Terry K K, Elswick B A, Stedman D B, Welsch F
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 22709.
Teratology. 1994 Mar;49(3):218-27. doi: 10.1002/tera.1420490318.
The industrial solvent 2-methoxyethanol (2-ME) elicits phase-specific terata in mice through its primary metabolite and proximate toxicant, 2-methoxyacetic acid (2-MAA). Recent pharmacokinetic studies indicate that the incidence and severity of digit malformations induced in CD-1 mice by 2-ME exposure on gestation day (gd) 11 (copulation plug = gd 0) correlate better with the total 2-MAA exposure over time (= area under the curve; AUC) than with its peak concentrations (Cmax) in maternal plasma, embryo and extraembryonic fluid. In this study, the phase specificity of exencephaly induction by 2-ME was investigated to ascertain whether the 2-ME/2-MAA dosimetry-teratogenicity relationship remains consistent throughout organogenesis. Following a single intravenous (iv) bolus dose of 250 mg 2-ME/kg given to pregnant mice, exposure on gd 8 was decidedly the gestation day that best balanced low embryo lethality and high malformation incidence as recorded in near-term fetuses. Concentrations of 2-MAA were measured during distribution and elimination in maternal plasma and conceptuses following iv bolus doses of 175, 250, and 325 mg 2-ME/kg, as well as during and after termination of subcutaneous (sc) constant-rate infusion (4, 6, and 8 hr; 8 microliters/hr) of 277, 392, and 606 mg 2-ME/kg total doses. For all administration regimens, exencephaly incidence rates were determined in fetuses on gd 18. Similar plasma 2-MAA Cmax values (approximately 5 mmol/l) and fetal malformation frequencies (approximately 12%) were induced by sc infusion of 392 mg 2-ME/kg or a bolus dose of 250 mg 2-ME/kg. However, the AUC produced by infusion was significantly larger than that following the iv bolus dose (38 vs. 26 mmol.hr/l, respectively). In both maternal plasma and conceptuses, the correlation coefficients between Cmax and exencephaly rates, as well as developmental toxicity, were higher than they were for AUC and those end points. This outcome suggests that dosimetry-teratogenicity determinants may be quite specific for a distinct developmental phase during which a particular organ differentiates and a specific chemical acts upon the embryo.
工业溶剂2-甲氧基乙醇（2-ME）通过其主要代谢产物及直接毒物2-甲氧基乙酸（2-MAA）在小鼠中引发特定阶段的畸形。近期的药代动力学研究表明，在妊娠第11天（交配栓=妊娠第0天）暴露于2-ME的CD-1小鼠中，指畸形的发生率和严重程度与随时间的总2-MAA暴露量（=曲线下面积；AUC）的相关性，比与母体血浆、胚胎和胚外液中的峰值浓度（Cmax）的相关性更好。在本研究中，对2-ME诱导无脑儿的阶段特异性进行了研究，以确定2-ME/2-MAA剂量测定-致畸性的关系在整个器官发生过程中是否保持一致。给怀孕小鼠单次静脉推注250mg 2-ME/kg后，妊娠第8天的暴露显然是使近期胎儿中记录的低胚胎致死率和高畸形发生率达到最佳平衡的妊娠日。在静脉推注175、250和325mg 2-ME/kg后，以及在皮下（sc）恒速输注（4、6和8小时；8微升/小时）277、392和606mg 2-ME/kg总剂量期间及之后，测定母体血浆和胚胎中2-MAA的浓度。对于所有给药方案，在妊娠第18天测定胎儿的无脑儿发生率。皮下输注392mg 2-ME/kg或静脉推注250mg 2-ME/kg可诱导相似的血浆2-MAA Cmax值（约5mmol/L）和胎儿畸形频率（约12%）。然而，输注产生的AUC明显大于静脉推注剂量后的AUC（分别为38和vs.26mmol·hr/L）。在母体血浆和胚胎中，Cmax与无脑儿发生率以及发育毒性之间的相关系数，高于AUC与这些终点之间的相关系数。这一结果表明，剂量测定-致畸性决定因素可能对特定器官分化以及特定化学物质作用于胚胎的特定发育阶段具有相当的特异性。
