Maternal Vitamin C Deficiency and Genetic Risk Factors Contribute to Congenital Malformations through Dysregulation of DNA Methylation. [CUT&Tag E8.5]

Vitamin C (VitC) is a critical co-factor for Ten-Eleven-Translocation (TET) DNA demethylases, but the impact of its deficiency on embryonic development remains unclear. Here, we show that insufficient maternal VitC combined with genetic susceptibility can give rise to congenital malformations, including neural tube defects (NTDs), through dysregulation of DNA methylation.

We previously reported NTDs in Tet1 knockout (KO) mice at low penetrance in C57BL/6J (B6) congenic inbred strains, but at two- to three-fold higher rates when outbred or highly backcrossed (incipient congenic) on a 129S6.B6 background. Similarly, maternal VitC deficiency in L-gulonolactone oxidase (Gulo) KO mice, which like humans are unable to synthesize VitC, resulted in highly penetrant congenital malformations in non-inbred mice, during a vulnerable window coinciding with gastrulation.