Ethylene glycol developmental toxicity: Unraveling the roles of glycolic acid and metabolic acidosis
Ethylene glycol developmental toxicity: Unraveling the roles of glycolic acid and metabolic acidosis
复制标题
DOI：
10.1093/toxsci/50.1.117
复制
发表时间：
1999-07-01
影响因子：
3.8
通讯作者：
Dryzga, MD
中科院分区：
文献类型：
--
作者：
Carney, EW;Freshour, NL;Dryzga, MD
本研究旨在确定乙醇酸（GA）——乙二醇（EG）一种在毒理学上具有重要意义的代谢产物——以及代谢性酸中毒在导致斯普拉格 - 道利大鼠发育毒性方面的相对作用。为了区分这两个相互关联的因素，我们开发了一种实验方法，无论是否存在代谢性酸中毒，都能使血液中乙醇酸水平升高。最初，在妊娠第10天（gd10），给先前植入颈动脉插管的大鼠分别经口给予40.3毫摩尔/千克（2500毫克/千克）的EG、8.5毫摩尔/千克（650毫克/千克）的GA，经皮下注射（sc）给予8.5毫摩尔/千克（833毫克/千克）的乙醇酸钠（NaG；pH值为7.4），或经口给予蒸馏水（作为对照）。在EG、GA和NaG组中，血清乙醇酸峰值几乎相同（8.4 - 8.8毫摩尔/升），并且正如预期的那样，EG和GA导致了代谢性酸中毒，但NaG组的酸碱平衡正常。随后，在妊娠第6 - 15天对25只定时交配的大鼠组给予这些处理，然后在妊娠第21天对胎儿进行评估。EG和GA降低了胎儿体重，并导致了一系列相似的发育影响，包括许多中轴骨骼畸形。NaG处理也导致胎儿体重略有下降、骨骼变异增加以及胎儿完全畸形。这些结果表明，在没有代谢性酸中毒的情况下，乙醇酸能够引起EG最敏感的发育影响，而代谢性酸中毒似乎在非常高的剂量下与乙醇酸相互作用，显著增强致畸作用。这些结果支持了先前的研究，这些研究表明乙醇酸是EG的近程发育毒物，并且GA的毒代动力学参数可用于确定EG诱导发育影响的定量的、基于生理学的阈值。
This study sought to determine the relative roles of glycolic acid (GA), a toxicologically important metabolite of ethylene glycol (EG), and metabolic acidosis in causing developmental toxicity in Sprague-Dawley rats. To tease apart these two interrelated factors, we developed an experimental approach in which high blood glycolate levels could be achieved, in either the presence or absence of metabolic acidosis. Initially, rats previously implanted with a carotid artery cannula were given, on gestation day (gd) 10, 40.3 mmol/kg (2500 mg/kg) of EG via gavage, 8.5 mmol/kg (650 mg/kg) of GA via gavage, 8.5 mmol/kg (833 mg/kg) of sodium glycolate (NaG; pH 7.4) via subcutaneous (sc) injection, or distilled water via gavage (control). Peak serum glycolate was nearly identical (8.4-8.8 mM) in the EG, GA, and NaG groups and, as expected, EG and GA caused a metabolic acidosis, but acid base balance was normal with NaG. Subsequently, these treatments were given on gd 6-15 to groups of 25 time-mated rats, followed by fetal evaluation on gd 21. EG and GA decreased fetal body weights and caused a similar spectrum of developmental effects, including numerous axial skeleton malformations. NaG treatment also caused slight decreases in fetal body weight, increases in skeletal variations, and totally malformed fetuses. These results indicate that glycolate, in the absence of metabolic acidosis, can cause the most sensitive of EG's developmental effects, whereas metabolic acidosis appears to interact with glycolate at very high doses to markedly enhance teratogenesis. These results support previous studies, which indicated that glycolate is the proximate developmental toxicant for EG, and that GA toxicokinetic parameters can be used to define a quantitative, physiologically based threshold for EG-induced developmental effects.