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ToxSci Advance Access published online on December 1, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfj060
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received September 2, 2005
Accepted November 21, 2005

Reproductive and Developmental Toxicology

Retinoid Receptor Antagonists Alter the Pattern of Apoptosis in Organogenesis Stage Mouse Limbs

Sarah E. Ali-Khan 1 and Barbara F. Hales 1 *

1 Department of Pharmacology and Therapeutics McGill University Montréal, Québec, Canada H3G 1Y6

* To whom correspondence should be addressed.
Barbara F. Hales, E-mail: barbara.hales{at}mcgill.ca


  Abstract

Exposure of murine limbs in vitro to vitamin A (retinol) induces limb reduction defects and apoptosis. To assess the relative roles of the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), gestation day 12 murine limbs were cultured with selective RAR or RXR antagonists in the presence or absence of teratogenic concentrations of retinol. Both antagonists alone impaired limb development; in the presence of teratogenic concentrations of retinol, both attenuated limb malformations. Abnormal limb morphology, whether caused by excessive or attenuated retinoid signaling by retinol or either antagonist, respectively, was correlated with increased apoptosis after 24 hours of drug exposure. We conclude that in the developing limb, antagonists selective for either member of the RAR/RXR heterodimer attenuate retinoid signaling and block the teratogenic signaling of excess retinol. Improvements in limb morphology in the presence of either the RAR or the RXR antagonist coincided with restoration of the extent and localization of limb bud apoptosis to control patterns.

Keywords: retinoic acid; limb development; limb malformations; teratogen.
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