Resolving studies on mechanism of developmental toxicity induced by chemical substances in culture system

为明确化学物质对胚胎发育毒性的作用机制，本研究建立了10.5~12.5天的大鼠胚胎培养体系。阿司匹林、水杨酸和氨基比林在妊娠11.5天对培养的大鼠胚胎产生畸形。咖啡因可致12.5天大鼠胚胎发育畸形。咖啡因对11.5天的胚胎也有类似的作用，但咖啡因的数量较少。用体外培养的10.5日龄大鼠胚胎研究了环磷酰胺和二甲基亚砜对胚胎的毒性作用。整个胚胎培养系统被利用，以避免潜在的混杂的物质因素。苯巴比妥预处理的大鼠S-9组分明显增加氨基比林的胚胎毒性和畸形率。4-氨基安替比林或4-乙酰氨基安替比林对大鼠胚胎的致畸作用弱于氨基比林。这些结果表明，氨基比林的内在致畸作用，即真正的活性物质，可能是3位羟基代谢物，而不是氨基比林本身或4位N-去甲基代谢物。围产期大鼠肝脏中γ-谷氨酰转肽酶活性的升高与胎儿半胱氨酸摄取的增加和蛋氨酸向半胱氨酸的转化减少相一致。本文研究了猴等实验动物肝脏谷胱甘肽S转移酶和细胞色素P-450的性别和物种差异。

To investigate clearly the mechanism of developmental toxicity induced by chemical substances, the whole embryo culture system using day 10.5 to 12.5 rat embryos of gestation was confirmed. Aspirin, salicylic acid and aminopyrine produced malformations in cultured rat embryos at day 11.5 of gestation. Caffeine caused malformation in cultured 12.5 day old rat embryo. Similar effect of caffeine was observed with 11.5 day old embryos, but in lower quantity. The embryotoxicity of cyclophosphamide and DMSO were evaluated in cultured 10.5 day old rat embryos. The whole embryo culture system was utilized in order to avoid potentially confounding meternal factors. Phenobarbital pretreated rat lever S-9 fraction singificantly increased the embryotoxicity and malformations of aminopyrine. And then teratological potency of 4-aminoantipyrine or 4-acetoamidoantipyrine was less than that of aminopyrine on cultured rat embryos. These results suggest that intrinsic teratogenicity, true active compound, of aminopyrine would be 3-position hydroxy metabolites rather than aminopyrine itself or 4-position N-demethyl metabolites. The increase of gamma-glutamyltranspeptidase activity in rat liver during perinatal period was observed in agreement with the elevation of cysteine consunption in fetus and the reduction of conversion from methionine to cysteine in this period. Sex and species differences of hepatic glutathione S-transferase and cytochrome P-450 in experimantal animals including monkey were investigated.