Developmental effects of combined exposure to ethanol and vitamin A.
The potential for ethanol (EtOH) to influence the developmental toxicity of vitamin A was investigated. 11 groups of approximately 31 FDA-bred Osborne-Mendel rats received either a control or isocaloric 6.4% EtOH liquid diet (containing 4000 IU vitamin A/litre) ad lib. The vehicle control, EtOH and pair-fed (pair-fed against the EtOH group) groups received corn oil (the vehicle) by gavage. Vitamin A was administered by gavage without EtOH at 40,000, 80,000, 120,000 or 160,000 IU/kg daily. Vitamin A was administered by gavage at 10,000, 20,000, 40,000 or 80,000 IU/kg with EtOH ad lib., daily throughout the study. Combined EtOH and vitamin A resulted in significant reductions in maternal diet consumption and body weight when doses of vitamin A were as low as 10,000 IU/kg. The most severe effects on overall (days 0-20) maternal body weight gain were observed in the groups receiving 120,000 or 160,000 IU vitamin A/kg alone or EtOH in combination with 80,000 IU vitamin A/kg. The overall diet consumption (days 0-20) paralleled the overall weight gain. In general, pups exposed to ethanol and vitamin A had a tendency to weigh less than those exposed to vitamin A alone, but to weigh more than those exposed to EtOH alone. EtOH combined with vitamin A at 80,000 IU/kg resulted in an increased incidence of cleft palate relative to the vehicle control or either treatment alone. The incidence of exencephaly and protruding tongue was significantly greater in the group given vitamin A at 160,000 IU/kg, compared with the vehicle control group. The most consistent statistically significant skeletal finding in the groups receiving combined treatment was a treatment-related increased incidence of supernumerary ribs [14th rib (C7), 14th rib bud (L1) and 15 ribs]. In addition, the incidence of misshapen zygomatic arch was also significantly increased in the group exposed to EtOH and vitamin A at 80,000 IU/kg. The incidence of moderately enlarged renal pelvis and severely enlarged ureter proximal to the kidney was increased in the group exposed to EtOH and vitamin A at 80,000 IU/kg relative to the vehicle control, or either treatment alone. Therefore, for some of the endpoints examined in this investigation, it would appear that ethanol potentiates the developmental effects of vitamin A.
Whitby
K E
KE
Center for Food Safety and Applied Nutrition, Food and Drug Administration, Washington, DC 20204.
Collins
T F
TF
Welsh
J J
JJ
Black
T N
TN
Flynn
T
T
Shackelford
M
M
Ware
S E
SE
O'Donnell
M W
MW
Sundaresan
P R
PR
D000014:Abnormalities, Drug-Induced; D000818:Animals; D002972:Cleft Palate / Q000139:chemically induced; D004032:Diet; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D000431:Ethanol / Q000008:administration & dosage* / Q000633:toxicity*; D005260:Female; D005333:Fetus / Q000033:anatomy & histology; D008297:Male; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D051381:Rats; D012098:Reproduction; D012272:Ribs / Q000002:abnormalities; D014059:Tongue / Q000002:abnormalities; D014801:Vitamin A / Q000008:administration & dosage* / Q000633:toxicity*; D015430:Weight Gain
D014801:Vitamin A; D000431:Ethanol