Research: LEE and COLLEAGUES,

Listed in Issue 269

Abstract

LEE and COLLEAGUES, 1. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong; 2. Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong; 3. Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong; 4. Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong; 5. Institute of Medical Sciences, University of Aberdeen, Aberdeen, U.K.; 6. Newlife Birth Defects Research Centre, Institute of Child Health, University College London, London, U.K.; 7. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong alisa-shum@cuhk.edu.hk investigated factors and risks in embryos exposed to Pregestational Diabetes.

Background

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.

Methodology

All-trans retinoic acid (RA) plays crucial roles in embryogenesis.

Results

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 signalling. Susceptibility to RA teratogenesis is further potentiated in embryos with a pre-existing 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.

Conclusion

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.

References

Lee LM1,2,3, Leung MB1, Kwok RC1, Leung YC3, Wang CC1,2,4, McCaffery PJ5, Copp AJ6, Shum AS7. Perturbation of Retinoid Homeostasis Increases Malformation Risk in Embryos Exposed to Pregestational Diabetes. Diabetes.;66(4):1041-1051. Apr 2017. doi: 10.2337/db15-1570. Epub Jan 13 2017.

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