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Transplacental arsenic exposure produced 5-methylcytosine methylation changes and aberrant microRNA expressions in livers of male fetal mice
Citation:
Liu, J., J. Cui, S. Gunewardena, C. Klaasseen, B. Chorley, AND Jon Corton. Transplacental arsenic exposure produced 5-methylcytosine methylation changes and aberrant microRNA expressions in livers of male fetal mice. TOXICOLOGY. Elsevier Science Ltd, New York, NY, 435:152409, (2020). https://doi.org/10.1016/j.tox.2020.152409
Impact/Purpose:
Arsenic is a known human carcinogen. Transplacental or early-life exposure to inorganic arsenic induces a spectrum of tumors and other diseases in humans (Smith et al., 2006; Liaw et al., 2008; Raqib et al., 2009; Rahman et al., 2010; Ahmed et al., 2012; Pilsner et al., 2012) and in experimental animals (Waalkes et al., 2003; Waalkes et al., 2007; Waalkes et al., 2008; Tokar et al., 2011; States et al., 2012; Tokar et al., 2012). Prenatal arsenic exposure in Bangladesh is associated with global DNA methylation changes in cord blood of male newborns (Pilsner et al., 2012), including hypermethylation of the promoter region of the tumor suppressor Tp53 (Intarasunanont et al., 2012). Prenatal arsenic exposure in humans increases oxidative stress markers in placenta and cord blood and alters CD4+ and CD8+ T cells, implying impaired thymic function (Ahmed et al., 2012). While detailed mechanisms of arsenic health effects remain unclear, accumulating evidence suggests an epigenetic basis (Ren et al., 2011; Boekelheide et al., 2012; Ren et al., 2015; Angrish et al., 2018). In the present study, we hypothesized that arsenic exposure in utero would lead to epigenetic changes in the fetal liver that would predetermine the adult onset of liver cancer. To address this hypothesis we examined global DNA methylation and miRNA changes after arsenic exposure conditions that lead to adult-onset of liver cancer.
Description:
Arsenic is a known human carcinogen. Early-life exposure to inorganic arsenic induces tumors in humans and in C3H mice. We hypothesized that arsenic exposure in utero may induce epigenetic changes at the level of DNA methylation and miRNA alterations that could lead to greater postnatal susceptibility to cancer. To test this hypothesis, pregnant C3H mice were given sodium arsenite at doses known to cause liver cancer (42.5 and 85 ppm in the drinking water) from gestation day 8–19, and the livers from male fetal mice were collected for analysis. The antibody against 5-methylcytosine was used to perform chromatin-immunoprecipitation coupled with sequencing (ChIP-Seq) to determine genome-wide methylation alterations. In utero arsenic exposure produced global DNA hypomethylation and an array of gene-specific DNA methylation changes, including hypomethylation of Cyclin D1 and hypermethylation of Tp53. Illumina Correlation Engine analysis revealed 260 methylation alterations that would affect 143 microRNAs. MicroRNA array further revealed 140 aberrantly expressed miRNAs out of the 718 miRNAs. The increased expression of miR-205, miR-203, miR-215, miR-34a, and decreased expression of miR-217 were confirmed by qPCR. Comparison of the methylation changes to those of microarray analyses indicates little if any correspondence between gene methylation and gene expression. The increased expression of Xist, Prrc2, Krit1, Nish, and decreased expression of Prss2, Spp1, Col1a2, and Lox were confirmed by qPCR. In summary, in utero arsenic exposure induced global alterations in DNA methylation and aberrant miRNA expression that might contribute to adult adverse outcomes including liver cancer.
URLs/Downloads:
DOI: Transplacental arsenic exposure produced 5-methylcytosine methylation changes and aberrant microRNA expressions in livers of male fetal mice
https://pubmed.ncbi.nlm.nih.gov/32068019/