Grant: Operating Grant

The prenatal period is a key time of fetal programming. In particular, one of the tissues of the fetus, the germ line, undergoes a genome-wide programming event that is critical for fertility of the resulting offspring and the health of future generations. Both animal and human studies have indicated that environmental exposures of male germ cells either during the period of fetal programming of male germ cells or prepubertally can lead to adult-onset diseases that are passed through a number of generations. Animal studies have linked these sex-specific, male-line transgenerational effects to epigenetic changes to the DNA of the developing germ cells. The epigenetic change identified was in the level of methylation of the DNA. DNA methylation is a chemical modification or 'tagging' of genes that is essential for normal developmental programs; it regulates gene expression and provides a way for genes to be turned on or off at specific times. The fetal period is the key period when DNA methylation is reprogrammed in germ cells. However, while DNA methylation is erased in both male and female fetal germ cells, it is only re-established before birth in male germ cells whereas the DNA of female germ cells doesn't become methylated until after puberty. Due the presence of fetal germ line DNA methylation reprogramming in the male but not the female, we hypothesize that male fetal germ cells are uniquely vulnerable to epigenetic abnormalities resulting from environmental insults occurring during pregnancy. Since epigenetic abnormalities are heritable, once induced, they have the potential to be passed on to future generations. Folate is a dietary exposure known to alter DNA methylation. In our research we are studying sex-specific susceptibility of male germ cells to perturbations of a key enzyme in the folate pathway, methylenetetrahydrofolate reductase (MTHFR) and/or dietary folate deficiency and supplementation in the mouse and human.