Dysregulation of <scp>DNA</scp> methylation induced by past arsenic treatment causes persistent genomic instability in mammalian cells

Mauro, Maurizio; Caradonna, Fabio; Klein, Catherine B.

doi:10.1002/em.21987

Cited by 37 publications

(15 citation statements)

References 63 publications

(82 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other mechanisms proposed to mediate iAs toxicity – namely changes in DNA methylation ( Huang et al, 2004 ; Hughes, 2002 ; Kile et al, 2012 ; Mauro et al, 2016 ) – were not identified by our studies in zebrafish (not shown). In fact, there is nearly no overlap in the gene expression changes induced by iAs and by mutants that have a defect in DNA methylation ( Chernyavskaya et al, 2017 ; Jacob et al, 2015 ), and our preliminary studies found neither an impact on global DNA methylation nor synergy with mutants that have DNA methylation loss (not shown).…”

Section: Discussionmentioning

confidence: 64%

Inorganic arsenic causes fatty liver and interacts with ethanol to cause alcoholic liver disease in zebrafish

Bambino

Zhang

Austin

et al. 2018

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

The rapid increase in fatty liver disease (FLD) incidence is attributed largely to genetic and lifestyle factors; however, environmental toxicants are a frequently overlooked factor that can modify the effects of more common causes of FLD. Chronic exposure to inorganic arsenic (iAs) is associated with liver disease in humans and animal models, but neither the mechanism of action nor the combinatorial interaction with other disease-causing factors has been fully investigated. Here, we examined the contribution of iAs to FLD using zebrafish and tested the interaction with ethanol to cause alcoholic liver disease (ALD). We report that zebrafish exposed to iAs throughout development developed specific phenotypes beginning at 4 days post-fertilization (dpf), including the development of FLD in over 50% of larvae by 5 dpf. Comparative transcriptomic analysis of livers from larvae exposed to either iAs or ethanol revealed the oxidative stress response and the unfolded protein response (UPR) caused by endoplasmic reticulum (ER) stress as common pathways in both these models of FLD, suggesting that they target similar cellular processes. This was confirmed by our finding that arsenic is synthetically lethal with both ethanol and a well-characterized ER-stress-inducing agent (tunicamycin), suggesting that these exposures work together through UPR activation to cause iAs toxicity. Most significantly, combined exposure to sub-toxic concentrations of iAs and ethanol potentiated the expression of UPR-associated genes, cooperated to induce FLD, reduced the expression of as3mt, which encodes an arsenic-metabolizing enzyme, and significantly increased the concentration of iAs in the liver. This demonstrates that iAs exposure is sufficient to cause FLD and that low doses of iAs can potentiate the effects of ethanol to cause liver disease.This article has an associated First Person interview with the first author of the paper.

show abstract

Section: Discussionmentioning

confidence: 64%

Inorganic arsenic causes fatty liver and interacts with ethanol to cause alcoholic liver disease in zebrafish

Bambino

Zhang

Austin

et al. 2018

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

show abstract

“…DNA methylation, histone modification and microRNA expression have been identified as the prominent epigenetic mechanisms of i As toxicity . i As alteration of epigenetic mechanisms has also been linked to an up‐regulation of cancer‐related genes, as well as a down‐regulation of programmed cell death .…”

Section: Mechanisms Involved In Arsenic Tumorigenesismentioning

confidence: 99%

State of the science review of the health effects of inorganic arsenic: Perspectives for future research

Tchounwou

Yedjou

Udensi

et al. 2018

Environmental Toxicology

128

View full text Add to dashboard Cite

Human exposure to inorganic arsenic (iAs) is a global health issue. Although there is strong evidence for iAs-induced toxicity at higher levels of exposure, many epidemiological studies evaluating its effects at low exposure levels have reported mixed results. We comprehensively reviewed the literature and evaluated the scientific knowledge on human exposure to arsenic, mechanisms of action, systemic and carcinogenic effects, risk characterization, and regulatory guidelines. We identified areas where additional research is needed. These priority areas include: (1) further development of animal models of iAs carcinogenicity to identify molecular events involved in iAs carcinogenicity; (2) characterization of underlying mechanisms of iAs toxicity; (3) assessment of genderspecific susceptibilities and other factors that modulate arsenic metabolism; (4) sufficiently powered epidemiological studies to ascertain relationship between iAs exposure and reproductive/ developmental effects; (5) evaluation of genetic/epigenetic determinants of iAs effects in children;and (6) epidemiological studies of people chronically exposed to low iAs concentrations.

show abstract

“…Taken together, the data of the present study provide novel in vitro and mammary tumor xenograft evidence that exposure to inorganic trivalent arsenic, such as NaAs III may increase resistance to endocrine therapy based on TAM through reduction in BRCA1 and ERα expression. Future studies with ERα-positive breast cancer patients residing in geographical regions at high risk of exposure to As III are warranted to investigate whether the dysregulation of CpG hypermethylation of BRCA1 and ESR1 causes persistent genomic instability (55), and variations in efficacy of therapies based on antagonists of the ERα. As DNA methylation changes are potentially reversible, they may offer a novel target for combination therapies of ER-positive breast tumors with epigenetic drugs.…”

Section: Discussionmentioning

confidence: 99%

Arsenic‑induced BRCA1 CpG promoter methylation is associated with the downregulation of ERα and resistance to tamoxifen in MCF7 breast cancer cells and mouse mammary tumor xenografts

et al. 2019

View full text Add to dashboard Cite

A significant percentage (~30%) of estrogen receptor-α (ERα)-positive tumors become refractory to endocrine therapies; however, the mechanisms responsible for this resistance remain largely unknown. Chronic exposure to arsenic through foods and contaminated water has been linked to an increased incidence of several tumors and long-term health complications. Preclinical and population studies have indicated that arsenic exposure may interfere with endocrine regulation and increase the risk of breast tumorigenesis. In this study, we examined the effects of sodium arsenite (NaAsIII) exposure in ERα-positive breast cancer cells in vitro and in mammary tumor xenografts. The results revealed that acute (within 4 days) and long-term (10 days to 7 weeks) in vitro exposure to environmentally relevant doses reduced breast cancer 1 (BRCA1) and ERα expression associated with the gain of cyclin D1 (CCND1) and folate receptor 1 (FOLR1), and the loss of methylenetetrahydrofolate reductase (MTHFR) expression. Furthermore, long-term exposure to NaAsIII induced the proliferation and compromised the response of MCF7 cells to tamoxifen (TAM). The in vitro exposure to NaAsIII induced BRCA1 CpG methylation associated with the increased recruitment of DNA methyltransferase 1 (DNMT1) and the loss of RNA polymerase II (PolII) at the BRCA1 gene. Xenografts of NaAsIII-preconditioned MCF7 cells (MCF7NaAsIII) into the mammary fat pads of nude mice produced a larger tumor volume compared to tumors from control MCF7 cells and were more refractory to TAM in association with the reduced expression of BRCA1 and ERα, CpG hypermethylation of estrogen receptor 1 (ESR1) and BRCA1, and the increased expression of FOLR1. These cumulative data support the hypothesis that exposure to AsIII may contribute to reducing the efficacy of endocrine therapy against ERα-positive breast tumors by hampering the expression of ERα and BRCA1 via CpG methylation, respectively of ESR1 and BRCA1.

show abstract

Dysregulation of DNA methylation induced by past arsenic treatment causes persistent genomic instability in mammalian cells

Cited by 37 publications

References 63 publications

Inorganic arsenic causes fatty liver and interacts with ethanol to cause alcoholic liver disease in zebrafish

Inorganic arsenic causes fatty liver and interacts with ethanol to cause alcoholic liver disease in zebrafish

State of the science review of the health effects of inorganic arsenic: Perspectives for future research

Arsenic‑induced BRCA1 CpG promoter methylation is associated with the downregulation of ERα and resistance to tamoxifen in MCF7 breast cancer cells and mouse mammary tumor xenografts

Contact Info

Product

Resources

About