It is well known that women are more susceptible to the adverse effects of alcohol than men. An estimated 5-20 percent of American women consume alcohol during pregnancy. Yet, almost no research has examined the effects of ethanol in the pregnant mother. We have developed a total enteral nutrition (TEN) model that supports the additional nutritional demands of pregnancy and which allows the systematic study of ethanol metabolism and disposition during this period. Using the TEN system we have made several important observations: First, with constant infusion of ethanol, blood and urine ethanol concentrations of male and non-pregnant female rats cycle between almost zero and over 500 mg/dl with a frequency of one pulse every 6 days. This is the consequence of what appears to be """"""""cyclic"""""""" ethanol metabolism mediated by ethanol-dependent increases in the major hepatic ethanol metabolizing enzyme, class ADH. Second, the amplitude of these ethanol pulses is markedly reduced (65 percent) in pregnant female rats compared to virgin rats infused the same level of ethanol and calories suggesting that ethanol metabolism is significantly increased in pregnancy. This would be protective since the rate of ethanol metabolism, at a given ethanol intake, determines the maternal blood ethanol concentrations and toxicity. Third, we have observed that undernutrition during pregnancy significantly elevates the amplitude of pulsatile ethanol concentrations to higher levels. This would be expected to increase maternal toxicity. We hypothesize that ethanol metabolism and clearance are significantly increased in the well nourished pregnant rat as a consequence of endocrine changes and increased energy intake which result in increased expression of hepatic ADH class 1. In addition, we hypothesize that undernutrition in pregnancy results in impairment of ADH-dependent ethanol metabolism, which will lead to increased ethanol toxicity to both mother and fetus. The goals of the current proposal are to use the TEN system to investigate the effects of ethanol, nutrition and ethanol/nutritional interactions on ethanol metabolism and clearance in pregnant and virgin rats and to identify the nutritional; endocrine; biochemical and molecular mechanisms underlying these effects.
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