Study on toxic effects of endocrine disruptors and their species-, gender-, and age-related differences

在这个项目中，我们研究了内分泌干扰物的毒性作用及其物种、性别和年龄相关的差异，得到的结果如下：1。雄性大鼠肝致癌物Trp-P-1可降低血清总睾酮水平和睾丸雄激素生物合成酶基因表达，提高肝细胞色素P4501A1水平。这些发现表明，Trp-P-1具有成为内分泌干扰物的潜力。使用UGT1A亚型缺陷小鼠进行的分析表明，苯巴比妥诱导的血清总甲状腺素（T4）的降低并不仅仅通过增加肝脏T4- udp -葡萄糖醛基转移酶来发生。大鼠与小鼠的对比研究表明，2,2',4,5,5'-五氯联苯甲基磺酰基代谢物的形成与血清T4水平的降低没有相关性。用TNF-α-敲除小鼠进行分析发现，可能是内分泌干扰物的硝酸铅通过TNF-a不依赖的途径下调肝脏胆固醇7 -a-羟化酶基因的表达。硝酸铅诱导肝脏固醇调控元件结合蛋白-2和3-羟基-3-甲基戊二酰辅酶a还原酶基因的表达与高胆固醇症的发生一致，雄性大鼠比雌性大鼠更快。肝细胞色素P4501A亚家族酶在大鼠中被硝基茴香胺异构体诱导，而在其他啮齿动物、小鼠和豚鼠中没有。

In this project, we studied on toxic effects of endocrine disruptors and their species-, gender-, and age-related differences and obtained the results as stated below.1. Administration of hepatocarcinogenic Trp-P-1 to male rats reduced the levels of serum total testosterone and gene expression of the testicular enzymes responsible for androgen biosynthesis and then increased the level of hepatic cytochrome P4501A1. These findings suggest that Trp-P-1 has the potential to become an endocrine disruptor.2. Analysis with the use of UGT1A isoform-deficient mice indicated that phenobarbital-induced decrease in serum total thyroxine (T4) did not occur only through increase in hepatic T4-UDP-glucuronosyltransferase.3. Comparative study using rats and mice indicated that there was no correlation between formation of methylsulfonyl metabolites of 2,2',4,5,5'-pentachlorobiphenyl and decrease in serum T4 level.4. Analysis with the use of TNF-α-knockout mice revealed that lead nitrate, a possible endocrine disruptor, downregulates the expression of hepatic cholesterol 7 a-hydroxylase gene through TNF-a-independent pathway.5. Lead nitrate induced the hepatic gene expression of sterol regulatory element binding protein-2 and 3-hydroxy-3-methylglutaryl-CoA reductase in coincidence with development of hypercholesteromia in male rats faster than in female.6. Hepatic cytochrome P4501A subfamily enzymes were induced by the nitroanisidine isomers in rats but not the other examined rodents, mice and guinea pigs.