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Relationships among Inorganic Arsenic, Nutritional Status CpG Methylation and microRNAs: A Review of the Literature.

ABSTRACT: Inorganic arsenic is a naturally occurring toxicant that poses a significant and persistent challenge to public health. The World Health Organization has identified many geographical regions where inorganic arsenic levels exceed safe limits in drinking water. Numerous epidemiological studies have associated exposure to inorganic arsenic with increased risk of adverse health outcomes. Randomized clinical trials have shown that nutritional supplementation can mitigate or reduce exacerbation of exposure-related effects. Although a growing body of evidence suggests that epigenetic status influences toxicity, the relationships among environmental exposure to arsenic, nutrition, and the epigenome are not well detailed. This review provides a comprehensive summary of findings from human, rodent, and in vitro studies highlighting these interactive relationships.

SUBMITTER: Venkatratnam A

PROVIDER: S-EPMC7868494 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Relationships among Inorganic Arsenic, Nutritional Status CpG Methylation and microRNAs: A Review of the Literature.

Venkatratnam Abhishek A Marable Carmen A CA Keshava Arjun M AM Fry Rebecca C RC

Epigenetics insights 20210205

Inorganic arsenic is a naturally occurring toxicant that poses a significant and persistent challenge to public health. The World Health Organization has identified many geographical regions where inorganic arsenic levels exceed safe limits in drinking water. Numerous epidemiological studies have associated exposure to inorganic arsenic with increased risk of adverse health outcomes. Randomized clinical trials have shown that nutritional supplementation can mitigate or reduce exacerbation of exp ...[more]

PMID: 33615137

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Project description:Arsenic occurs naturally in the environment, and exists predominantly as inorganic arsenite (As (III) and arsenate As (V)). Arsenic contamination of drinking water has long been recognized as a major global health concern. Arsenic exposure causes changes in skin color and lesions, and more severe health conditions such as black foot disease as well as various cancers originating in the lungs, skin, and bladder. In order to efficiently metabolize and excrete arsenic, it is methylated to monomethylarsonic and dimethylarsinic acid. One single enzyme, arsenic methyltransferase (AS3MT) is responsible for generating both metabolites. AS3MT has been purified from several mammalian and nonmammalian species, and its mRNA sequences were determined from amino acid sequences. With the advent of genome technology, mRNA sequences of AS3MT have been predicted from many species throughout the animal kingdom. Horizontal gene transfer had been postulated for this gene through phylogenetic studies, which suggests the importance of this gene in appropriately handling arsenic exposures in various organisms. An altered ability to methylate arsenic is dependent on specific single nucleotide polymorphisms (SNPs) in AS3MT. Reduced AS3MT activity resulting in poor metabolism of iAs has been shown to reduce expression of the tumor suppressor gene, p16, which is a potential pathway in arsenic carcinogenesis. Arsenic is also known to induce oxidative stress in cells. However, the presence of antioxidant response elements (AREs) in the promoter sequences of AS3MT in several species does not correlate with the ability to methylate arsenic. ARE elements are known to bind NRF2 and induce antioxidant enzymes to combat oxidative stress. NRF2 may be partly responsible for the biotransformation of iAs and the generation of methylated arsenic species via AS3MT. In this article, arsenic metabolism, excretion, and toxicity, a discussion of the AS3MT gene and its evolutionary history, and DNA methylation resulting from arsenic exposure have been reviewed.

Project description:IntroductionAberrant DNA methylation has been found frequently in human breast cancers, associated with the loss of expression of a number of regulatory genes for growth and correlated to clinical outcomes. The present study was undertaken to determine whether methylation of a set of growth-suppressor genes would correlate to the expression of estrogen receptors (ERs) and progesterone receptors (PRs).MethodsWe used a pyrosequencing methylation analysis to study the methylation of 12 known growth-suppressor genes in 90 pairs of malignant/normal breast tissues. We also examined the expression of ERs and PRs in those specimens by immunohistochemistry. Mutations of p53 in tumor cells were detected by direct sequencing.ResultsTwelve tumor-suppressor genes: ARHI, RASSF1A, HIN-1, RARbeta2, hMLH1, 14-3-3 sigma, RIZ1, p16, E-cadherin, RIL, CDH13, and NKD2 were selected for this methylation study. Five of them (RIL, HIN-1, RASSF1A, CDH13, and RARbeta2) were frequently methylated in breast cancers (57%, 49%, 58%, 44%, and 17%, respectively) but not the normal breast (0-4%). Two panels of methylation profiles were defined. The methylation of the HIN-1/RASSFIA panel strongly correlated to the expression of ERs, PRs, and hormone receptors (HRs; which were defined as 'positive' if ERs and/or PRs were positive; p < 0.001). Conversely, the methylation of the RIL/CDH13 panel strongly correlated to negative ER, PR, and HR expression (p = 0.001, 0.025, and 0.001, respectively). The subset of triple-negative breast cancers (in other words, those with negative ER, PR, and HER-2/neu status) was positively associated with the methylation of the RIL/CDH13 panel and negatively associated with the HIN-1/RASSF1A panel. Mutations of p53 were found in nine breast tumors (11%), seven of which lacked methylation in both panels.ConclusionWe have defined two panels (HIN-1/RASSFIA, and RIL/CDH13) of methylation profiles, which correlated, either positively or negatively, to HR status.

Dataset Information

Relationships among Inorganic Arsenic, Nutritional Status CpG Methylation and microRNAs: A Review of the Literature.

Publications

Relationships among Inorganic Arsenic, Nutritional Status CpG Methylation and microRNAs: A Review of the Literature.

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