This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Approximately 2% of US births are affected by fetal alcohol syndrome (FAS) and related disorders (FASD). These children are characterized by intrauterine growth retardation (IUGR), craniofacial abnormalities and neurological defects such as reflex and cognitive impairment. In selected animal models, gestational alcohol exposure induced IUGR is paired with maturity onset obesity. Alcohol consumption inhibits liver desaturase activity resulting in deficits in specific Omega-3 fatty acid availability (docosahexanoic and eicosapentanoic acids). In the current application we propose to test the central hypothesis: Maternal dietary supplementation with Omega-3 will partially alleviate alcohol exposure-induced IUGR through modulation of maternal liver Sirt1 activation with coordinately increased fetal lipid availability. The alleviation of alcohol induced fetal IUGR is predicted to eliminate pup metabolic reprogramming characterized by maturity onset obesity through normalization of Omega-3 containing lipid content in the offspring hypothalamus with attendant normalization of HPA-axis function. Further, metabolic protein expression in the hippocampus and cerebral cortex will be compromised which may underlie the prenatal alcohol exposure induced neurocognitive and behavioral abnormalities. We specifically propose to 1) examine the impact of Omega-3 fatty acid supplementation during gestational alcohol exposure on Sirt1 expression and protein markers of tissue function;and 2) examine the impact of Omega-3 fatty acid supplementation during gestational alcohol exposure on fetal nutrient availability and pup metabolic status. If correct, we will have identified prenatal dietary modulation of Sirt1 signaling as preventative for FAS associated molecular tissue remodeling which persists past exposure. We will have also identified potential molecular markers in maternal plasma which are indicative of aberrant fetal development and which may be broadly applicable to diseases other than alcohol intoxication.
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