Rogers J M, Mole M L
Developmental Biology Branch, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Teratology. 1997 Jun;55(6):364-72. doi: 10.1002/(SICI)1096-9926(199706)55:6<364::AID-TERA2>3.0.CO;2-Y.
Exposure of pregnant CD-1 mice to methanol (MeOH) by inhalation on gestation days (gd) 6-15 results in dose-related increases in fetal cleft palate, exencephaly, and skeletal defects. Here, critical periods for the developmental toxicity of MeOH were assessed in pregnant CD-1 mice exposed to 10,000 ppm MeOH or filtered air for 7 hr/day on 2 consecutive days during gd 6-13, or to single day (7 hr) exposures to 10,000 ppm MeOH during gd 5-9. Mice received water but not food during exposure. Maternal blood MeOH was determined at times during, at the end of, and subsequent to a single 7 hr exposure on gd 7. On gd 17, remaining mice were weighed, killed, and gravid uteri removed. Live, dead, and resorbed fetuses were counted, and live fetuses were examined, weighed, and preserved in 70% ethanol. All fetuses were examined externally and for cleft palate, eviscerated, and stained with Alizarin red for skeletal examination. Pregnant mice lost an average of 0.3-2.9 g during 7 hr exposure to either filtered air or MeOH, but a MeOH treatment effect was evident only with 2-day exposure on gd 7-8. Peak maternal blood MeOH concentration (at the end of exposure) was approximately 4 mg/ml, and MeOH was cleared from maternal blood within 24 hr. Some fully resorbed litters were observed with 2-day MeOH exposures on gd 6-7 or 7-8, or 1-day exposure on gd 7. With 1-day MeOH exposure on gd 7, the number live was lower than with exposure on any other day. As previously reported, cleft palate, exencephaly, and skeletal defects were the fetal anomalies observed in this mouse strain. Cleft palate occurred with 2-day exposures on gd 6-7 through gd 11-12 (peak on gd 7-8), and with 1-day exposure on gd 5 through gd 9 (peak on gd 7). Exencephaly occurred with 2-day exposures on gd 6-7 through gd 8-9 (peak gd 6-7) or 1-day exposure on gd 5 through gd 8 (peak on gd 7). Skeletal elements malformed included the exoccipital (peak gd 6-7, gd 5), atlas (peak gd 6-7, gd 5,6), axis (peak gd 6-7, gd 7), cervical vertebra 7 with a rib (peak gd 6-7, gd 7), and lumbar vertebra 1 with a rib (peak gd 7-8, gd 7). An increased incidence of fetuses with 25 presacral vertebrae (normal = 26) was observed with methanol exposure on gd 5, whereas an increased incidence of fetuses with 27 presacral vertebrae was observed with MeOH exposure on gd 7. These results indicate that gastrulation and early organogenesis represent a period of increased embryonal sensitivity to methanol.
在妊娠第6至15天通过吸入方式使怀孕的CD - 1小鼠暴露于甲醇（MeOH）中，会导致胎儿腭裂、无脑畸形和骨骼缺陷呈剂量相关增加。在此，对妊娠第6至13天连续2天每天7小时暴露于10,000 ppm MeOH或过滤空气中，或在妊娠第5至9天单日（7小时）暴露于10,000 ppm MeOH的怀孕CD - 1小鼠中甲醇发育毒性的关键时期进行了评估。暴露期间小鼠只饮水不进食。在妊娠第7天单次7小时暴露期间、结束时及之后测定母血中的甲醇含量。在妊娠第17天，称剩余小鼠体重、处死并取出妊娠子宫。对存活、死亡和吸收的胎儿进行计数，对存活胎儿进行检查、称重并保存在70%乙醇中。对所有胎儿进行外部检查及腭裂检查，取出内脏并用茜素红染色进行骨骼检查。怀孕小鼠在暴露于过滤空气或甲醇7小时期间平均体重减轻0.3 - 2.9克，但仅在妊娠第7至8天进行2天暴露时甲醇处理效果明显。母血甲醇浓度峰值（暴露结束时）约为4毫克/毫升，且甲醇在24小时内从母血中清除。在妊娠第6至7天或7至8天进行2天甲醇暴露，或在妊娠第7天进行1天暴露时观察到一些完全吸收的窝。在妊娠第7天进行1天甲醇暴露时，存活胎儿数量低于其他任何一天的暴露情况。如先前报道，腭裂、无脑畸形和骨骼缺陷是在该小鼠品系中观察到的胎儿异常情况。腭裂出现在妊娠第6至7天至11至12天的2天暴露时（第7至8天达到峰值），以及妊娠第5至9天的1天暴露时（第7天达到峰值）。无脑畸形出现在妊娠第6至7天至8至9天的2天暴露时（第6至7天达到峰值）或妊娠第5至8天的1天暴露时（第7天达到峰值）。骨骼畸形的部位包括枕外骨（第6至7天、第5天达到峰值）、寰椎（第6至7天、第5、6天达到峰值）、枢椎（第6至7天、第7天达到峰值）、第7颈椎带肋骨（第6至7天、第7天达到峰值）和第1腰椎带肋骨（第7至8天、第7天达到峰值）。在妊娠第5天甲醇暴露时观察到骶前椎骨为25块（正常为26块）的胎儿发生率增加，而在妊娠第7天甲醇暴露时观察到骶前椎骨为27块的胎儿发生率增加。这些结果表明，原肠胚形成和早期器官发生代表胚胎对甲醇敏感性增加的时期。
