Research Project
10301279
Project Summary Despite public health efforts to reduce prenatal alcohol exposure (PAE), 11.7% of pregnant women in the U.S. consume alcohol and 3.9% binge drink. PAE can lead to growth retardation, facial dysmorphology and neurobehavioral disabilities, the key manifestations of Fetal Alcohol Spectrum Disorders (FASD). Although the growth deficits correlate with the cognitive and behavioral impairments, we lack mechanistic insight into the basis for these growth deficits. A major driver of fetal growth deficits is maternal metabolic disruption, and although alcohol is well-known to alter metabolism, surprisingly, this has been minimally investigated in PAE. My preliminary data address this knowledge gap, and show that alcohol reduces maternal-fetal glucose pools, with commensurate rise in fetal amino acid catabolites including urea. Although alcohol stimulates skeletal muscle catabolism, I find no sign that this happens in alcohol-exposed dams. Instead, my preliminary studies find that alcohol-exposed dams fail to undergo an expected adaptation to an insulin-resistant state. Moreover, I find that alcohol-driven changes in maternal fasting glucose and insulin correlate with the alcohol-mediated reductions in fetal body and brain weight. Launching from these data, this proposal uses an established mouse model of PAE and tests the hypothesis that alcohol prevents the dam from entering an insulin-resistant state, thus limiting fetal glucose availability, and thereby increasing fetal reliance on amino acids to support gluconeogenesis instead of growth. The first phase of the K99 portion quantifies maternal-fetal fed/fasted glucose levels, gluconeogenesis, and their related metabolite pools to understand how alcohol alters maternal-fetal energetics to reduce fetal glucose availability. The second phase of the K99 portion quantifies insulin signaling, and glucose storage and utilization in maternal liver, to test the hypothesis that alcohol prevents maternal adaptation to insulin resistance. Finally, the R00 phase will identify the underlying mechanism(s) that mediates this adaptive failure in alcohol-exposed dams, focusing on major candidate drivers including leptin-resistance, and prolactin and placental lactogen activity. Future studies will test these candidates functionally using organ-targeted transgenic and knockout mouse models. I will be trained in the methodologies of whole-animal and cellular metabolic assessment and an in-depth understanding of insulin/leptin signaling in pregnancy. I will also be trained in mouse behavioral assessment, looking toward future studies of how these metabolic changes may impact cognitive function. This work provides novel, mechanistic insight into the basis for the fetal growth deficits that typify FASD, focusing on key, heretofore overlooked metabolic processes. These data may also inform the development of a metabolite fingerprint or hormone test to identify at-risk pregnancies, and they will offer insights into nutrient-based interventions that could improve gestational outcomes in those pregnancies.
