Arsenic Exposure and the Epigenome: Evaluating Effects of Periconceptional and Gestational Arsenic Exposure on DNA Methylation

Abstract

Exposures before conception can impact sperm and oocyte epigenomes, morphology, and function with potential consequences for the developing fetus and child. The motivation of this work is to evaluate how early life exposure to arsenic can impact offspring epigenomes. To address this, we begin by studying the impacts of maternal arsenic levels on DNA methylation and DNA methylation-based age estimations that serve as potential approximations of gestational maturity in cord blood and placental tissues. Our findings indicate that there are sites sensitive to arsenic exposure across populations and tissue types and that biological clocks that estimate gestational duration are sensitive to arsenic exposure. We then explore DNA methylation as a function of parental arsenic exposure in a study of children born with spina bifida to determine whether observations about DNA methylation in this group can shed light on the biological pathways linking arsenic exposure and spina bifida – a neural tube defect with complex etiology. While specific arsenic-associated etiology remains unclear, our results indicate that DNA methylation of tissues taken from children born to mothers with higher arsenic exposure differs from those taken from mothers with lower arsenic. Finally, we evaluate the role of folate and arsenic on rDNA methylation of sperm in mice exposed through their mothers. We conclude from these investigations that arsenic and folate impact rDNA methylation with specific loci in the rDNA being sensitive to variations in both. Taken altogether, this work demonstrates the role of gestational arsenic on the epigenome in multiple tissues and sheds light on this relationship in understudied tissues and segments of the DNA.