Nelson B K, Vorhees C V, Scott W J, Hastings L
Department of Environmental Health, University of Cincinnati Medical School, OH 45267.
Neurotoxicol Teratol. 1989 May-Jun;11(3):273-84. doi: 10.1016/0892-0362(89)90070-6.
The industrial solvent 2-methoxyethanol (2ME) is a reproductive and developmental toxicant when administered by inhalation, gavage, and IP injection. The present research established that this solvent can produce teratogenicity in rats when administered in liquid diet. Groups of 10 Sprague-Dawley rats were given various percentages of 2ME in liquid diet on gestation days 7-18. Day 20 fetuses were examined for visceral or skeletal malformations. Concentrations above 0.025% 2ME (approximately 73 mg/kg/day) produced total embryo-mortality. Cardiovascular malformations were produced at lower levels. The teratogenic no-effect level was 0.006% 2ME (16 mg/kg). In a second experiment, groups of 12 Sprague-Dawley rats were given 0, 0.006 and 0.012% of 2ME as above. Litters were culled to 8 pups, and tested for auditory and tactile startle and conditioned lick suppression, and for performance in figure-8 activity and the Cincinnati water maze on postnatal days 48-65. The high dose of 2ME produced approximately 50% mortality in the offspring and increased the number of errors in the Cincinnati maze. No other behavioral effects were observed at either dose. An interaction study was conducted to determine if simultaneous exposure to 2ME and ethanol would reduce the teratogenicity of 2ME, but no reduction was observed. The hypothesis that 2ME acts by altering embryonic intracellular pH was tested by injecting 0.33 ml/kg of 2ME into rats on gestation day 13, and determining embryonic intracellular pH at 2, 4, 8, and 24 hours thereafter. There was an increase in pH at 4 hours, but not at later time points. Another group of rats was given 2ME along with amiloride, which blocks the sodium/hydrogen antiporter. The combined 2ME-amiloride exposure produced an incidence of cardiovascular malformations in fetuses twice that of 2ME alone. These studies confirmed the structural teratogenicity of 2ME even when given in liquid diet, as it was given for the first time in the present study. At nonteratogenic doses, developmental toxicity (e.g., postnatal deaths) persisted, but only limited evidence of behavioral teratogenicity was observed. The pH data are consistent with the concept that 2ME may alter embryonic intracellular pH at critical stages of organogenesis.
工业溶剂2-甲氧基乙醇（2ME）通过吸入、灌胃和腹腔注射给药时是一种生殖和发育毒物。本研究证实，当以液体饲料形式给药时，这种溶剂可在大鼠中产生致畸性。在妊娠第7至18天，将10只斯普拉格-道利大鼠分为几组，给予含不同百分比2ME的液体饲料。在第20天检查胎儿的内脏或骨骼畸形。2ME浓度高于0.025%（约73毫克/千克/天）会导致胚胎全部死亡。较低剂量会导致心血管畸形。致畸无作用水平为0.006%的2ME（16毫克/千克）。在第二项实验中，将12只斯普拉格-道利大鼠分为几组，如上所述给予0、0.006%和0.012%的2ME。每窝挑选8只幼崽，在出生后第48至65天测试其听觉和触觉惊吓反应、条件性舔舐抑制，以及在8字迷宫活动和辛辛那提水迷宫中的表现。高剂量的2ME导致后代约50%的死亡率，并增加了在辛辛那提迷宫中的错误数量。两种剂量均未观察到其他行为影响。进行了一项相互作用研究，以确定同时暴露于2ME和乙醇是否会降低2ME的致畸性，但未观察到降低。通过在妊娠第13天给大鼠注射0.33毫升/千克的2ME，并在之后的2、4、8和24小时测定胚胎细胞内pH值，来检验2ME通过改变胚胎细胞内pH值起作用的假设。4小时时pH值升高，但在之后的时间点未升高。另一组大鼠在给予2ME的同时给予氨氯地平，氨氯地平可阻断钠/氢反向转运体。2ME与氨氯地平联合暴露导致胎儿心血管畸形的发生率是单独给予2ME时的两倍。这些研究证实了2ME即使以液体饲料形式给药时的结构致畸性，这是本研究首次进行此类给药。在非致畸剂量下，发育毒性（如出生后死亡）持续存在，但仅观察到有限的行为致畸证据。pH值数据与2ME可能在器官发生的关键阶段改变胚胎细胞内pH值的概念一致。
