Wentzel Parri, Eriksson Ulf J
Department of Medical Cell Biology, Biomedical Center, Uppsala Universitet, SE-751 23 Uppsala, Sweden.
Toxicol Sci. 2006 Aug;92(2):416-22. doi: 10.1093/toxsci/kfl024. Epub 2006 May 26.
Intrauterine exposure to ethanol causes embryonic and fetal maldevelopment. Oxidative stress in mother and offspring has been suggested to be part of the teratogenic mechanism of ethanol. Here we aimed to assess the importance of maternal and fetal antioxidative capability for the risk of dysmorphogenesis in the offspring. We used male and female mice with different levels of superoxide dismutase (SOD) activity-wild-type (WT) mice, mice with a targeted SOD mutation (KO, decreased CuZnSOD mRNA), and mice transgenic for SOD (TG, increased CuZnSOD mRNA). Female WT, KO (heterozygous), and TG (heterozygous) mice were given drinking water containing 20% ethanol before and throughout gestation. Non-ethanol-exposed WT, KO, and TG mice served as controls. The female mice were mated with males with identical genotype, and the pregnancy was interrupted on gestational day 18 when the offspring was evaluated and genotyped. Fetal hepatic isoprostane (8-epi-PGF(2alpha)) levels were measured to assess the degree of fetal oxidative stress. Exposure to 20% ethanol decreased fetal weight by 9-13% in the three groups. Ethanol exposure roughly doubled the rates of maldeveloped WT and KO offspring but did not affect TG offspring. The fetal hepatic levels of 8-epi-PGF(2alpha) were increased in the ethanol-exposed WT and KO mice but not in ethanol-exposed TG mice. Ethanol exposure preferentially damaged WT fetuses in pregnant KO mice, whereas no such effect was found in the litters of ethanol-consuming TG mice. Administration of ethanol to pregnant mice disturbs embryogenesis by oxidative stress, and the adverse effects are more pronounced in offspring of mice with low antioxidative capacity.
子宫内暴露于乙醇会导致胚胎和胎儿发育异常。母亲和后代的氧化应激被认为是乙醇致畸机制的一部分。在这里，我们旨在评估母体和胎儿抗氧化能力对后代畸形发生风险的重要性。我们使用了具有不同超氧化物歧化酶（SOD）活性水平的雄性和雌性小鼠——野生型（WT）小鼠、具有靶向SOD突变的小鼠（KO，铜锌超氧化物歧化酶mRNA减少）以及SOD转基因小鼠（TG，铜锌超氧化物歧化酶mRNA增加）。雌性WT、KO（杂合子）和TG（杂合子）小鼠在妊娠前及整个妊娠期饮用含20%乙醇的饮用水。未暴露于乙醇的WT、KO和TG小鼠作为对照。雌性小鼠与具有相同基因型的雄性小鼠交配，并在妊娠第18天中断妊娠，此时对后代进行评估和基因分型。测量胎儿肝脏异前列腺素（8-表-前列腺素F2α）水平以评估胎儿氧化应激程度。三组中，暴露于20%乙醇使胎儿体重降低了9%-13%。乙醇暴露使发育异常的WT和KO后代的发生率大致增加了一倍，但对TG后代没有影响。乙醇暴露的WT和KO小鼠胎儿肝脏中8-表-前列腺素F2α水平升高，但乙醇暴露的TG小鼠中未升高。乙醇暴露优先损害妊娠KO小鼠中的WT胎儿，而在饮用乙醇的TG小鼠的窝仔中未发现这种效应。给妊娠小鼠施用乙醇会通过氧化应激干扰胚胎发育，并且在抗氧化能力低的小鼠后代中不良反应更明显。
