Preconception iAs exposure: diabetes and epigenetic inheritance

ABSTRACT: PROJECT 2 Chronic exposure to inorganic arsenic (iAs) has been linked to type 2 diabetes (T2D) in epidemiologic studies. Yet, critical windows of iAs exposure leading to the development of T2D have not been identified. The association between iAs exposure and T2D has been reported in populations exposed to iAs for generations. Thus, iAs exposure of parents prior to conception may contribute to development of T2D in the progeny. Our studies showed that iAs exposure of both parents prior to conception produces diabetic phenotypes in offspring of wild- type (WT) mice. However, WT mice metabolize (i.e., detoxify) iAs more efficiently than humans. Project 2 will use unique genetically diverse humanized mice that express the human AS3MT, the key enzyme in the pathway for detoxification of iAs. These mice demonstrate a human-like pattern of iAs metabolism, and are more sensitive to iAs toxicity than WT mice. We hypothesize that preconception iAs exposure causes heritable changes in the epigenome in parental germ cells, resulting in sex-specific diabetic phenotypes in F1 and F2 offspring, and that the extent and character of these effects depend on genetic makeup of the humanized mice and dietary intake of methyl group donors, folate, and vitamin B12. We will characterize diabetogenic effects of parent-specific preconception iAs exposure in F1 and F2 male and female offspring of humanized mice from Collaborative Cross (CC) that metabolize iAs with different efficiency (Aim 1), determine the role of the epigenome as a driver of these effects (Aim 2), and establish if supplementation with folate and vitamin B12 protects against these effects by either stimulating iAs detoxification in parental generation or preventing iAs- induced differential gene methylation in parental germ cells (Aim 3). An alternative hypothesis will also be tested, which links the diabetic phenotype in the offspring to heritable iAs-induced changes in the gut microbiome of the parents. The diabetogenic effects of maternal and paternal preconception exposures will be examined independently using environmentally relevant exposures to iAs in drinking water. The innovative experimental design will provide direct evidence that DNA methylation and gene expression changes induced by preconception iAs exposure are restricted to the chromosome inherited from the exposed parent. Using the humanized CC mouse strains will facilitate translation of mouse data to human populations. This project is led by a strong team with complimentary expertise in (epi)genetics, molecular biology, iAs toxicology and metabolism, iAs-induced T2D and statistics. The project is aligned with the theme of the UNC-SRP “Protecting vulnerable populations from iAs-induced metabolic dysfunction with a vision for exposure reduction and disease prevention.” Answering questions about which parent drives the effects of preconception iAs exposure and how efficiency of iAs metabolism influences the outcomes will have a significant public health impact, providing scientific basis for interventions and treatments to reduce risk of iAs-associated disease.