Perturbation of Retinoid Homeostasis Increases Malformation Risk in Embryos Exposed to Pregestational Diabetes
| Autor: | Alisa S.W. Shum, Leo M Y Lee, Rachel C.Y. Kwok, Maran B.W. Leung, Peter McCaffery, Yun Chung Leung, Andrew J. Copp, Chi Chiu Wang |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty medicine.drug_class Endocrinology Diabetes and Metabolism Retinoic acid Pregnancy in Diabetics Down-Regulation Embryonic Development Tretinoin Article Congenital Abnormalities Diabetes Mellitus Experimental 03 medical and health sciences chemistry.chemical_compound CYP26A1 Mice 0302 clinical medicine Downregulation and upregulation Pregnancy Diabetes mellitus Internal medicine Internal Medicine medicine Animals Homeostasis Retinoid business.industry Retinoic Acid 4-Hydroxylase medicine.disease Penetrance 030104 developmental biology Endocrinology chemistry Gene Knockdown Techniques Female Gene-Environment Interaction business 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Diabetes. 66(4) |
| ISSN: | 1939-327X |
| Popis: | 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 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. |
| Databáze: | OpenAIRE |
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