eprintid: 1538449 rev_number: 29 eprint_status: archive userid: 608 dir: disk0/01/53/84/49 datestamp: 2017-01-28 22:22:54 lastmod: 2021-12-16 01:04:08 status_changed: 2017-05-03 14:40:42 type: article metadata_visibility: show creators_name: Lee, LM creators_name: Leung, MB creators_name: Kwok, RC creators_name: Leung, YC creators_name: Wang, CC creators_name: McCaffery, PJ creators_name: Copp, AJ creators_name: Shum, AS title: Perturbation of Retinoid Homeostasis Increases Malformation Risk in Embryos Exposed to Pregestational Diabetes ispublished: pub divisions: UCL divisions: B02 divisions: D13 divisions: G22 note: © 2017 by the American Diabetes Association. This is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes. The American Diabetes Association (ADA), publisher of Diabetes, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version will be available in a future issue of Diabetes in print and online at http://diabetes.diabetesjournals.org. abstract: 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. date: 2017-01-13 date_type: published official_url: http://doi.org/10.2337/db15-1570 oa_status: green full_text_type: other language: eng primo: open primo_central: open_green article_type_text: Journal Article verified: verified_manual elements_id: 1204803 doi: 10.2337/db15-1570 pii: db15-1570 lyricists_name: Copp, Andrew lyricists_id: ACOPP78 actors_name: Copp, Andrew actors_name: Laslett, David actors_id: ACOPP78 actors_id: DLASL34 actors_role: owner actors_role: impersonator full_text_status: public publication: Diabetes volume: 66 number: 4 article_number: db151570 pagerange: 1041-1051 event_location: United States issn: 1939-327X citation: Lee, LM; Leung, MB; Kwok, RC; Leung, YC; Wang, CC; McCaffery, PJ; Copp, AJ; Lee, LM; Leung, MB; Kwok, RC; Leung, YC; Wang, CC; McCaffery, PJ; Copp, AJ; Shum, AS; - view fewer <#> (2017) Perturbation of Retinoid Homeostasis Increases Malformation Risk in Embryos Exposed to Pregestational Diabetes. Diabetes , 66 (4) , Article db151570. 10.2337/db15-1570 <https://doi.org/10.2337/db15-1570>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/1538449/1/Copp_Lee%20et%20al%252C%20Diabetes%252C%202017%252C%20MS%252BFigs%20combined.pdf