Fetal Alcohol Spectrum Disorders (FASD) affects an estimated 2?5% of young school age children in the U.S., with an estimated cost of $1.4 million per individual. Two cardinal outcomes of FASD are fetal growth restriction and neurodevelopmental deficits. Efforts to successfully prevent or ameliorate these teratogenic effects of alcohol abuse have been impeded by a limited understanding of alcohol?s complex mechanisms of action, which impact multiple organ systems. In addition, etiological reports on FASD outcomes have been mostly limited to investigating indirect downstream mediators. We propose the molecular pathway governing phosphatidylethanol (PEth; 100% specific, most sensitive biomarker for gestational alcohol exposure) formation can yield novel insights into FASD etiology, as during alcohol metabolism, phosphatidylcholine is hydrolyzed to PEth instead of phosphatidic acid (PA, an essential nutrient for growth/neuron development). In an established FASD model, our novel preliminary data shows alcohol decreases PA bioavailability and concurrently increases PEth levels in maternal and fetal compartments. Our data also show alcohol-induced impairment of maternal uterine artery (related to fetal growth) and fetal brain vascular (related to neurodevelopmental outcomes) adaptations. Interestingly, PA addition in vitro to the uterine and middle cerebral arteries reverses alcohol-induced dysfunction in these vessels, and in vivo PA administration reverses FASD growth deficit. Our data also identify a role for endothelial nitric oxide (NO) synthase (eNOS) and mTORC1 signaling in this alcohol/PEth/PA framework.
In Aim #1, we hypothesize that in our FASD model, PA plays a major role in alcohol-mediated vasodilatory deficits and the related eNOS pathway in maternal uterine and developing cranially directed arteries, and that alcohol impairs the NO system via PA-mediated mTORC1 system alteration. Following mechanistic in vitro blockade of PA, mTORC1, and related signaling, we will assess uterine and developing cranially directed arterial adaptations using arteriography, LC-MS/MS, immunoblotting, immunofluorescence, RNA-seq, RT-PCR, and patch clamp.
In Aim#2, we hypothesize PA administration in vivo reverses alcohol-induced decreases in uterine artery and fetal cranially directed blood flow, and improves fetal nutrient delivery, growth phenotypes, and deficits in alcohol-sensitive neurobiological outcomes. We will measure growth indices, uterine blood flow, uterine O2/nutrient delivery, fetal cranially directed blood flow, and neuronal function/morphology to assess the role of PA in the etiology of two cardinal FASD outcomes. We anticipate that the proposed experiments will provide a much-needed breakthrough in the FASD field by identifying a promising etiological molecular pathway(s) for FASD growth and/or neurodevelopmental deficits. These studies will pave way for future novel prevention/treatment studies strategically aimed at rescuing FASD cardinal outcome phenotypes through manipulation of direct alcohol targets.
Maternal alcohol abuse during pregnancy can result in a range of physical, mental, behavioral and learning disabilities termed as Fetal Alcohol Spectrum Disorders. Efforts to successfully prevent or ameliorate the deleterious effects of maternal alcohol consumption have been impeded in part by a limited understanding of alcohol?s complex mechanisms of action involving multiple organ systems. The proposed R01 studies are designed to identify novel etiological molecular pathway(s) for FASD cardinal outcomes using integrative physiologic approaches.
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