title: Perturbation of Retinoid Homeostasis Increases Malformation Risk in Embryos Exposed to Pregestational 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-transretinoic acid (RA) plays crucial roles in embryogenesis. Here, we find thatCyp26a1, 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 expressingCyp26a1show 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 gene-environment 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.
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.|Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.|Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong.
authors.forename: Leo M Y
authors.initials: LM
authors.lastname: Lee
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Maran B W
authors.initials: MB
authors.lastname: Leung
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Rachel C Y
authors.initials: RC
authors.lastname: Kwok
authors.affiliation: Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong.
authors.forename: Yun Chung
authors.initials: YC
authors.lastname: Leung
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.|Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.|Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Chi Chiu
authors.initials: CC
authors.lastname: Wang
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen, U.K.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McCaffery
authors.affiliation: Newlife Birth Defects Research Centre, Institute of Child Health, University College London, London, U.K.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Copp
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong alisa-shum@cuhk.edu.hk.
authors.forename: Alisa S W
authors.initials: AS
authors.lastname: Shum
mesh_terms: D000818:Animals; D000013:Congenital Abnormalities / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D015536:Down-Regulation; D047108:Embryonic Development / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D059647:Gene-Environment Interaction; D006706:Homeostasis; D051379:Mice; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000378:metabolism*; D000072516:Retinoic Acid 4-Hydroxylase / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D014212:Tretinoin; C000607080:Cyp26a1 protein, mouse; D000072516:Retinoic Acid 4-Hydroxylase