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Susan M. Smith
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 Dr. Smith's laboratory studies the molecular mechanisms by which dietary components affect prenatal development, adversely and beneficially. Work focuses on three agents which are linked at the molecular level: retinoids (vitamin A), ethanol, and dioxin (e.g. Agent Orange). Our long-term goal is to identify maternal intakes which pose a risk to healthy fetal development. Retinoids are the active hormone forms of vitamin A, and when bound to their nuclear receptors act as transcriptional regulators of gene expression within target tissues. Retinoids are critical mediators of cell differentiation and positional identity of diverse embryonic tissues, such as face, heart, limb, and nervous system, and gestational retinoid deficiency and over supplementation cause specific birth defects within these structures. The most common may be congenital cardiac malformations, which affect 0.7/1000 live births and often go undiagnosed until adulthood. We use both avian toxicity and mammalian deficiency models to study retinoid roles during heart development. These functions include assignment of heart laterality and chamber identity, formation of valves and septa, and cardiomyocyte differentiation and metabolism. Approaches such as subtractive hybridization library screens, transgenic and deficient animals, retroviral transfections, and physiological techniques are used to characterize retinoid contributions at molecular and functional levels. The most common teratogen in the diet is ethanol, and prenatal alcohol exposure is the largest known cause of mental retardation in the US, exceeding such better known disorders as Down's Syndrome. Our work examines the molecular mechanisms by which alcohol causes the specific neurobehavioral and craniofacial dysmorphologies which characterize Fetal Alcohol Syndrome (FAS). We have found that alcohol exposure at particular times of development activates a cell suicide pathway called apoptosis in selected neuronal and facial populations. Our lab investigates the mechanism of this apoptosis and particularly whether ethanol causes localized retinoid deficiencies via competition for retinoid dehydrogenases. We also study the influence of maternal genetics on fetal alcohol sensitivity and current experiments investigate the molecular basis for this sensitivity. We hope to improve our understanding of the risks posed by prenatal alcohol exposure.
E. A. Thackaberry, E. J. Bedrick, M. B. Goens, L. Danielson, A. K. Lund, D. Gabaldon, S. M. Smith, and M. K. Walker Insulin Regulation in AhR-null Mice: Embryonic Cardiac Enlargement, Neonatal Macrosomia, and Altered Insulin Regulation and Response in Pregnant and Aging AhR-null Females. Toxicol. Sci., Dec 2003; 76: 407 - 417. Su, B., K.A. Debelak, L.A. Tessmer, M.M. Cartwright, and S.M. Smith. 2001. Genetic influences on craniofacial outcome in an avian model of prenatal alcohol exposure. Alcohol. Clin. Exp. Res. 25:60-69. Walker, M.K., S.E. Heid, S.M. Smith, and H. Swanson. 2000. Molecular characterization and developmental expression of the chicken aryl hydrocarbon receptor. Comp. Biochem. Physiol. Part C 126:305-319.
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7/31/2004 by rowley@waisman.wisc.edu
