Teratologic potential of 2-methoxyethanol and transplacental distribution of its metabolite, 2-methoxyacetic acid, in non-human primates.
Teratologic potential of 2-methoxyethanol and transplacental distribution of its metabolite, 2-methoxyacetic acid, in non-human primates.
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2-甲氧基乙醇的致畸潜力及其代谢物 2-甲氧基乙酸在非人类灵长类动物中的经胎盘分布。
DOI：
10.1002/tera.1420390408
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发表时间：
1989
期刊：
影响因子：
--
通讯作者：
Nau,H
中科院分区：
文献类型：
--
作者：
Scott,WJ;Fradkin,R;Wittfoht,W;Nau,H
在非人灵长类动物中研究了2-甲氧基乙醇（2-ME）的胚胎毒性效应，以更好地评估育龄期女性暴露于该药剂的风险。在整个妊娠器官发生阶段（第20-45天），食蟹猴雌性动物每天通过灌胃给药，并在第100天通过剖腹产收集胎仔。在最高剂量（0.47 mmol/kg）下，所有8次妊娠均以胚胎死亡告终。其中一个死亡的胚胎是不正常的，每个前肢上都缺少一个手指。在中等剂量（0.32 mmole/kg）下，10例妊娠中有3例以胚胎死亡告终，推测是由于2-ME暴露，13例妊娠中有3例在低剂量（0.16 mmole/kg）下出现类似结局。在这两组中，每一组都有额外的妊娠因流产而丢失，但两者都被认为是自发的，通常发生在10-20%未经治疗的猕猴妊娠中。这些结果表明，2-ME对发育中的灵长类动物胚胎是一种强效毒素，因此进一步关注妊娠女性暴露于该药物，尽管在几乎所有接受治疗的妊娠中母体毒性明显，并且在高剂量动物中尤其严重。2-ME的主要代谢产物2-甲氧基乙酸（2-MAA）的分布表明半衰期较长（约20 h），导致每日重复给药后代谢产物在母体血清中蓄积。经胎盘研究显示，在胚胎和胚外液中均匀分布，浓度与母体血清相似。另一方面，卵黄囊积累了非常高浓度的2-MAA，但该观察结果的胚胎毒性意义尚不清楚。
The embryotoxic effects of 2‐methoxyethanol (2‐ME) were studied in non‐human primates to better assess the risk for women of child‐bearing age exposed to this agent.Macaca fascicularisfemales were treated daily throughout the organogenetic phase of pregnancy (days 20–45) by gavage and the fetuses collected at day 100 by Caesarean section. At the highest dose (0.47 mmole/kg), all eight pregnancies ended in death of the embryo. One of these dead embryos was abnormal, missing a digit on each forelimb. At the middle dose (0.32 mmole/kg), three of 10 pregnancies ended in embryonic death, presumably due to 2‐ME exposure and three of 13 pregnancies met a similar fate at the low dose (0.16 mmole/kg). In each of these two groups, an additional pregnancy was lost to abortion, but both were thought to be spontaneous, which usually occurs in 10–20% of untreated macaque pregnancies. These results indicate that 2‐ME is a potent toxin to the developing primate embryo and thereby furthers the concern about exposure of pregnant women to this agent, although maternal toxicity was evident in nearly all treated pregnancies and was especially severe in the high‐dosage animals. Distribution of the major metabolite of 2‐ME, 2‐methoxyacetic acid (2‐MAA), indicated a long half‐life (ca.20 h), resulting in accumulation of metabolite in maternal serum after repeated daily dosing. Transplacental studies revealed uniform distribution in the embryo and extraembryonic fluids at a concentration similar to that in maternal serum. The yolk sac, on the other hand, accumulated a very high concentration of 2‐MAA, but the embryotoxic significance of this observation is unknown.