The goal of the proposed studies is to develop Drosophila melanogaster as an animal model to investigate fetal alcohol syndrome. Previous studies indicate that genetic factors can modulate the degree of alcohol teratogenic risk, yet the identification of specific genes that influence developmental ethanol toxicity has been elusive. The proposed research will both characterize the developmental, behavioral and neuroanatomical changes that occur upon developmental ethanol exposure in flies, and identify novel gene products that alter developmental ethanol toxicity. Preliminary data has shown that flies reared on 5% ethanol food are half as viable compared to control animals and significantly delayed in developmental time. In addition, ethanol-reared flies are more sensitive, as adults, to the locomotor-stimulant effects of vaporized ethanol, indicating that ethanol rearing causes permanent behavioral changes. To define the stage of ethanol-induced lethality and the critical time window of ethanol toxicity, a series of experiments will be performed rearing animals on 0% and 5% ethanol food during discrete developmental stages. Behavioral deficits commonly associated with fetal alcohol syndrome, such as learning and memory deficits, motor dysfunction, circadian rhythm deregulation, as well as eating and sleeping disturbances will be evaluated in both ethanol-reared and unexposed control adult flies. The behavioral disorders of fetal alcohol syndrome are thought to be caused by ethanol-induced injury to the developing central nervous system. Therefore, neuroanatomical damage and/or alterations following developmental ethanol exposure will be examined in both the embryonic and adult central nervous system using immunocytochemistry and the GAL4/UAS binary expression system, respectively. Finally, gene products that modify ethanol teratogenesis will be identified using both a candidate gene approach and an unbiased, forward genetic screen of single gene insertional mutations. Functional analysis of genes that modulate ethanol teratogenesis will be through a combination of molecular, behavioral and genetic approaches. Relevance to Public Health: The prevalence of fetal alcohol syndrome in the world is one to three per 1,000 births, indicating a serious health problem. Using the fruit fly to study the precise mechanisms of fetal alcohol syndrome has the potential to promote a better understanding of the actions of alcohol during development and to point the way to developing strategies that prevent (or mitigate) the damages of prenatal alcohol exposure.
