Submitted to: Society of Toxicology
Publication Type: Abstract only
Publication Acceptance Date: 9/30/2002
Publication Date: 3/15/2003
Citation: RONIS, M., ZIPPERMAN, M., GARDNER, W., FLETCHER, T.W., BADGER, T.M., FERGUSON, M., HALE, K., HALEY, R. EFFECTS OF CALORIC INTAKE ON ETHANOL METABOLISM IN PREGNANT RATS: ROLE OF ALCOHOL DEHYDROGENASE AND ALDEHYDE DEHYDROGENASE.. SOCIETY OF TOXICOLOGY. 2003. v. 72(S1). p. 341. Abstract No. 1532. Interpretive Summary: Although quite large numbers of pregnant women drink alcohol, fetal alcohol syndrome is a relatively rare occurrence and appears to be related to binge drinking. Experimental studies have suggested that the severity of fetal alcohol effects are determined by the level of alcohol in the mother's circulation. This in turn is related to the rate at which the mother metabolizes alcohol during pregnancy. We have shown that pregnant rats have a lower ethanol level in their urine than non-pregnant rats given the same ethanol dose directly into the stomach as part of a semi-purified liquid diet. This implies that pregnant animals metabolize ethanol faster than non-pregnant animals and that this might be a protective mechanism for the fetus. In the current studies we are examining the molecular mechanisms underlying this effect. We show that even when food intake is the same in both groups, less alcohol appears in urine from pregnant rats. This suggests that increased alcohol metabolism is not due to increases in basal metabolic rate. No differences were found in activity of the major alcohol-metabolizing enzyme, alcohol dehydrogenase (ADH) in the mother's liver. However, significant increases were observed in the activity of aldehyde dehydrogenase (ALDH) which converts the acetaldehyde made from ethanol by ADH to acetate. Therefore ALDH increases in pregnancy may be responsible for the increased rate of alcohol metabolism. When pregnant animals are malnourished, urine ethanol concentrations were markedly higher at the same ethanol dose. This suggests that underfeeding impaired alcohol metabolism in pregnancy and can be a serious risk factor for fetal alcohol syndrome. In these animals ADH activity was significantly reduced, suggesting that ADH is regulated in response to diet.
Technical Abstract: Urine ethanol concentration (UEC) dynamics were examined in animals infused ethanol intragastrically via total enteral nutrition at caloric levels of 220, 187 or 154 kcal3/4/kgd. When ethanol was infused into pregnant rats from gestational day (GD) 6 as part of 220 kcal diets beginning at 10 g/kg/d and ending with constant infusion at 12 g/kg/d on GD 12, little ethanol was found in the urine. When ethanol infusion began at 12.5 g/kg/d and ended at 15 g/kg/d, UECs peaked at 300-500 mg/dl on GD 15-17 (d 9-10 of infusion). When pregnant rats were infused with 10-12 g/kg/d ethanol as part of 154 kcal diets, UECs peaked at 400-600 mg/dl on GD 12-13 (d 6-7 of infusion). In a second study, when a similar protocol was utilized to compare infusion of 10-12 g/kg/d ethanol in non-pregnant rats fed 187 or 220 kcal diets with pregnant rats fed 220 kcal, UECs peaked at d 6-7 of infusion in the non-pregnant rats but only at d 9-10 of infusion in the pregnant animals and the area under the UEC-time curve was reduced in the pregnant rats (p less than/equal to 0.05) compared to the other two groups. Although we have evidence that pulsatile UECs are associated with increased expression and activity of hepatic class I alcohol dehydrogenase (ADH), maternal hepatic ADH activity measured on GD 20 was identical in non-pregnant and pregnant rats fed 220 kcal diets. However, maternal hepatic aldehyde dehydrogenase (ALDH) activity was significantly elevated on GD 20. In contrast, under-nutrition using 154 kcal resulted in reduced hepatic maternal ADH activity on GD 20 (p less than/equal to 0.05). Thus ALDH may be responsible for increased ethanol metabolism in pregnancy and impaired ADH activity may account for increased UECs in undernourished pregnant animals.