UCSF

There is a growing appreciation that environmental factors can impact embryonic development and program long-term physiology, but the underlying mechanisms remain largely unknown. The embryonic germline is of particular interest because of the potential for intergenerational epigenetic effects. The mammalian germline undergoes extensive DNA demethylation that is carried out in part by Tet enzymes, the activity of which has been shown to be modulated in vitro by nutrients and metabolites, including Vitamin C. Here we report that maternal Vitamin C is required in vivo for proper DNA demethylation and development of female fetal germ cells in a mouse model. Withdrawal of Vitamin C from the maternal diet does not affect overall embryonic development but leads to defects in the fetal germline, which persist well after Vitamin C re-supply during late gestation. These defects include reduced germ cell numbers in female embryos, delayed entry into meiosis, and reduced fecundity in adulthood with increased incidence of fetal loss. The transcriptome of germ cells from Vitamin C-deficient embryos is remarkably similar to that of embryos carrying a null mutation in Tet1, an enzyme responsible for DNA demethylation and activation of regulators of meiosis. In agreement with these results, Vitamin C deficiency leads to an aberrant DNA methylation profile that includes incomplete demethylation of key regulators of meiosis and transposable elements. These findings reveal that deficiency in Vitamin C during gestation recapitulates mutation of Tet1 and disrupts germline reprogramming and development. Our work further indicates that the embryonic germline is sensitive to perturbations of the maternal diet, providing a potential intergenerational mechanism for adjusting fecundity to environmental conditions.