Ward K W, Pollack G M
Curriculum in Toxicology, School of Medicine, University of North Carolina at Chapel Hill, 27599-7360, USA.
Toxicol Appl Pharmacol. 1996 Oct;140(2):203-10. doi: 10.1006/taap.1996.0214.
Methanol is teratogenic in rodents; it has been postulated that this teratogenicity may be mediated in part by conceptal hypoxia. To construct a model to predict conceptal risk following maternal methanol exposure, conceptal disposition of methanol must be determined and any effects of such exposure on blood flow must be quantitated. In the present study, these toxicokinetic and toxico-dynamic parameters were evaluated by in vivo intrauterine microdialysis. Microdialysis probes were inserted into the uteri of Gestational Day (gd) 20 rats; methanol was administered as either an iv bolus (100 or 500 mg/kg) or infusion (100 or 1000 mg/kg/hr). In separate experiments, methanol (100 or 500 mg/kg) and 3H2O (20 microCi/kg) were administered iv to gd 20 and 14 rats and gd 18 mice. In both experiments, maternal blood and uterine microdialysate were collected and analyzed for methanol or 3H2O content. The methanol concentration-time data were consistent with saturable maternal elimination and apparent first-order transfer between maternal and conceptal compartments; at distribution equilibrium, conceptal methanol concentrations exceeded those in the dam by approximately 25%. The initial rate of conceptal permeation of methanol was proportional to the reciprocal of maternal blood methanol concentration (r2 = 0.910). Methanol also reduced significantly the rate of 3H2O uptake into the conceptus in a concentration-dependent fashion in gd 14 and 20 rats and gd 18 mice. These data indicate that methanol may decrease uteroplacental blood flow, decreasing methanol presentation to the conceptus and possibly producing conceptal hypoxia.
甲醇对啮齿动物具有致畸性；据推测，这种致畸性可能部分是由胚胎缺氧介导的。为构建一个预测母体接触甲醇后胚胎风险的模型，必须确定甲醇在胚胎中的处置情况，并对这种接触对血流的任何影响进行定量分析。在本研究中，通过体内子宫微透析评估了这些毒代动力学和毒效动力学参数。将微透析探针插入妊娠第20天（gd20）大鼠的子宫内；甲醇以静脉推注（100或500mg/kg）或输注（100或1000mg/kg/hr）的方式给药。在单独的实验中，将甲醇（100或500mg/kg）和3H2O（20微居里/kg）静脉注射给gd20和14的大鼠以及gd18的小鼠。在这两个实验中，收集母体血液和子宫微透析液，并分析甲醇或3H2O的含量。甲醇浓度-时间数据与母体消除的饱和性以及母体和胚胎隔室之间明显的一级转运一致；在分布平衡时，胚胎甲醇浓度比母鼠体内的浓度高出约25%。甲醇进入胚胎的初始渗透率与母体血液甲醇浓度的倒数成正比（r2 = 0.910）。甲醇还以浓度依赖性方式显著降低了gd14和20的大鼠以及gd18的小鼠胚胎对3H2O的摄取率。这些数据表明，甲醇可能会减少子宫胎盘血流量，减少向胚胎提供的甲醇量，并可能导致胚胎缺氧。
