MOLECULAR ANALYSIS OF ETHANOL-INDUCED OROFACIAL DEFECTS

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Substantial clinical and experimental evidence indicates that alcohol consumption during pregnancy results in a variety of adverse pregnancy outcomes. The multisystem abnormalities resulting from in utero alcohol exposure, termed "fetal alcohol syndrome" (FAS), include: 1) pre- and postnatal growth retardation, 2) cranial/facial defects such as microcephaly, short palpebral fissures, midfacial hypoplasia, and cleft lip and/or cleft palate and 3) central nervous system dysfunction including atypical neonatal behavior, intellectual impairment, and developmental delays. Although clinical and experimental research related to FAS has been intense, the mechanisms underlying alcohol teratogenicity remain an enigma. Whereas significant strides have been made in addressing the pathogenesis of alcohol-induced central nervous system abnormalities, few, if any, insights have been provided regarding the cellular mechanism(s) underlying the striking orofacial dysmorphology associated with FAS, despite the fact that a characteristic orofacial phenotype is the most indicative feature of alcohol teratogenesis. The preponderance of existing clinical and experimental literature dealing with alcohol-induced orofacial dysmorphology is a descriptive nature indicating that the cellular and molecular mechanisms whereby ethanol interferes with normal orofacial ontogenesis have yet to be adequately addressed. The principal phenotypic manifestation of FAS, particularly in the orofacial region, is hypoplasia. Therefore, in the current application, we propose to analyze several basic cellular and molecular processes, perturbation of which could result in a hypoplastic facial phenotype such as that characteristic of children with FAS. Since normal growth and ontogenesis of the facial region is largely dependent on precisely orchestrated patterns and rates of cell proliferation, and expression of repertoire of extracellular matrix macromolecules, and since both of these are sites of action for alcohol in several adult and fetal tissues, it is reasonable to speculate that these processes may be cellular targets of ethanol in the developing orofacial region. Since studies on the direct effects of ethanol on cellular events during orofacial ontogenesis are critical to the advancement of mechanistic hypotheses, our overall objectives in the current application will focus on: 1) determination of the effects of ethanol on cellular proliferation in the developing murine orofacial processes and on 2) analysis of the effects of ethanol on the expression of various extracellular matrix macromolecules during murine orofacial ontogenesis.