ESPE Abstracts

Background: Common metabolic diseases, including diabetes and obesity, are the result of interactions between genes and environment. It is well-recognized that the maternal intrauterine environment is an important modifier of this risk. Thus, fetuses carried by women who are obese, diabetic or suffer from suboptimal nutrition are at increased risk of insulin resistance, obesity, type 2 diabetes (T2D), and cardiovascular disease as adults. Emerging data indicate that paternal environmental exposures also influence disease risk in offspring.

Objective and hypotheses: The objective of our studies is to identify molecular mechanisms contributing to paternally-mediated intergenerational risk. To test our hypotheses that paternally-mediated intergenerational risk is mediated via epigenetic marks in male germ cells, we assessed DNA methylation in sperm using our mouse model of intergenerational nutritional risk.

Method: Sperm were isolated from young male offspring exposed to maternal undernutrition in utero, and DNA methylation was assessed using MeDIP-sequencing. Selected differentially methylated regions were assessed by pyrosequencing. Functional analysis was performed in tissues of second-generation embryos and adults.

Results: In utero undernutrition results in perturbed DNA methylation in spermatozoa of adult males. This is associated with differential expression of genes neighboring these differentially methylated regions in F2 embryos.

Conclusion: Both prior nutritional exposures in utero and current metabolic health of males can alter epigenetic marks in sperm, contributing to altered gene expression and disease risk in his offspring.