Meredith A Bostrom
- David H. Murdock Research Institute, Kannapolis, North Carolina, United States
| | - Ruchir R Shah
- Sciome, LLC, Research Triangle Park, North Carolina, United States
| | - Garron M Wright
- David H. Murdock Research Institute, Kannapolis, North Carolina, United States
| | - Xinguo Wang
- David H. Murdock Research Institute, Kannapolis, North Carolina, United States
| | - Oksana Gordon
- David H. Murdock Research Institute, Kannapolis, North Carolina, United States
| | - Katherine E Pelch
- Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States
| | - Scott S Auerbach
- Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States
| | - Richard S Paules
- Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States
| | - Michael J DeVito
- Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States
| | - Michael P Waalkes
- Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States
| | - Erik J Tokar
- Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States
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Amouzougan EA, Lira R, Klimecki WT. Chronic exposure to arsenite enhances influenza virus infection in cultured cells. J Appl Toxicol 2020; 40:458-469. [PMID: 31960482 PMCID: PMC7931812 DOI: 10.1002/jat.3918] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 09/30/2019] [Accepted: 10/02/2019] [Indexed: 12/13/2022]
Abstract
Arsenic is a ubiquitous environmental toxicant that has been associated with human respiratory diseases. In humans, arsenic exposure has been associated with increased risk of respiratory infection. Considering the existing epidemiological evidence and the well-established impact of arsenic on epithelial cell biology, we posited that the effect of arsenic exposure in epithelial cells could enhance viral infection. In this study, we characterized influenza virus A/WSN/33 (H1N1) infection in Madin-Darby Canine Kidney (MDCK) cells chronically exposed to low levels of sodium arsenite (75 ppb). We observed a 27.3-fold increase in viral matrix (M2) protein (24 hours postinfection [p.i.]), a 1.35-fold increase in viral mRNA levels, and a 126% increase in plaque area in arsenite-exposed MDCK cells (48 hours p.i.). Arsenite exposure resulted in 114% increase in virus attachment-positive cells (2 hours p.i.) and 224% increase in α-2,3 sialic acid-positive cells. Interestingly, chronic exposure to arsenite reduced the effect of the antiviral drug, oseltamivir in MDCK cells. We also found that exposure to sodium arsenite resulted in a 4.4-fold increase in viral mRNA levels and significantly increased cytotoxicity in influenza A/Udorn/72 (H3N2) infected BEAS-2B cells. This study suggests that chronic arsenite exposure could result in enhanced influenza infection in epithelial cells, and that this may be mediated through increased sialic acid binding. Finally, the decreased effectiveness of the anti-influenza drug, oseltamivir, in arsenite-exposed cells raises substantial public health concerns if this effect translates to arsenic-exposed, influenza-infected people.
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Affiliation(s)
- Eva A. Amouzougan
- Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85724, United States
| | - Ricardo Lira
- Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85724, United States
| | - Walter T. Klimecki
- Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85724, United States
- College of Veterinary Medicine, The University of Arizona, Tucson, Arizona 85724, United States
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Lim JT, Tan YQ, Valeri L, Lee J, Geok PP, Chia SE, Ong CN, Seow WJ. Association between serum heavy metals and prostate cancer risk - A multiple metal analysis. ENVIRONMENT INTERNATIONAL 2019; 132:105109. [PMID: 31491608 DOI: 10.1016/j.envint.2019.105109] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 07/30/2019] [Accepted: 08/19/2019] [Indexed: 06/10/2023]
Abstract
BACKGROUND Prostate cancer is one of the most prevalent cancers in men. Exposure to heavy metals and their association with prostate cancer risk has been studied extensively, but combined effects remain largely inconclusive. OBJECTIVES To elucidate the association between serum concentrations of heavy metals and prostate cancer risk. METHODS Inductively coupled plasma mass spectrometry (ICP-MS) was used to determine the concentrations of a panel of 10 heavy metals (Mn, Cu, Zn, As, Se, Sb, Co, Cu, Cd and Pb) in serum samples of 141 cases and 114 controls in the Singapore Prostate Cancer Study. Linear probit regression models were used to estimate risk differences (RDs) and 95% confidence intervals (CIs) for the associations between log-centered serum metal concentrations and prostate cancer risk with adjustment for potential confounders. Bayesian kernel machine regression (BKMR) models were used to account for nonlinear, interactive, and joint metal effects. RESULTS Using probit regression, four heavy metals (As, Zn, Mn, Sb) were significantly and positively associated with prostate cancer risk in the unadjusted models. Using BKMR analysis, both As and Zn had positive risk differences on prostate cancer risk when all other metals were held fixed at the 25th and 50th percentiles (RD, 25th percentile: As: 0.15, Zn: 0.19, RD, 50th percentile: As: 0.45, Zn: 0.37). In addition, the overall mixture risk difference was positive and the 95% credible intervals did not include 0 when all metals in the mixture were jointly above their 55th percentile, as compared to when all metals were below their median values. CONCLUSIONS In summary, we found positive associations between the serum levels of As and Zn and prostate cancer risk on the risk difference scale using BKMR models. The overall mixture effect was also associated with increased prostate cancer risk. Future studies are warranted to validate these findings in prospective studies.
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Affiliation(s)
- Jue Tao Lim
- Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore
| | - Yue Qian Tan
- Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore
| | - Linda Valeri
- Department of Biostatistics, Columbia University Mailman School of Public Health, New York, NY, USA
| | - Jingyi Lee
- NUS Environmental Research Institute, National University of Singapore, Singapore
| | - Per Poh Geok
- NUS Environmental Research Institute, National University of Singapore, Singapore
| | - Sin Eng Chia
- Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore
| | - Choon Nam Ong
- Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore; NUS Environmental Research Institute, National University of Singapore, Singapore
| | - Wei Jie Seow
- Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore.
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Zimta AA, Schitcu V, Gurzau E, Stavaru C, Manda G, Szedlacsek S, Berindan-Neagoe I. Biological and molecular modifications induced by cadmium and arsenic during breast and prostate cancer development. ENVIRONMENTAL RESEARCH 2019; 178:108700. [PMID: 31520827 DOI: 10.1016/j.envres.2019.108700] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 08/07/2019] [Accepted: 08/26/2019] [Indexed: 06/10/2023]
Abstract
Breast and prostate cancer are two of the most common malignancies worldwide. Both cancers can develop into hormone -dependent or -independent subtypes and are associated to environmental exposure in the context of an inherited predisposition. As and Cd have been linked to the onset of both cancers, with the exception of As, which lacks a definitive association with breast carcinogenesis. The two elements exert an opposite effect dependent on acute versus chronic exposure. High doses of As or Cd were shown to induce cell death in acute experimental exposure, while chronic exposure triggers cell proliferation and viability, which is no longer limited by telomere shortening and apoptosis. The chronically exposed cells also increase their invasion capacity and tumorigenic potential. At molecular level, malignant transformation is evidenced mainly by up-regulation of BCL-2, MMP-2, MMP-9, VIM, Snail, Twist, MT, MLH and down-regulation of Casp-3, PTEN, E-CAD, and BAX. The signaling pathways most commonly activated are KRAS, p53, TGF-β, TNF-α, WNT, NRF2 and AKT. This knowledge could potentially raise public awareness over the health risks faced by the human population living or working in a polluted environment and smokers. Human exposure to As and Cd should be minimize as much as possible. Healthcare policies targeting people belonging to these risk categories should include analysis of: DNA damage, oxidative stress, molecular alterations, and systemic level of heavy metals and of essential minerals. In this review, we present the literature regarding cellular and molecular alterations caused by exposure to As or Cd, focusing on the malignant transformation of normal epithelial cells after long-term intoxication with these two carcinogens.
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Affiliation(s)
- Alina-Andreea Zimta
- MEDFUTURE - Research Center for Advanced Medicine, "Iuliu-Hatieganu" University of Medicine and Pharmacy, 23 Gheorghe Marinescu Street, 400337, Cluj-Napoca, Romania
| | - Vlad Schitcu
- The Oncology Institute "Prof. Dr. Ion Chiricuta", Republicii 34-36 Street, 400015, Cluj-Napoca, Romania; "Iuliu Hatieganu" University of Medicine and Pharmacy, 8 Victor Babes Street, 400012, Cluj-Napoca, Romania
| | - Eugen Gurzau
- Cluj School of Public Health, College of Political, Administrative and Communication Sciences, Babes-Bolyai University, 7 Pandurilor Street, Cluj-Napoca, Romania; Environmental Health Center, 58 Busuiocului Street, 400240, Cluj-Napoca, Romania; Faculty of Environmental Science and Engineering, Babes-Bolyai University, 30 Fantanele Street, Cluj- Napoca, Romania
| | - Crina Stavaru
- Cantacuzino National Institute of Research and Development for Microbiology, 103 Splaiul Independentei Street, Bucharest, 050096, Romania
| | - Gina Manda
- "Victor Babes" National Institute of Pathology, 99-101 Splaiul Independentei Street, 050096, Bucharest, Romania
| | - Stefan Szedlacsek
- Department of Enzymology, Institute of Biochemistry of the Romanian Academy, 296 Splaiul Independentei Street, Bucharest, 060031, Romania
| | - Ioana Berindan-Neagoe
- MEDFUTURE - Research Center for Advanced Medicine, "Iuliu-Hatieganu" University of Medicine and Pharmacy, 23 Gheorghe Marinescu Street, 400337, Cluj-Napoca, Romania; Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Marinescu 23 Street, 400337, Cluj-Napoca, Romania; Department of Functional Genomics and Experimental Pathology, The Oncology Institute "Prof. Dr. Ion Chiricuta", Republicii 34-36 Street, Cluj-Napoca, Romania.
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Merrick BA, Phadke DP, Bostrom MA, Shah RR, Wright GM, Wang X, Gordon O, Pelch KE, Auerbach SS, Paules RS, DeVito MJ, Waalkes MP, Tokar EJ. Arsenite malignantly transforms human prostate epithelial cells in vitro by gene amplification of mutated KRAS. PLoS One 2019; 14:e0215504. [PMID: 31009485 PMCID: PMC6476498 DOI: 10.1371/journal.pone.0215504] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 04/04/2019] [Indexed: 12/20/2022] Open
Abstract
Inorganic arsenic is an environmental human carcinogen of several organs including the urinary tract. RWPE-1 cells are immortalized, non-tumorigenic, human prostate epithelia that become malignantly transformed into the CAsE-PE line after continuous in vitro exposure to 5μM arsenite over a period of months. For insight into in vitro arsenite transformation, we performed RNA-seq for differential gene expression and targeted sequencing of KRAS. We report >7,000 differentially expressed transcripts in CAsE-PE cells compared to RWPE-1 cells at >2-fold change, q<0.05 by RNA-seq. Notably, KRAS expression was highly elevated in CAsE-PE cells, with pathway analysis supporting increased cell proliferation, cell motility, survival and cancer pathways. Targeted DNA sequencing of KRAS revealed a mutant specific allelic imbalance, ‘MASI’, frequently found in primary clinical tumors. We found high expression of a mutated KRAS transcript carrying oncogenic mutations at codons 12 and 59 and many silent mutations, accompanied by lower expression of a wild-type allele. Parallel cultures of RWPE-1 cells retained a wild-type KRAS genotype. Copy number analysis and sequencing showed amplification of the mutant KRAS allele. KRAS is expressed as two splice variants, KRAS4a and KRAS4b, where variant 4b is more prevalent in normal cells compared to greater levels of variant 4a seen in tumor cells. 454 Roche sequencing measured KRAS variants in each cell type. We found KRAS4a as the predominant transcript variant in CAsE-PE cells compared to KRAS4b, the variant expressed primarily in RWPE-1 cells and in normal prostate, early passage, primary epithelial cells. Overall, gene expression data were consistent with KRAS-driven proliferation pathways found in spontaneous tumors and malignantly transformed cell lines. Arsenite is recognized as an important environmental carcinogen, but it is not a direct mutagen. Further investigations into this in vitro transformation model will focus on genomic events that cause arsenite-mediated mutation and overexpression of KRAS in CAsE-PE cells.
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Affiliation(s)
- B. Alex Merrick
- Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States of America
- * E-mail:
| | - Dhiral P. Phadke
- Sciome, LLC, Research Triangle Park, North Carolina, United States of America
| | - Meredith A. Bostrom
- David H. Murdock Research Institute, Kannapolis, North Carolina, United States of America
| | - Ruchir R. Shah
- Sciome, LLC, Research Triangle Park, North Carolina, United States of America
| | - Garron M. Wright
- David H. Murdock Research Institute, Kannapolis, North Carolina, United States of America
| | - Xinguo Wang
- David H. Murdock Research Institute, Kannapolis, North Carolina, United States of America
| | - Oksana Gordon
- David H. Murdock Research Institute, Kannapolis, North Carolina, United States of America
| | - Katherine E. Pelch
- Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States of America
| | - Scott S. Auerbach
- Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States of America
| | - Richard S. Paules
- Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States of America
| | - Michael J. DeVito
- Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States of America
| | - Michael P. Waalkes
- Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States of America
| | - Erik J. Tokar
- Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States of America
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Roh T, Lynch CF, Weyer P, Wang K, Kelly KM, Ludewig G. Low-level arsenic exposure from drinking water is associated with prostate cancer in Iowa. ENVIRONMENTAL RESEARCH 2017; 159:338-343. [PMID: 28841521 PMCID: PMC5623650 DOI: 10.1016/j.envres.2017.08.026] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 07/24/2017] [Accepted: 08/12/2017] [Indexed: 05/02/2023]
Abstract
Inorganic arsenic is a toxic naturally occurring element in soil and water in many regions of the US including the Midwest. Prostate cancer is the second most common type of cancer in men in Iowa, surpassed only by non-melanotic skin cancer. Epidemiology studies have evaluated arsenic exposure from drinking water and prostate cancer, but most have focused on high-level exposures outside the US. As drinking water from groundwater sources is a major source of arsenic exposure, we conducted an ecologic study to evaluate prostate cancer and arsenic in drinking water from public water sources and private wells in Iowa, where exposure levels are low, but duration of exposure can be long. Arsenic data from public water systems were obtained from the Iowa Safe Drinking Water Information System for the years 1994-2003 and for private wells from two Iowa Well Water Studies, the Iowa Community Private Well Study (ICPWS, 2002-2003) and Iowa Statewide Rural Well Water Survey Phase 2 (SWIRL2, 2006-2008) that provided data for 87 Iowa counties. Prostate cancer incidence data from 2009 to 2013 for Iowa were obtained from Surveillance, Epidemiology and End Results' SEER*Stat software. County averages of water arsenic levels varied from 1.08 to 18.6 ppb, with three counties above the current 10 ppb limit. Based on the tertiles of arsenic levels, counties were divided into three groups: low (1.08-2.06 ppb), medium (2.07-2.98 ppb), and high (2.99-18.6 ppb). Spatial Poisson regression modeling was conducted to estimate the risk ratios (RR) of prostate cancer by tertiles of arsenic level at a county level, adjusted for demographic and risk factors. The RR of prostate cancer were 1.23 (95% CI, 1.16-1.30) and 1.28 (95% CI, 1.21-1.35) in the medium and high groups, respectively, compared to the low group after adjusting for risk factors. The RR increased to 1.36 (95% CI, 1.28-1.45) in the high group when analyses were restricted to aggressive prostate cancers (Gleason score ≥ 7). This study shows a significant dose-dependent association between low-level arsenic exposure and prostate cancer, and if this result is replicated in future individual-level studies, may suggest that 10 ppb is not protective for human health.
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Affiliation(s)
- Taehyun Roh
- Interdisciplinary Graduate Program in Human Toxicology, University of Iowa, Iowa City, IA 52242, United States
| | - Charles F Lynch
- Department of Epidemiology, University of Iowa, Iowa City, IA 52242, United States
| | - Peter Weyer
- Center for Health Effects of Environmental Contamination, University of Iowa, Iowa City, IA 52242, United States
| | - Kai Wang
- Department of Biostatistics, University of Iowa, Iowa City, IA 52242, United States
| | - Kevin M Kelly
- Department of Occupational and Environmental Health, University of Iowa, Iowa City, IA 52242, United States
| | - Gabriele Ludewig
- Interdisciplinary Graduate Program in Human Toxicology, University of Iowa, Iowa City, IA 52242, United States; Department of Occupational and Environmental Health, University of Iowa, Iowa City, IA 52242, United States.
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Bonaventura MM, Bourguignon NS, Bizzozzero M, Rodriguez D, Ventura C, Cocca C, Libertun C, Lux-Lantos VA. Arsenite in drinking water produces glucose intolerance in pregnant rats and their female offspring. Food Chem Toxicol 2017; 100:207-216. [DOI: 10.1016/j.fct.2016.12.025] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Revised: 12/15/2016] [Accepted: 12/20/2016] [Indexed: 10/20/2022]
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Hallauer J, Geng X, Yang HC, Shen J, Tsai KJ, Liu Z. The Effect of Chronic Arsenic Exposure in Zebrafish. Zebrafish 2016; 13:405-12. [PMID: 27140519 PMCID: PMC5035366 DOI: 10.1089/zeb.2016.1252] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Arsenic is a prevalent environmental toxin and a Group one human carcinogenic agent. Chronic arsenic exposure has been associated with many human diseases. The aim of this study is to evaluate zebrafish as an animal model to assess arsenic toxicity in elevated long-term arsenic exposure. With prolonged exposure (6 months) to various concentrations of arsenic from 50 ppb to 300 ppb, effects of arsenic accumulation in zebrafish tissues, and phenotypes were investigated. Results showed that there are no significant changes of arsenic retention in zebrafish tissues, and zebrafish did not exhibit any visible tumor formation under arsenic exposure conditions. However, the zebrafish demonstrate a dysfunction in their neurological system, which is reflected by a reduction of locomotive activity. Moreover, elevated levels of the superoxide dismutase (SOD2) protein were detected in the eye and liver, suggesting increased oxidative stress. In addition, the progenies of arsenic-treated parents displayed a smaller biomass (four-fold reduction in body weight) compared with those from their parental controls. This result indicates that arsenic may induce genetic or epigenetic changes that are then passed on to the next generation. Overall, this study demonstrates that zebrafish is a convenient vertebrate model with advantages in the evaluation of arsenic-associated neurological disorders as well as its influences on the offspring.
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Affiliation(s)
- Janell Hallauer
- Department of Biological Sciences, Oakland University, Rochester, Michigan
| | - Xiangrong Geng
- Department of Biological Sciences, Oakland University, Rochester, Michigan
| | - Hung-Chi Yang
- Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Jian Shen
- Department of Pathology, Creighton University School of Medicine, Omaha, Nebraska
| | - Kan-Jen Tsai
- School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
| | - Zijuan Liu
- Department of Biological Sciences, Oakland University, Rochester, Michigan
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Bulka CM, Jones RM, Turyk ME, Stayner LT, Argos M. Arsenic in drinking water and prostate cancer in Illinois counties: An ecologic study. ENVIRONMENTAL RESEARCH 2016; 148:450-456. [PMID: 27136670 PMCID: PMC4874890 DOI: 10.1016/j.envres.2016.04.030] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Revised: 04/20/2016] [Accepted: 04/21/2016] [Indexed: 05/03/2023]
Abstract
BACKGROUND Inorganic arsenic is a lung, bladder, and skin carcinogen. One of the major sources of exposure to arsenic is through naturally contaminated drinking water. While positive associations have been observed between arsenic in drinking water and prostate cancer, few studies have explored this association in the United States. OBJECTIVES To evaluate the association between inorganic arsenic concentrations in community water systems and prostate cancer incidence in Illinois using an ecologic study design. METHODS Illinois Environmental Protection Agency data on arsenic concentrations in drinking water from community water systems throughout the state were linked with county-level prostate cancer incidence data from 2007 to 2011 from the Illinois State Cancer Registry. Incidence rates were indirectly standardized by age to calculate standardized incidence ratios (SIRs) for each county. A Poisson regression model was used to model the association between county-level SIRs and mean arsenic tertile (0.33-0.72, 0.73-1.60, and 1.61-16.23ppb), adjusting for potential confounders. RESULTS For counties with mean arsenic levels in the second tertile, the SIR was 1.05 (95% CI: 0.96-1.16). For counties with mean arsenic levels in the third tertile, the SIR was 1.10 (95% CI: 1.03-1.19). There was a significant linear dose-response relationship observed between mean arsenic levels and prostate cancer incidence (p for trend=0.003). CONCLUSIONS In this ecologic study, counties with higher mean arsenic levels in community water systems had significantly higher prostate cancer incidence. Individual-level studies of prostate cancer incidence and low-level arsenic exposure are needed.
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Affiliation(s)
- Catherine M Bulka
- University of Illinois at Chicago, School of Public Health, Epidemiology and Biostatistics Division, 1603 W. Taylor Street, Chicago, IL 60612, United States.
| | - Rachael M Jones
- University of Illinois at Chicago, School of Public Health, Environmental and Occupational Health Sciences Division, 2121W. Taylor Street, Chicago, IL 60612, United States.
| | - Mary E Turyk
- University of Illinois at Chicago, School of Public Health, Epidemiology and Biostatistics Division, 1603 W. Taylor Street, Chicago, IL 60612, United States.
| | - Leslie T Stayner
- University of Illinois at Chicago, School of Public Health, Epidemiology and Biostatistics Division, 1603 W. Taylor Street, Chicago, IL 60612, United States.
| | - Maria Argos
- University of Illinois at Chicago, School of Public Health, Epidemiology and Biostatistics Division, 1603 W. Taylor Street, Chicago, IL 60612, United States.
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Gore AC, Chappell VA, Fenton SE, Flaws JA, Nadal A, Prins GS, Toppari J, Zoeller RT. EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals. Endocr Rev 2015; 36:E1-E150. [PMID: 26544531 PMCID: PMC4702494 DOI: 10.1210/er.2015-1010] [Citation(s) in RCA: 1427] [Impact Index Per Article: 142.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Accepted: 09/01/2015] [Indexed: 02/06/2023]
Abstract
The Endocrine Society's first Scientific Statement in 2009 provided a wake-up call to the scientific community about how environmental endocrine-disrupting chemicals (EDCs) affect health and disease. Five years later, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans-especially during development-may lay the foundations for disease later in life. At this point in history, we have much stronger knowledge about how EDCs alter gene-environment interactions via physiological, cellular, molecular, and epigenetic changes, thereby producing effects in exposed individuals as well as their descendants. Causal links between exposure and manifestation of disease are substantiated by experimental animal models and are consistent with correlative epidemiological data in humans. There are several caveats because differences in how experimental animal work is conducted can lead to difficulties in drawing broad conclusions, and we must continue to be cautious about inferring causality in humans. In this second Scientific Statement, we reviewed the literature on a subset of topics for which the translational evidence is strongest: 1) obesity and diabetes; 2) female reproduction; 3) male reproduction; 4) hormone-sensitive cancers in females; 5) prostate; 6) thyroid; and 7) neurodevelopment and neuroendocrine systems. Our inclusion criteria for studies were those conducted predominantly in the past 5 years deemed to be of high quality based on appropriate negative and positive control groups or populations, adequate sample size and experimental design, and mammalian animal studies with exposure levels in a range that was relevant to humans. We also focused on studies using the developmental origins of health and disease model. No report was excluded based on a positive or negative effect of the EDC exposure. The bulk of the results across the board strengthen the evidence for endocrine health-related actions of EDCs. Based on this much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, these findings can be much better translated to human health. Armed with this information, researchers, physicians, and other healthcare providers can guide regulators and policymakers as they make responsible decisions.
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Affiliation(s)
- A C Gore
- Pharmacology and Toxicology (A.C.G.), College of Pharmacy, The University of Texas at Austin, Austin, Texas 78734; Division of the National Toxicology Program (V.A.C., S.E.F.), National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709; Department of Comparative Biosciences (J.A.F.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61802; Institute of Bioengineering and CIBERDEM (A.N.), Miguel Hernandez University of Elche, 03202 Elche, Alicante, Spain; Departments of Urology, Pathology, and Physiology & Biophysics (G.S.P.), College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612; Departments of Physiology and Pediatrics (J.T.), University of Turku and Turku University Hospital, 20520 Turku, Finland; and Biology Department (R.T.Z.), University of Massachusetts at Amherst, Amherst, Massachusetts 01003
| | - V A Chappell
- Pharmacology and Toxicology (A.C.G.), College of Pharmacy, The University of Texas at Austin, Austin, Texas 78734; Division of the National Toxicology Program (V.A.C., S.E.F.), National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709; Department of Comparative Biosciences (J.A.F.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61802; Institute of Bioengineering and CIBERDEM (A.N.), Miguel Hernandez University of Elche, 03202 Elche, Alicante, Spain; Departments of Urology, Pathology, and Physiology & Biophysics (G.S.P.), College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612; Departments of Physiology and Pediatrics (J.T.), University of Turku and Turku University Hospital, 20520 Turku, Finland; and Biology Department (R.T.Z.), University of Massachusetts at Amherst, Amherst, Massachusetts 01003
| | - S E Fenton
- Pharmacology and Toxicology (A.C.G.), College of Pharmacy, The University of Texas at Austin, Austin, Texas 78734; Division of the National Toxicology Program (V.A.C., S.E.F.), National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709; Department of Comparative Biosciences (J.A.F.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61802; Institute of Bioengineering and CIBERDEM (A.N.), Miguel Hernandez University of Elche, 03202 Elche, Alicante, Spain; Departments of Urology, Pathology, and Physiology & Biophysics (G.S.P.), College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612; Departments of Physiology and Pediatrics (J.T.), University of Turku and Turku University Hospital, 20520 Turku, Finland; and Biology Department (R.T.Z.), University of Massachusetts at Amherst, Amherst, Massachusetts 01003
| | - J A Flaws
- Pharmacology and Toxicology (A.C.G.), College of Pharmacy, The University of Texas at Austin, Austin, Texas 78734; Division of the National Toxicology Program (V.A.C., S.E.F.), National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709; Department of Comparative Biosciences (J.A.F.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61802; Institute of Bioengineering and CIBERDEM (A.N.), Miguel Hernandez University of Elche, 03202 Elche, Alicante, Spain; Departments of Urology, Pathology, and Physiology & Biophysics (G.S.P.), College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612; Departments of Physiology and Pediatrics (J.T.), University of Turku and Turku University Hospital, 20520 Turku, Finland; and Biology Department (R.T.Z.), University of Massachusetts at Amherst, Amherst, Massachusetts 01003
| | - A Nadal
- Pharmacology and Toxicology (A.C.G.), College of Pharmacy, The University of Texas at Austin, Austin, Texas 78734; Division of the National Toxicology Program (V.A.C., S.E.F.), National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709; Department of Comparative Biosciences (J.A.F.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61802; Institute of Bioengineering and CIBERDEM (A.N.), Miguel Hernandez University of Elche, 03202 Elche, Alicante, Spain; Departments of Urology, Pathology, and Physiology & Biophysics (G.S.P.), College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612; Departments of Physiology and Pediatrics (J.T.), University of Turku and Turku University Hospital, 20520 Turku, Finland; and Biology Department (R.T.Z.), University of Massachusetts at Amherst, Amherst, Massachusetts 01003
| | - G S Prins
- Pharmacology and Toxicology (A.C.G.), College of Pharmacy, The University of Texas at Austin, Austin, Texas 78734; Division of the National Toxicology Program (V.A.C., S.E.F.), National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709; Department of Comparative Biosciences (J.A.F.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61802; Institute of Bioengineering and CIBERDEM (A.N.), Miguel Hernandez University of Elche, 03202 Elche, Alicante, Spain; Departments of Urology, Pathology, and Physiology & Biophysics (G.S.P.), College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612; Departments of Physiology and Pediatrics (J.T.), University of Turku and Turku University Hospital, 20520 Turku, Finland; and Biology Department (R.T.Z.), University of Massachusetts at Amherst, Amherst, Massachusetts 01003
| | - J Toppari
- Pharmacology and Toxicology (A.C.G.), College of Pharmacy, The University of Texas at Austin, Austin, Texas 78734; Division of the National Toxicology Program (V.A.C., S.E.F.), National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709; Department of Comparative Biosciences (J.A.F.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61802; Institute of Bioengineering and CIBERDEM (A.N.), Miguel Hernandez University of Elche, 03202 Elche, Alicante, Spain; Departments of Urology, Pathology, and Physiology & Biophysics (G.S.P.), College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612; Departments of Physiology and Pediatrics (J.T.), University of Turku and Turku University Hospital, 20520 Turku, Finland; and Biology Department (R.T.Z.), University of Massachusetts at Amherst, Amherst, Massachusetts 01003
| | - R T Zoeller
- Pharmacology and Toxicology (A.C.G.), College of Pharmacy, The University of Texas at Austin, Austin, Texas 78734; Division of the National Toxicology Program (V.A.C., S.E.F.), National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709; Department of Comparative Biosciences (J.A.F.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61802; Institute of Bioengineering and CIBERDEM (A.N.), Miguel Hernandez University of Elche, 03202 Elche, Alicante, Spain; Departments of Urology, Pathology, and Physiology & Biophysics (G.S.P.), College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612; Departments of Physiology and Pediatrics (J.T.), University of Turku and Turku University Hospital, 20520 Turku, Finland; and Biology Department (R.T.Z.), University of Massachusetts at Amherst, Amherst, Massachusetts 01003
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Huang L, Wu H, van der Kuijp TJ. The health effects of exposure to arsenic-contaminated drinking water: a review by global geographical distribution. INTERNATIONAL JOURNAL OF ENVIRONMENTAL HEALTH RESEARCH 2014; 25:432-452. [PMID: 25365079 DOI: 10.1080/09603123.2014.958139] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Chronic arsenic exposure through drinking water has been a vigorously studied and debated subject. However, the existing literature does not allow for a thorough examination of the potential regional discrepancies that may arise among arsenic-related health outcomes. The purpose of this article is to provide an updated review of the literature on arsenic exposure and commonly discussed health effects according to global geographical distribution. This geographically segmented approach helps uncover the discrepancies in the health effects of arsenic. For instance, women are more susceptible than men to a few types of cancer in Taiwan, but not in other countries. Although skin cancer and arsenic exposure correlations have been discovered in Chile, Argentina, the United States, and Taiwan, no evident association was found in mainland China. We then propose several globally applicable recommendations to prevent and treat the further spread of arsenic poisoning and suggestions of future study designs and decision-making.
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Affiliation(s)
- Lei Huang
- a State Key Laboratory of Pollution Control & Resource Reuse , School of the Environment, Nanjing University , Nanjing , China
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Doolan G, Benke G, Giles G. An Update on Occupation and Prostate Cancer. Asian Pac J Cancer Prev 2014; 15:501-16. [DOI: 10.7314/apjcp.2014.15.2.501] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Sung TI, Wang YJ, Chen CY, Hung TL, Guo HR. Increased serum level of epidermal growth factor receptor in liver cancer patients and its association with exposure to arsenic. THE SCIENCE OF THE TOTAL ENVIRONMENT 2012; 424:74-78. [PMID: 22446113 DOI: 10.1016/j.scitotenv.2012.02.079] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2011] [Revised: 02/29/2012] [Accepted: 02/29/2012] [Indexed: 05/31/2023]
Abstract
Arsenic is a human carcinogen and can activate epidermal growth factor receptor (EGFR) in human cell lines. As EGFR is associated with the occurrence of cancers, we conducted a study to evaluate whether serum EGFR may increase in liver cancer patients, particularly in those with exposure to arsenic. We recruited 100 patients of liver cancer and 100 age- and sex-matched controls in Taiwan and determined EGFR levels in sera by enzyme-linked immunosorbent assay. The patients had higher EGFR levels (668.1 vs. 243.1 fmol/mL, p<0.01), and after adjusting for hepatitis B and C, they still had an average EGFR level 406.1 fmol/mL higher than that of the controls (p<0.01). When we compared 22 patients residing in an endemic area of arsenic intoxication to 22 age- and sex-matched patients residing outside the area, we found that patients from the endemic area had higher EGFR levels (882.8 vs. 511.6 fmol/mL, p = 0.04). We concluded that EGFR is over-expressed in patients of liver cancer, particularly in those with exposure to arsenic, and therefore, serum EGFR level is not only a potential biomarker of liver cancer, but also a potential biomarker of cancers associated with arsenic exposure.
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Affiliation(s)
- Tzu-I Sung
- Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, Taiwan
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Walsh L, Dufey F, Tschense A, Schnelzer M, Sogl M, Kreuzer M. Prostate cancer mortality risk in relation to working underground in the Wismut cohort study of German uranium miners, 1970-2003. BMJ Open 2012; 2:bmjopen-2012-001002. [PMID: 22685223 PMCID: PMC3371580 DOI: 10.1136/bmjopen-2012-001002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVE A recent study and comprehensive literature review has indicated that mining could be protective against prostate cancer. This indication has been explored further here by analysing prostate cancer mortality in the German 'Wismut' uranium miner cohort, which has detailed information on the number of days worked underground. DESIGN An historical cohort study of 58 987 male mine workers with retrospective follow-up before 1999 and prospective follow-up since 1999. SETTING AND PARTICIPANTS Uranium mine workers employed during the period 1970-1990 in the regions of Saxony and Thuringia, Germany, contributing 1.42 million person-years of follow-up ending in 2003. OUTCOME MEASURE Simple standardised mortality ratio (SMR) analyses were applied to assess differences between the national and cohort prostate cancer mortality rates and complemented by refined analyses done entirely within the cohort. The internal comparisons applied Poisson regression excess relative prostate cancer mortality risk model with background stratification by age and calendar year and a whole range of possible explanatory covariables that included days worked underground and years worked at high physical activity with γ radiation treated as a confounder. RESULTS The analysis is based on miner data for 263 prostate cancer deaths. The overall SMR was 0.85 (95% CI 0.75 to 0.95). A linear excess relative risk model with the number of years worked at high physical activity and the number of days worked underground as explanatory covariables provided a statistically significant fit when compared with the background model (p=0.039). Results (with 95% CIs) for the excess relative risk per day worked underground indicated a statistically significant (p=0.0096) small protective effect of -5.59 (-9.81 to -1.36) ×10(-5). CONCLUSION Evidence is provided from the German Wismut cohort in support of a protective effect from working underground on prostate cancer mortality risk.
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Affiliation(s)
- Linda Walsh
- Department of "Radiation Protection and Health", Federal Office for Radiation Protection, Oberschleissheim, Germany
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Gomez-Rubio P, Klimentidis YC, Cantu-Soto E, Meza-Montenegro MM, Billheimer D, Lu Z, Chen Z, Klimecki WT. Indigenous American ancestry is associated with arsenic methylation efficiency in an admixed population of northwest Mexico. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2012; 75:36-49. [PMID: 22047162 PMCID: PMC3572940 DOI: 10.1080/15287394.2011.615107] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/02/2023]
Abstract
Many studies provide evidence relating lower human arsenic (As) methylation efficiency, represented by high percent urinary monomethylarsonic acid (MMA(V)), with several As-induced diseases, possibly due to the fact that MMA(V) serves as a proxy for MMA(III), the most toxic As metabolite. Some epidemiological studies suggested that indigenous Americans (AME) methylate As more efficiently; however, data supporting this have been equivocal. The aim of this study was to characterize the association between AME ancestry and As methylation efficiency using a panel of ancestry informative genetic markers to determine individual ancestry proportions in an admixed population (composed of two or more isolated ancestral populations) of 746 individuals environmentally exposed to As in northwest Mexico. Total urinary As (TAs) mean and range were 170.4 and 2.3-1053.5 μg/L, while percent AME (%AME) mean and range were 72.4 and 23-100. Adjusted (gender, age, AS3MT 7388/M287T haplotypes, body mass index [BMI], and TAs) multiple regression model showed that higher AME ancestry is significantly associated with lower percentage of urinary As excreted as MMA(V) (%uMMA) in this population (p < .01). Data also demonstrated a significant interaction between BMI and gender, indicating negative association between BMI and %uMMA, stronger in women than men (p < .01). Moreover, age and the AS3MT variants 7388 (intronic) and M287T (nonsynonymous) were also significantly associated with As methylation efficiency (p < .01). This study highlights the importance of BMI and indigenous American ancestry in some of the observed variability in As methylation efficiency, underscoring the need to be considered in epidemiology studies, particularly those carried out in admixed populations.
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Affiliation(s)
- Paulina Gomez-Rubio
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona
| | - Yann C. Klimentidis
- Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama
| | - Ernesto Cantu-Soto
- Department of Environmental Sciences, Instituto Tecnologico de Sonora, Ciudad Obregon, Sonora, Mexico
| | - Maria M. Meza-Montenegro
- Department of Environmental Sciences, Instituto Tecnologico de Sonora, Ciudad Obregon, Sonora, Mexico
| | - Dean Billheimer
- Department of Agricultural and Biosystems Engineering, University of Arizona, Tucson, Arizona
| | - Zhenqiang Lu
- Arizona Statistical Consulting Laboratory, University of Arizona, Tucson, Arizona
| | - Zhao Chen
- Division of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona
| | - Walter T. Klimecki
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona
- To whom correspondence should be addressed: Walter Klimecki, DVM, Ph.D., 1657 E Helen St, RM319, Thomas Keating Bldg. Tucson, AZ 85721, Tel. 520-626-7470, Fax. 520-626-2466,
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Bauer-Mehren A, Bundschus M, Rautschka M, Mayer MA, Sanz F, Furlong LI. Gene-disease network analysis reveals functional modules in mendelian, complex and environmental diseases. PLoS One 2011; 6:e20284. [PMID: 21695124 PMCID: PMC3114846 DOI: 10.1371/journal.pone.0020284] [Citation(s) in RCA: 119] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2011] [Accepted: 04/27/2011] [Indexed: 02/05/2023] Open
Abstract
Background Scientists have been trying to understand the molecular mechanisms of diseases to design preventive and therapeutic strategies for a long time. For some diseases, it has become evident that it is not enough to obtain a catalogue of the disease-related genes but to uncover how disruptions of molecular networks in the cell give rise to disease phenotypes. Moreover, with the unprecedented wealth of information available, even obtaining such catalogue is extremely difficult. Principal Findings We developed a comprehensive gene-disease association database by integrating associations from several sources that cover different biomedical aspects of diseases. In particular, we focus on the current knowledge of human genetic diseases including mendelian, complex and environmental diseases. To assess the concept of modularity of human diseases, we performed a systematic study of the emergent properties of human gene-disease networks by means of network topology and functional annotation analysis. The results indicate a highly shared genetic origin of human diseases and show that for most diseases, including mendelian, complex and environmental diseases, functional modules exist. Moreover, a core set of biological pathways is found to be associated with most human diseases. We obtained similar results when studying clusters of diseases, suggesting that related diseases might arise due to dysfunction of common biological processes in the cell. Conclusions For the first time, we include mendelian, complex and environmental diseases in an integrated gene-disease association database and show that the concept of modularity applies for all of them. We furthermore provide a functional analysis of disease-related modules providing important new biological insights, which might not be discovered when considering each of the gene-disease association repositories independently. Hence, we present a suitable framework for the study of how genetic and environmental factors, such as drugs, contribute to diseases. Availability The gene-disease networks used in this study and part of the analysis are available at http://ibi.imim.es/DisGeNET/DisGeNETweb.html#Download.
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Affiliation(s)
- Anna Bauer-Mehren
- Research Programme on Biomedical Informatics (GRIB), IMIM (Hospital del Mar Research Institute), Universitat Pompeu Fabra, Barcelona, Spain
| | - Markus Bundschus
- Institute for Computer Science, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Michael Rautschka
- Research Programme on Biomedical Informatics (GRIB), IMIM (Hospital del Mar Research Institute), Universitat Pompeu Fabra, Barcelona, Spain
| | - Miguel A. Mayer
- Research Programme on Biomedical Informatics (GRIB), IMIM (Hospital del Mar Research Institute), Universitat Pompeu Fabra, Barcelona, Spain
| | - Ferran Sanz
- Research Programme on Biomedical Informatics (GRIB), IMIM (Hospital del Mar Research Institute), Universitat Pompeu Fabra, Barcelona, Spain
| | - Laura I. Furlong
- Research Programme on Biomedical Informatics (GRIB), IMIM (Hospital del Mar Research Institute), Universitat Pompeu Fabra, Barcelona, Spain
- * E-mail:
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Abstract
Arsenic is a metalloid that generates various biological effects on cells and tissues. Depending on the specific tissue exposed and the time and degree of exposure, diverse responses can be observed. In humans, prolonged and/or high dose exposure to arsenic can have a variety of outcomes, including the development of malignancies, severe gastrointestinal toxicities, diabetes, cardiac arrhythmias, and death. On the other hand, one arsenic derivative, arsenic trioxide (As(2)O(3)), has important antitumor properties. This agent is a potent inducer of antileukemic responses, and it is now approved by the Food and Drug Administration for the treatment of acute promyelocytic leukemia in humans. The promise and therapeutic potential of arsenic and its various derivatives have been exploited for hundreds of years. Remarkably, research focused on the potential use of arsenic compounds in the treatment of human diseases remains highly promising, and it is an area of active investigation. An emerging approach of interest and therapeutic potential involves efforts to target and block cellular pathways activated in a negative feedback manner during treatment of cells with As(2)O(3). Such an approach may ultimately provide the means to selectively enhance the suppressive effects of this agent on malignant cells and render normally resistant tumors sensitive to its antineoplastic properties.
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Affiliation(s)
- Leonidas C Platanias
- Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
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