Sex-dependent effects of prenatal alcohol exposure on developmental programming

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PROJECT SUMMARY Prenatal alcohol exposure (PAE) is associated with developmental, cognitive, behavioral, and physical abnormalities termed Fetal Alcohol Spectrum Disorders (FASD). With a prevalence ranging from 2 to 5 in 100 children and an estimated added annual cost of $21,000 for an individual afflicted with FASD, therapies aimed at treating FASD will be of significant societal benefit. Our goal is to identify molecular mechanisms through which alcohol alters the developing fetus and to use this information to advance targeted interventions that reverse or reduce the long-term consequences of PAE. PAE “programs” development of the organism, producing changes that can persist throughout the lifespan. In many cases, the effects of PAE are mediated by glucocorticoids (GCs) acting via glucocorticoid receptors (GRs) and are influenced by the sex of the organism. We hypothesize that PAE modifies the in utero programming of GRs in a sex- and development-specific manner as the result of differential effects of PAE on placental and fetal brain levels of 1.) 11β-HSD1 and 11β-HSD2, which catalyze interconversion of active and inactive GC, and 2.) the long noncoding RNA Growth arrest-specific 5 (Gas5), which binds to the GR DNA- binding domain, inhibiting GR-dependent gene expression. These studies will identify effects of PAE on microRNA-mediated mechanisms that regulate GR programming. Additionally, we assess the role of placental exosomes as mediators of the effects of PAE on fetal brain Gas5. Elucidation of the effects of PAE on placental 11β-HSDs, Gas5 and exosomes may serve to identify 1.) biomarkers for identification of alcohol consumption during human pregnancy, 2.) predictors of progeny outcomes, and 3.) novel targets for the treatment of FASDs.