Impact of genetic factors on antioxidant rescue of maternal diabetes–associated congenital heart disease

Congenital heart disease (CHD) affects approximately 1% of live births. Although genetic and environmental etiologic contributors have been identified, the majority of CHD lacks a definitive cause, suggesting the role of gene-environment interactions (GxEs) in disease pathogenesis. Maternal diabetes mellitus (matDM) is among the most prevalent environmental risk factors for CHD. However, there is a substantial knowledge gap in understanding how matDM acts upon susceptible genetic backgrounds to increase disease expressivity. Previously, we reported a GxE between Notch1 haploinsufficiency and matDM leading to increased CHD penetrance. Here, we demonstrate a cell lineage-specific effect of Notch1 haploinsufficiency in matDM-exposed embryos, implicating endothelial/endocardial tissues in the developing heart. We report impaired atrioventricular cushion morphogenesis in matDM-exposed Notch1+/- animals and show a synergistic effect of NOTCH1 haploinsufficiency and oxidative stress in dysregulation of gene regulatory networks critical for endocardial cushion morphogenesis in vitro. Mitigation of matDM-associated oxidative stress via superoxide dismutase 1 overexpression did not rescue CHD in Notch1-haploinsufficient mice compared to wild-type littermates. Our results show the combinatorial interaction of matDM-associated oxidative stress and a genetic predisposition, Notch1 haploinsufficiency, on cardiac development, supporting a GxE model for CHD etiology and suggesting that antioxidant strategies alone may be ineffective in genetically susceptible individuals.