|Gardner, William - ACNC|
|Fletcher, Terry - UAMS|
|Ferguson, Matt - ACNC|
|Hale, Kim - ACNC|
|Zipperman, Michelle - ACNC|
Submitted to: Society of Toxicology
Publication Type: Abstract Only
Publication Acceptance Date: September 30, 2002
Publication Date: March 15, 2003
Citation: RONIS, M., GARDNER, W., FLETCHER, T.W., FERGUSON, M., HALE, K., BADGER, T.M., ZIPPERMAN, M. EFFECTS OF CALORIC INTAKE AND ETHANOL METABOLISM ON FETAL ETHANOL TOXICITY IN RATS. SOCIETY OF TOXICOLOGY. 2003. v. 72. Abstract p. 315. 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. This suggests that the severity of alcohol effects on the fetus are determined by the level of alcohol in the mothers 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 level of unmetabolized alcohol in their urine than non-pregnant rats given the same alcohol dose directly into the stomach as part of a semi-purified liquid diet. This implies that pregnant animals metabolize alcohol faster than non-pregnant animals and that this might be a protective mechanism for the fetus because alcohol cnecentrations reaching the fetus are lower. In the current study we have examined the role of food intake and alcohol metabolism in pregnancy on the fetal toxicity of alcohol. Rats were fed liquid diets via a tube directly into the stomach to produce optimal food take for pregnant animals and alcohol was substituted for carbohydrate calories. Increasing doses of ethanol during pregnancy only resulted in toxic effects in the pups (reduced birth weight, pup mortality) at doses above 13 g/kg/d and urine alcohol concentrations of greater than 200 mg/dl (0.2%). However, when food intake was reduced by 30%, highly significant fetal toxicity was observed at alcohol doses producing no effect in well-fed animals. This was accompanied by a significant increase in urine alcohol concentrations from 157 to 233 mg/dl. Therefore, undernutrition impairs alcohol metabolism in pregnant animals and as a result increases fetal toxicity because the alcohol concentrations are higher and must be considered a risk factor in development of FAS.
Technical Abstract: Urine ethanol concentrations (UEC) are significantly lower in pregnant than non-pregnant Sprague-Dawley rats infused with the same ethanol dose via total enteral nutrition. Under-nutrition appears to abolish this effect. Increased ethanol metabolism in pregnancy may be a protective mechanism that could account for the low penetrance of fetal alcohol syndrome (FAS) among the children of alcoholic mothers. In contrast, under-nutrition may be a risk factor for FAS. Groups of 3-15 time-impregnated female Sprague-Dawley rats were intragastrically infused TEN diets containing an optimal 220 kcal/kg3/4/d for nutritional support during pregnancy from gestational (GE) d 6 until GE d 20. Ethanol was substituted isocalorically for carbohydrate calories at levels of 8-14 g/kg/d. UECs were measured and averaged from 69 plus/minus 6 to 327 plus/minus 22 mg/dl. No full litter resorptions occurred at ethanol doses below 11.8 g/kg/d and no significant reductions in birth weight were observed at ethanol doses lower than 13 g/kg/d. At 14 g/kg/d ethanol, 33% of litters were resorbed and those that survived had significant fetal wastage (p greater than/equal to 0.05) and reduced birth weight (3.7 plus/minus 0.3 g, control vs. 1.4 g plus/minus 0.2 g, ethanol). When groups of N = 7-8 dams were infused with 13 g/kg ethanol and fed TEN diets containing either optimal 220 kcal/kg3/4/d or restricted to 154 kcal/kg3/4/d, full litter resorptions were noted in 63% of the 154 kcal rats and none of the 220 kcal rats. Decreased birth weights (p less than/equal to 0.05) were observed in pups from the 154 kcal animals accompanied by significantly increased blood and urine ethanol levels (average UEC, 233 plus/minus 34 vs. 157 plus/minus 20 mg/dl) . Therefore, increased ethanol metabolism in pregnancy protects the fetus against ethanol toxicity and this toxicity is increased by under-feeding as a result of impaired ethanol clearance and increased fetal exposure.