Hunter E S, Tugman J A, Sulik K K, Sadler T W
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.
Toxicol In Vitro. 1994 Jun;8(3):413-21. doi: 10.1016/0887-2333(94)90163-5.
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.
乙醇摄入对发育的不良影响已在人类和动物模型中得到证实。在动物模型中，受乙醇给药影响的器官系统取决于异生物素给药时的妊娠阶段。先前的研究表明，在啮齿类动物胚胎的早期体节阶段开始进行24 - 48小时的暴露会在体外改变神经管闭合。然而，这种效应的浓度和时间依赖性尚未完全明确。因此，采用全胚胎培养法，将3 - 6体节的小鼠胚胎（ICR品系）暴露于浓度为300、450、600和800mg/dl的乙醇中。选择较高浓度是为了接近已证实在体内具有致畸性的血清乙醇峰值浓度。24小时的暴露导致神经管缺陷（NTDs）呈浓度依赖性增加，并伴有生长迟缓。当采用较短的暴露时间（8、10、12或20小时）时，NTDs的发生率取决于乙醇浓度和暴露时间。在600和800mg/dl浓度下，8小时或更长时间的暴露会导致NTDs，但在24小时培养期结束时评估，较短时间（4和6小时）不会影响神经管闭合。在450mg/dl浓度下，20小时的暴露会诱导NTDs，但12小时的该浓度暴露则不会。将胚胎暴露于乙醇的时间与其在体内的半衰期相似时，不会诱导NTDs，且最高浓度仅产生蛋白质含量降低的趋势。当将NTDs的发生率与时间和浓度曲线下面积（AUC）作图时，相关系数为0.5779。协方差分析表明，在300和450mg/dl浓度以及600和800mg/dl浓度下，NTDs与AUC之间的关系相似。相比之下，在300、450和600mg/dl浓度下，胚胎蛋白质含量与AUC之间的关系没有差异，但均与800mg/dl水平下的关系不同。这些结果表明，乙醇诱导的NTDs似乎并非仅由胚胎生长迟缓所致。此外，乙醇诱导的神经管缺陷是暴露持续时间以及血清峰值浓度的函数。
