Project Summary/Abstract Ethanol is the most common teratogen and the leading cause of mental retardation. Fetal alcohol exposure can cause numerous birth defects, most commonly effecting the nervous system. Fetal Alcohol Spectrum Disorder describes the full range of potential ethanol-induced birth defects and has been estimated to have a prevalence of 10 in 1000 births. The timing and concentration of fetal alcohol exposure are important determinants of FASD phenotypes. There also appears to be genetic susceptibility to FASD, yet we know little about the nature of these susceptibility loci and the mechanisms by which they modify the teratogenicity of ethanol. The zebrafish embryo is particularly useful to identify and characterize loci that may underlie the neural defects associated with FASD. In Aim 1, we characterize the effect of ROS on ethanol teratogenesis. In Aim 2, we determine how mTORC1 signaling, downstream of ROS, modulates ethanol teratogenesis. In Aim 3, we characterize risk and resilience factors modulating ethanol teratogenicity. Because of the conservation of gene function between zebrafish and humans, the results from our studies will provide key insights into the genetic loci that interact with ethanol to cause FASD.