Effects of short-term exposure to ethanol on mouse embryos in vitro.
The adverse developmental effects of ethanol consumption have been documented in humans and in animal models. In animal models, the organ system affected by ethanol administration is dependent on the point in gestation at which the xenobiotic is administered. Previous studies have shown that an exposure of 24-48 hr beginning at the early somite stage in rodent conceptuses alters neural tube closure in vitro. However, the concentration and time dependency of this effect have not been fully defined. Whole embryo culture was therefore used to expose 3-6-somite mouse conceptuses (ICR strain) to ethanol at 300, 450, 600 and 800 mg/dl. The higher concentrations were selected to approximate the peak serum ethanol concentrations that have been shown to be teratogenic in vivo. A 24-hr exposure produced a concentration-dependent increase in neural tube defects (NTDs) and concomitant growth retardation. When shorter exposure periods were used (8, 10, 12 or 20 hr) the incidence of NTDs was dependent on the ethanol concentration and exposure period. At the 600 and 800 mg/dl concentrations an exposure of 8 hr or more produced NTDs, but shorter periods (4 and 6 hr) did not affect neural tube closure when evaluated at the end of a 24-hr culture period. At the 450 mg/dl concentration a 20-hr exposure induced NTDs, but a 12-hr exposure to this level did not. Exposure of conceptuses to ethanol for periods similar to their half-life in vivo did not induce NTDs and the highest concentration produced only a trend towards a reduction in protein content. When the incidence of NTDs was plotted against the area under the time and concentration curve (AUC) the correlation coefficient was 0.5779. An analysis of covariance indicated that the relationships between NTDs and AUC were similar at the 300 and 450 mg/dl concentrations and also at the 600 and 800 mg/dl concentrations. In contrast, the relationships between embryonic protein content and AUC did not differ at the 300, 450 and 600 mg/dl concentrations, but all differed from that at the 800 mg/dl level. These results indicate that ethanol-induced NTDs do not appear to be due solely to embryonic growth retardation. Additionally, ethanol-induced neural tube defects are a function of duration of exposure as well as of peak serum concentration.
Hunter
E S
ES
Developmental and Reproductive Toxicology, National Toxicology Program, National Institute of Environmental Health Sciences, PO Box 12233, Research Triangle Park, NC 27709, USA; Department of Cell Biology and Anatomy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27516, USA.
Tugman
J A
JA
Sulik
K K
KK
Sadler
T W
TW