Intrauterine growth restriction (IUGR) is a distinctive feature of fetal alcohol spectrum disorder (FASD), which is a consequence of prenatal alcohol exposure (PAE). Placenta is a specialized organ of pregnancy that supplies nutrients, such as amino acids (AAs), to the fetus for its growth. AAs are especially important and, when they are limiting due to reductions in placental AA transport and/or mTOR signaling, fetal growth is impaired and IUGR ensues. Indeed, placental AA supply is reduced in many pregnancy disorders associated with IUGR, but whether this contributes to fetal growth deficits in PAE remains unknown. I hypothesize that PAE causes IUGR, at least in part, by reducing placental AA supply to the fetus, and that this is a consequence of downregulated placental mTOR signaling, AA transport, and altered AA metabolism. I further propose that inadequate maternal protein intake, as seen in South African PAE cohorts, worsens this dysfunctional AA metabolism to exacerbate the growth deficits caused by PAE. To test this, I will feed pregnant mice a protein- sufficient (NP) or a low protein (LP) diet throughout pregnancy and administer alcohol or isocaloric maltodextrin during late gestation (GD14.5 ? GD17.5), the period during which placenta sharply upregulates AA transport to accelerate fetal growth. At GD17.5, I will comprehensively assess maternal, placental, and fetal AA metabolism.
Aim 1 performs a comprehensive metabolomics analysis to characterize how PAE decreases AA supply and metabolic fate along the maternal-placental-fetal axis.
Aim 2 performs transcriptomics analysis, western blotting and immunohistochemistry in placenta to test the hypothesis that downregulation of placental AA transporters and metabolic genes contributes to the altered AA levels in PAE.
Aim 3 performs western blotting in placenta to test the hypothesis that these changes in AA transport and metabolism are accompanied by inhibition of placental mTOR pathways, which is a major regulator of AA availability and fetal growth. I further predict PAE will exacerbate these changes under a LP diet. These studies use cutting-edge techniques to create a global portrait of how PAE affects placental AA supply and offer novel mechanistic insight into how PAE and PAE-LP contribute to the IUGR phenotype seen in FASD. These findings lay groundwork for future studies that examine postnatal neural and metabolic health, the modulatory effect of genetic risk factors, and the effectiveness of maternal AA supplementation and/or increasing maternal protein intake to improve outcomes of PAE pregnancies.
Prenatal alcohol exposure is known to impair offspring intrauterine growth, but the underlying mechanisms responsible for this adverse developmental outcome are still poorly understood. This project examines the effect of maternal alcohol consumption on placental supply of amino acids, an essential nutrient for fetal growth, as well as the modulatory effect of poor maternal protein intake on this placental function. Results from this proposed project will guide future studies conducted in populations where alcohol use during pregnancy is a common phenomenon and will inform intervention strategies, future medical practice and public health policy for improving the outcomes of children who are exposed to alcohol prenatally.
