Abstract
A growing number of studies have reported that gestational exposures to a variety of environmental factors cause health effects on not only offspring but also the following generations. As for arsenic, our previous study in C3H mice, whose males tend to develop hepatic tumors, showed that arsenic exposure of F0 pregnant mice increases the incidence of hepatic tumors in F2 mice via F1 males. While the molecular mechanisms of such intergenerational inheritance are largely unknown, paternal inheritance is mainly attributable to changes in the sperm epigenome.
DNA methylation, a pivotal factor of epigenome, is known to be affected by arsenic exposure. Thus, seeking the mechanism of F2 inheritance, we investigated the DNA methylation changes of F1 sperm by gestational arsenic exposure. Next-generation sequencing showed that gestational arsenic exposure induces genome-wide DNA hypomethylation with particularly high incidence of DNA hypomethylation at retrotransposon LINE and LTR regions in F1 sperm.
On the other hand, it has not been known whether environmentally acquired DNA methylation changes in sperm are inherited in the embryos, since DNA methylation is largely deleted and reconstituted after fertilization. To address this issue, we investigated DNA methylation of F2 embryos obtained by crossing F1 males derived from arsenic-exposed dams or control F1 males with control females. The study showed that F2 embryos of arsenic group present similar features of DNA methylation pattern after reconstitution.
DNA methylation plays a pivotal role in suppression of harmful retrotransposition of retrotransposons. The present study showed that gestational arsenic exposure induces DNA methylation changes, particularly in LINE and LTR regions, in the sperm of F1 offspring and the features are inherited by the next generation.
