Altered gene expression in murine branchial arches following in utero exposure to retinoic acid.

Retinoic acid (RA) in the form of isotretinoin (Accutane) and tretinoin (Retin-A) is a clinically important compound in the treatment of dermatologic disorders. However, it is also a potent teratogen associated with a number of serious congenital malformations. Generally, these malformations involve the craniofacial structures derived from the first and second branchial arches. To determine how altered gene expression may contribute to the observed RA-induced defects, pregnant LM/Bc mice were administered (5 mg/kg) all-trans RA on gestational day (GD) 8:12. First and second branchial arches were removed from control and teratogen-treated embryos on GD 10:00 10:12, or 12:00, processed by in situ transcription/aRNA techniques, and analyzed for alterations in gene expression. In these studies, a panel of 40 candidate genes that are known to be important in mammalian craniofacial development were examined. This analysis revealed significant differences in the expression level of the nicotinic acetylcholine receptor subunit alpha (NAChR), transforming growth factor beta 2 (TGF beta 2), type 1 cellular retinoid binding protein (CRBP-1), retinoic acid receptor gamma (RAR gamma), and cAMP response element binding protein (CREB). The alterations observed in the expression of these genes following RA exposure may prohibit normal morphogenetic processes within the second branchial arch and lead to the observed malformations.