title: A paradoxical teratogenic mechanism for retinoic acid.
abstract: Retinoic acid, an active metabolite of vitamin A, plays essential signaling roles in mammalian embryogenesis. Nevertheless, it has long been recognized that overexposure to vitamin A or retinoic acid causes widespread teratogenesis in rodents as well as humans. Although it has a short half-life, exposure to high levels of retinoic acid can disrupt development of yet-to-be formed organs, including the metanephros, the embryonic organ which normally differentiates into the mature kidney. Paradoxically, it is known that either an excess or a deficiency of retinoic acid results in similar malformations in some organs, including the mammalian kidney. Accordingly, we hypothesized that excess retinoic acid is teratogenic by inducing a longer lasting, local retinoic acid deficiency. This idea was tested in an established in vivo mouse model in which exposure to excess retinoic acid well before metanephric rudiments exist leads to failure of kidney formation several days later. Results showed that teratogen exposure was followed by decreased levels of Raldh transcripts encoding retinoic acid-synthesizing enzymes and increased levels of Cyp26a1 and Cyp26b1 mRNAs encoding enzymes that catabolize retinoic acid. Concomitantly, there was significant reduction in retinoic acid levels in whole embryos and kidney rudiments. Restoration of retinoic acid levels by maternal supplementation with low doses of retinoic acid following the teratogenic insult rescued metanephric kidney development and abrogated several extrarenal developmental defects. This previously undescribed and unsuspected mechanism provides insight into the molecular pathway of retinoic acid-induced teratogenesis.
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Leo M Y
authors.initials: LM
authors.lastname: Lee
authors.forename: Chun-Yin
authors.initials: CY
authors.lastname: Leung
authors.forename: Walfred W C
authors.initials: WW
authors.lastname: Tang
authors.forename: Heung-Ling
authors.initials: HL
authors.lastname: Choi
authors.forename: Yun-Chung
authors.initials: YC
authors.lastname: Leung
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McCaffery
authors.forename: Chi-Chiu
authors.initials: CC
authors.lastname: Wang
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Woolf
authors.forename: Alisa S W
authors.initials: AS
authors.lastname: Shum
mesh_terms: D000014:Abnormalities, Drug-Induced; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects / Q000196:embryology* / Q000502:physiology; D018811:Maternal Exposure; D051379:Mice; D011247:Pregnancy; D011270:Pregnancy, Animal; D012333:RNA, Messenger / Q000378:metabolism; D000072516:Retinoic Acid 4-Hydroxylase; D015398:Signal Transduction; D013723:Teratogens / Q000737:chemistry*; D013997:Time Factors; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D013723:Teratogens; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; C000607079:CYP26B1 protein, human; C000607080:Cyp26a1 protein, mouse; C000607081:Cyp26b1 protein, mouse; D000072516:Retinoic Acid 4-Hydroxylase