Goldman A S, Baker L, Piddington R, Marx B, Herold R, Egler J
Proc Natl Acad Sci U S A. 1985 Dec;82(23):8227-31. doi: 10.1073/pnas.82.23.8227.
Congenital malformations now represent the largest single cause of mortality in the infant of the diabetic mother. The mechanism by which diabetes exerts its teratogenic effects is not known. This study evaluated whether arachidonic acid might be involved, a possibility raised by the role of arachidonic acid in palatal elevation and fusion, processes analogous to neural tube folding and fusion. This hypothesis was tested in two animal models of diabetic embryopathy, the in vivo pregnant diabetic rat and the in vitro hyperglycemic mouse embryo culture. The subcutaneous injection of arachidonic acid (200-400 mg/kg per day) into pregnant diabetic rats during the period of organ differentiation (days 6-12) did not alter the maternal glucose concentration, the maternal weight gain, or the weight of the embryos. However, the incidence of neural tube fusion defects was reduced from 11% to 3.8% (P less than 0.005), the frequency of cleft palate was reduced from 11% to 4% (P less than 0.005), and the incidence of micrognathia was reduced from 7% to 0.8% (P less than 0.001). The addition of arachidonic acid to B10.A mouse embryos in culture also resulted in a reversal of hyperglycemia-induced teratogenesis. The teratogenic effect of D-glucose (8 mg/ml) in the medium resulted in normal neural tube fusion in only 32% of the embryos (P less than 0.006 when compared to controls). Arachidonic acid supplementation (1 or 10 micrograms/ml) produced a rate of neural tube fusion (67%) that was not significantly different from that observed in controls. The evidence presented indicates that arachidonic acid supplementation exerts a significant protective effect against the teratogenic action of hyperglycemia in both in vivo (rat) and in vitro (mouse) animal models. These data therefore suggest that the mechanism mediating the teratogenic effect of an increased glucose concentration involves a functional deficiency of arachidonic acid at a critical stage of organogenesis.
先天性畸形现在是糖尿病母亲所生婴儿死亡的最大单一原因。糖尿病发挥致畸作用的机制尚不清楚。本研究评估了花生四烯酸是否可能与之有关，花生四烯酸在腭部抬高和融合中的作用引发了这种可能性，而腭部抬高和融合过程类似于神经管的折叠和融合。在两种糖尿病胚胎病动物模型中对这一假设进行了检验，即体内怀孕的糖尿病大鼠和体外高血糖小鼠胚胎培养。在器官分化期（第6 - 12天）向怀孕的糖尿病大鼠皮下注射花生四烯酸（每天200 - 400毫克/千克），并未改变母体血糖浓度、母体体重增加或胚胎重量。然而，神经管融合缺陷的发生率从11%降至3.8%（P小于0.005），腭裂频率从11%降至4%（P小于0.005），小颌畸形的发生率从7%降至0.8%（P小于0.001）。在培养的B10.A小鼠胚胎中添加花生四烯酸也导致高血糖诱导的致畸作用逆转。培养基中D - 葡萄糖（8毫克/毫升）的致畸作用导致只有32%的胚胎神经管正常融合（与对照组相比，P小于0.006）。补充花生四烯酸（1或10微克/毫升）产生的神经管融合率（67%）与对照组观察到的无显著差异。所提供的证据表明，在体内（大鼠）和体外（小鼠）动物模型中，补充花生四烯酸对高血糖的致畸作用具有显著的保护作用。因此，这些数据表明，介导葡萄糖浓度升高致畸作用的机制涉及器官发生关键阶段花生四烯酸的功能缺陷。
