Submitted to: Toxicologist
Publication Type: Abstract Only
Publication Acceptance Date: 10/3/2004
Publication Date: 3/15/2005
Citation: Shankar, K., Hidestrand, M., Yarberry, B., Xiao, R., Simmen, F.A., Badger, T.M., Ronis, M.J. 2005. Microarray-based analysis of nutrtion-ethanol interactions during gestation. The Toxicologist. 84(S-1):274. Interpretive Summary: Undernutrition claims the lives of thousands of people each year and leaves many others with long-term, severe health problems. It is also estimated that thousands of children are born with at least some disorders related to exposure to ethanol during fetal life. Unfortunately, undernutrition and alcohol consumption can occur simultaneously during pregnancy, and this study aimed at learning the consequences. It was determined that: 1) undernutrition alone or ethanol alone during pregnancy resulted in permanent changes in the way certain genes functioned; 2) animals who were both undernourished and who consumed ethanol during pregnancy had lower birth weights and more severe gene changes; and 3) undernutrition actually resulted in higher blood ethanol levels, suggesting the level of maternal nutrition is an important determinant in maintaining health of the fetus and in predicting future health of children born to women who insist upon drinking ethanol while pregnant.
Technical Abstract: Undernutrition markedly potentiated fetal toxicity of ethanol (EtOH) during pregnancy. To understand the mechanisms of this interaction time-impregnated rats were fed either adequate (NRC requirements, 220 kcal/kg 3/4/d) or undernourished diets (30% less calories, 160 kcal/kg 3/4/d) via intragastric infusion containing either 12g/kg/d EtOH or isocaloric amount of carbohydrates from gestation days (GD) 6-15. Undernourished dams had 1.6 fold greater urine EtOH concentrations (p=0.007), higher complete litter resorptions (33% vs. 0%), lower litter weight and lower numbers of pups/litter (p<0.05) compared to control rats given the same dose of EtOH but fed adequate diets. Undernutrition in the absence of EtOH did not increase any parameters of fetal toxicity. Affymetrix RU34A GeneChip microarray-based comparisons were performed on maternal hepatic gene expression on GD 15. Expression of 101 genes was alter by the combination of EtOH and undernutrition as compared to only 30 genes in the rats fed an adequate diet in the presence of EtOH (p<0.05). Hierarchical clustering of gene expression data resolved the affected genes into 8 clusters. Gene ontology analysis revealed that genes associated with stress and external stimulus responses, transcriptional regulation, cellular homeostasis and protein metabolism were affected uniquely in the EtOH-nutrition group, but not by EtOH alone. Microarray data were confirmed using real-time RT-PCR. Nutritional induction of metallothionein 1, rev-erbA (alpha) and (Beta), IGFBP-1 and 4 and repression of rPer2, and gluckinase was observed (p<0.01). Undernourished EtOH-fed animals had 2-fold lower IGF1 mRNA and 10-fold lower serum IGF1 protein levels compared to undernourished controls (p = 0.0002). The present data suggest that undernutrition may potentiate the fetal toxicity of EtOH in part by disrupting IGF1 synthesis and bioavailability and zinc availability to the fetus.