Terry K K, Stedman D B, Bolon B, Welsch F
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709, USA.
Teratology. 1996 Nov;54(5):219-29. doi: 10.1002/(SICI)1096-9926(199611)54:5<219::AID-TERA2>3.0.CO;2-V.
The potent developmental toxicant, 2-methoxyethanol (2-ME), elicits exencephaly in near-term mouse fetuses following a single maternal treatment early on gestation day (gd) 8. Deleterious morphological consequences to the neurulating embryo shortly after exposure have not been reported. The present study was designed to fill this gap and to investigate the impact of 2-ME treatment on cell death patterns in the embryonic neural folds. Dams were injected subcutaneously with saline, 250 or 325 mg 2-ME/kg 2 hr prior to the beginning of gd 8. The effect of 2-ME on gross and microscopic neural development was examined in conceptuses on gd 9, 6 hr (9:6), 10:6, and 18:0. Compared to saline, 2-ME treatment increased the percentage of embryos with open neural tubes (ONTs) at all gestation days. Although few statistically significant differences (P < 0.05) existed among the ONT rates on the 3 observation days, an interesting biological response occurred. Both high and low 2-ME doses appeared to elicit the greatest incidence of neural tube patency on gd 9:6 (affecting approximately 27% of embryos). During the subsequent 24 hr, recovery occurred and many neural folds apparently closed. Consequently, the ONT incidences on gd 10:6 (approximately 11%) were quite similar to the gd 18 exencephaly rates elicited by both chemical treatments (approximately 15%). A dose response was not seen due to a substantial increase in resorption rates following the 325 mg/kg dose. Compared to the other treatment groups, the low 2-ME dose significantly inhibited embryonic growth as indicated by reduced crown-rump and head lengths and increased incidence of developmentally delayed brain maturation. To evaluate chemically induced changes in cell death, neurulating embryos were collected on gd 8:6 and either immersed in the vital dye, Nile blue sulfate (NBS), or processed for histopathology. In 2-ME-exposed embryos, excessive NBS uptake occurred in neural fold neuroepithelium at sites of nonclosure. Using histopathology, the extent of cell death in the cephalic neural folds was dependent on the 2-ME dose, and the neuroepithelium was more severely affected than the mesenchyme. These observations suggest 1) a trend toward repair and catch-up growth later in gestation which may ameliorate the overt early effects of 2-ME, and 2) an association between enhanced cell death and regions of the neural tube particularly vulnerable to nonclosure.
强效发育毒物2-甲氧基乙醇（2-ME）在妊娠第8天（gd8）早期对母鼠进行单次处理后，会导致近足月小鼠胎儿出现无脑畸形。暴露后不久对神经胚形成期胚胎的有害形态学后果尚未见报道。本研究旨在填补这一空白，并研究2-ME处理对胚胎神经褶细胞死亡模式的影响。在gd8开始前2小时，给孕鼠皮下注射生理盐水、250或325mg 2-ME/kg。在gd9、6小时（9:6）、10:6和18:0对胚胎进行检查，以观察2-ME对大体和微观神经发育的影响。与生理盐水相比，2-ME处理在所有妊娠天数均增加了神经管开放（ONT）胚胎的百分比。虽然在3个观察日的ONT发生率之间几乎没有统计学显著差异（P<0.05），但出现了一个有趣的生物学反应。高剂量和低剂量的2-ME似乎在gd9:6时引起神经管通畅的发生率最高（影响约27%的胚胎）。在随后的24小时内，出现了恢复，许多神经褶明显闭合。因此，gd10:6时的ONT发生率（约11%）与两种化学处理引起的gd18无脑畸形发生率（约15%）相当相似。由于325mg/kg剂量后吸收率大幅增加，未观察到剂量反应。与其他处理组相比，低剂量的2-ME显著抑制胚胎生长，表现为顶臀长度和头长缩短以及发育迟缓的脑成熟发生率增加。为了评估化学诱导的细胞死亡变化，在gd8:6收集神经胚形成期胚胎，要么浸入活性染料硫酸尼罗蓝（NBS）中，要么进行组织病理学处理。在暴露于2-ME的胚胎中，神经褶神经上皮在未闭合部位出现过量的NBS摄取。使用组织病理学方法，头部神经褶中的细胞死亡程度取决于2-ME剂量，神经上皮比间充质受影响更严重。这些观察结果表明：1）妊娠后期有修复和追赶生长的趋势，这可能会改善2-ME早期的明显影响；2）细胞死亡增加与神经管中特别容易出现未闭合的区域之间存在关联。
