A paradoxical teratogenic mechanism for retinoic acid

Research output: Contribution to journalArticle

  • External authors:
  • Leo M Y Lee
  • Chun Yin Leung
  • Walfred W C Tang
  • Heung Ling Choi
  • Yun Chung Leung
  • Peter J. McCaffery
  • Chi Chiu Wang
  • Alisa S W Shum

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 themammalian 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.

Bibliographical metadata

Original languageEnglish
Pages (from-to)13668-13673
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number34
DOIs
Publication statusPublished - 21 Aug 2012