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ARS Home » Southeast Area » Little Rock, Arkansas » Arkansas Children's Nutrition Center » Research » Publications at this Location » Publication #195507
Title: PHYSIOLOGIC AND GENOMIC ANALYSES OF NUTRITION-ETHANOL INTERACTIONS DURING GESTATION: IMPLICATIONS FOR FETAL ETHANOL TOXICITY

Author
item SHANKAR, KARTIK - ACNC/UAMS
item HIDESTRAND, MATS - ACNC/UAMS
item LIU, XIAOLI - ACNC/UAMS
item XIAO, RIJIN - ACNC
item SKINNER, CHARLES - ACNC
item SIMMEN, FRANK - ACNC/UAMS
item BADGER, THOMAS - ACNC/UAMS
item RONIS, MARTIN - ACNC/UAMS

Submitted to: Experimental Biology and Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/18/2006
Publication Date: 9/15/2006
Citation: Shankar, K., Hidestrand, M., Liu, X., Xiao, R., Skinner, C.M., Simmen, F.A., Badger, T.M., Ronis, M.J. 2006. Physiologic and genomic analyses of nutrition-ethanol interactions during gestation: implications for fetal ethanol toxicity. Experimental Biology and Medicine. 231(8):1379-1397.

Interpretive Summary: Alcohol consumption during pregnancy remains a significant health issue. The factors that might mitigate or exacerbate toxicity of alcohol to either the fetus or the mother during pregnancy are hence of importance to understand. In the present rodent studies, we have found that undernutrition, caused by decreasing the amount of food provided to the animal, significantly increases the toxicity of alcohol on the fetus. Further examination revealed that the increased toxicity was at least partly associated with the inability of the undernourished rats to effectively metabolize alcohol. We have attempted to understand the changes in the liver due to alcohol consumption in the undernourished pregnant rat as compared to an adequately fed rat, given the same dose of alcohol. Our studies employed microarrays that allow the monitoring of large numbers of genes in a single experiment. Firstly, the data from these analyses showed that undernutrition by itself changed a large number of genes in the liver of pregnant rats. Further these data also show that alcohol-mediated changes in hepatic gene expression are dependent on nutritional status. Our data suggest that undernutrition potentiates the fetal toxicity of EtOH in part by disrupting maternal GH-IGF-1 signaling thereby decreasing maternal uterine capacity and placental growth.

Technical Abstract: Nutrition-ethanol (EtOH) interactions during gestation remain unclear, primarily due to the lack of appropriate rodent models. In the present report we utilize total enteral nutrition (TEN) to specifically understand the roles of nutrition and caloric intake in EtOH-induced fetal toxicity. Time-impregnated rats were intragastrically fed either control or EtOH (8-14 g/kg/d) containing diets at a recommended caloric intake for pregnant rats or undernourished 30%, from gestation day (GD) 6-20. Decreased fetal weight and litter size (p < 0.05) and increased full litter resorptions (33% vs. 0%), were observed in undernourished dams compared to adequately-fed rats given the same dose of EtOH, while undernutrition alone did not produce any fetal toxicity. Undernutrition led to impairment of EtOH metabolism, increased blood EtOH concentrations (160%), and decreased maternal hepatic ADH1 mRNA, protein and activity. Microarray analyses of maternal hepatic gene expression on GD15 revealed 369 genes were altered by EtOH in the presence of undernutrition as compared to only 37 genes by EtOH per se (+2-fold, p <0.05). Hierarchical clustering and gene ontology analysis revealed that stress and external stimulus responses, transcriptional regulation, cellular homeostasis, and protein metabolism were affected uniquely in the EtOH-undernutrition group, but not by EtOH alone. Microarray data were confirmed using real-time RT-PCR. Undernourished EtOH-fed animals had 2-fold lower IGF-1 mRNA and 10-fold lower serum IGF-1 protein levels compared to undernourished controls (p < 0.0005). Examination of maternal GH signaling via STAT5a and 5b revealed significant reduction in both gene and protein expression in an EtOH-undernutrition interactive manner. However, despite significantly elevated fetal BECs, fetal IGF-1 mRNA and protein were not affected by EtOH or EtOH-undernutrition combination. Our data suggest that undernutrition potentiates the fetal toxicity of EtOH in part by disrupting maternal GH-IGF-1 signaling, thereby decreasing maternal uterine capacity and placental growth.