van der Veer, B. K.; Custers, C.; Brangers, W.; Cornelis, R.; Champeris Tsaniras, S.; De Ridder, K.; Thienpont, B.; Cheng, H.; Chen, Q.; Kraushaar, D.; Finnell, R. H.; Gross, S.; Koh, K. P.

Maternal dietary insufficiencies can reshape the fetal epigenome during gestation, contributing to birth defects and developmental disorders. Vitamin C (VitC) is a critical co-factor for Ten-Eleven-Translocation (TET) DNA demethylases, but the impact of its deficiency on embryonic development has gone largely unappreciated. Here, we show that maternal VitC deficiency in L-gulonolactone oxidase (Gulo)-deficient mice, which like humans are unable to synthesize VitC, can cause highly penetrant developmental delays and malformations in non-inbred embryos during the vulnerable period of gastrulation. DNA hypermethylation in Gulo-/- embryonic neural tissues of susceptible strains increases with VitC dose reduction and with the severity of embryonic pathologies, coinciding with hallmarks of TET1 dysfunction. A moderate reduction in VitC status is sufficient to induce DNA hypermethylation and cause neural tube defects. Our results suggest that promoting timely VitC supplementation by at-risk pregnant mothers may prevent a range of birth defects and enhance health outcomes of future generations.