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.