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Title: Perturbation of retinoid homeostasis increases malformation risk in embryos exposed to pregestational diabetes
Authors: Lee, LMY 
Leung, MBW
Kwok, RCY
Leung, YC 
Wang, CC
McCaffery, PJ
Copp, AJ
Shum, ASW
Issue Date: 2017
Publisher: American Diabetes Association
Source: Diabetes, 2017, v. 66, no. 4, p. 1041-1051 How to cite?
Journal: Diabetes 
Abstract: Pregestational diabetes is highly associated with an increased risk of birth defects. However, factors that can increase or reduce the expressivity and penetrance of malformations in pregnancies in women with diabetes 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 downregulated in embryos of diabetic mice. Embryonic tissues expressing Cyp26a1 show reduced efficiency of RA clearance. Embryos exposed to diabetes are thus sensitized to RA and more vulnerable to the deleterious effects of increased RA signaling. Susceptibility to RA teratogenesis is further potentiated in embryos with a preexisting genetic defect of RA metabolism. Increasing RA clearance efficiency using a preconditioning approach can counteract the increased susceptibility to RA teratogenesis in embryos of diabetic mice. Our findings provide new insight into geneenvironment interactions that influence individual risk in the manifestation of diabetes-related birth defects and shed light on environmental risk factors and genetic variants for a stratified medicine approach to screening women with diabetes who are of childbearing age and assessing the risk of birth defects during pregnancy.
ISSN: 0012-1797
EISSN: 1939-327X
DOI: 10.2337/db15-1570
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