Epigenetic effects of low-level sodium arsenite exposure on human liver HepaRG cells
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INORGANIC COMPOUNDS
Epigenetic effects of low‑level sodium arsenite exposure on human liver HepaRG cells Volodymyr P. Tryndyak1 · Barbara Borowa‑Mazgaj1 · Colleen R. Steward1 · Frederick A. Beland1 · Igor P. Pogribny1 Received: 14 May 2020 / Accepted: 12 August 2020 © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2020
Abstract Chronic exposure to inorganic arsenic is associated with a variety of adverse health effects, including lung, bladder, kidney, and liver cancer. Several mechanisms have been proposed for arsenic-induced tumorigenesis; however, insufficient knowledge and many unanswered questions remain to explain the integrated molecular pathogenesis of arsenic carcinogenicity. In the present study, using non-tumorigenic human liver HepaRG cells, we investigated epigenetic alterations upon prolonged exposure to a noncytotoxic concentration of sodium arsenite ( NaAsO2). We demonstrate that continuous exposure of HepaRG cells to 1 µM sodium arsenite (NaAsO2) for 14 days resulted in substantial cytosine DNA demethylation and hypermethylation across the genome, among which the claudin 14 (CLDN14) gene was hypermethylated and the most down-regulated gene. Another important finding was a profound loss of histone H3 lysine 36 (H3K36) trimethylation, which was accompanied by increased damage to genomic DNA and an elevated de novo mutation frequency. These results demonstrate that continuous exposure of HepaRG cells to a noncytotoxic concentration of NaAsO2 results in substantial epigenetic abnormalities accompanied by several carcinogenesis-related events, including induction of epithelial-to-mesenchymal transition, damage to DNA, inhibition of DNA repair genes, and induction of de novo mutations. Importantly, this study highlights the intimate mechanistic link and interplay between two fundamental cancer-associated events, epigenetic and genetic alterations, in arsenic-associated carcinogenesis. Keywords Epigenetics · Sodium arsenite · Hepatotoxicity · HepaRG cells
Introduction Inorganic arsenic is one of the most abundant natural contaminants found in soil, water, food, and air (Hughes et al. 2011; Bailey et al. 2016; Zhou and Xi 2018). Chronic exposure to inorganic arsenic is associated with a variety of adverse health effects, including several types of cancers (Zhou and Xi 2018). Existing evidence indicates that the liver is one of the target organs of inorganic arsenic-induced Volodymyr P. Tryndyak and Barbara Borowa-Mazgaj contributed equally to this article. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00204-020-02872-6) contains supplementary material, which is available to authorized users. * Igor P. Pogribny [email protected] 1
Division of Biochemical Toxicology, FDA-National Center for Toxicological Research, Jefferson, AR, USA
toxicity and carcinogenicity. This is evidenced by an increased risk of several chronic human liver pathologies, ranging from nonalcoholi
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