Perturbation of Retinoid Homeostasis Increases Malformation Risk in Embryos Exposed to Pregestational Diabetes

Pregestational diabetes is highly associated with increased risk of birth defects. However, factors that can increase or reduce expressivity and penetrance of malformations in diabetic pregnancies remain poorly identified. All-trans retinoic acid (RA) plays crucial roles in embryogenesis. Here, we find that Cyp26a1, which encodes a key enzyme for catabolic inactivation of RA required for tight control of local RA concentrations, is significantly down-regulated in embryos of diabetic mice. Embryonic tissues expressing Cyp26a1 show reduced efficiency of RA clearance. Diabetes-exposed embryos are thus sensitized to RA and more vulnerable to the deleterious effects of increased RA signalling. Susceptibility to RA teratogenesis is further potentiated in embryos with a pre-existing genetic defect of RA metabolism. Increasing RA clearance efficiency by a pre-conditioning approach can counteract the increased susceptibility to RA teratogenesis in embryos of diabetic mice. Our findings provide new insight into gene-environment interactions that influence individual risk in manifestation of diabetes-related birth defects, and shed light on the environmental risk factors and genetic variants for a stratified medicine approach to screen diabetic women of childbearing age and assess risk of birth defects during pregnancy.