Genetic and Molecular Mechanisms of Ethanol-Induced Developmental Defects

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DESCRIPTION (provided by applicant): Prenatal exposure to ethanol in mammals leads to a range of developmental problems, from growth deficiency to mental retardation and behavioral abnormalities. In humans, these symptoms are collectively described as fetal alcohol syndrome (FAS). Ethanol exposure is especially damaging to the developing nervous system and this has long-term consequences on adult behavior. The toxicity of developmental ethanol exposure has been attributed to numerous mechanisms, including ethanol metabolism and related oxidative stress, neuronal cell loss, and inhibition of growth factors and/or their signal transduction pathways. Finally, while human epidemiological data, twin studies, and animal models indicate that genetic factors confer risk for and protection from fetal alcohol injury, no genes altering susceptibility to FAS have been conclusively identified. The goal of our research is to identify and study the molecular targets of developmental ethanol using the genetically amenable model organism Drosophila melanogaster. Drosophila melanogaster, the common fruit fly, has been utilized extensively in biological research, particularly in genetics and development. Drosophila are particularly amenable to sophisticated genetic analyses, including genomic approaches, reverse and molecular genetics, and traditional forward genetic screens. Moreover, over a century of research has led to an extensive collection of genomic, molecular and genetic tools, making Drosophila tremendously powerful in the elucidation of gene function. We have developed a genetic model of FAS in flies. We have shown that developmental ethanol exposure causes reduced viability and growth delay. In addition, as in mammals, flies reared on ethanol have altered behavioral responses to ethanol intoxication as adults. Finally, we have found that the developmental and behavioral defects are due to ethanol's effects on insulin signaling, as well as effects on the epidermal growth factor receptor (EgfR) pathway. Our research will further elucidate the role of insulin signaling in the development of FAS, as well as identify additional genetic and cellular targets of developmental ethanol exposure, both downstream and independent of insulin signaling. Our specific aims are: 1) to determine the role of the EgfR pathway in ethanol's effects on growth, viability, and behavior, 2) to investigate the role of insulin signaling in the development of tolerance in ethanol-reared flies, and 3) to identiy ethanol's molecular targets through microarray analysis.