Adverse effects of endocrine-disrupting chemicals and the mechanism via nuclear receptor in relation to the risk assessment

2,4-二氯苯氧乙酸（2,4- d）明显降低了野生型小鼠血清和睾丸睾酮水平，并造成精小管和支持细胞空泡损伤。这些变化在过氧化物酶体增殖物激活受体α(PPAR α)缺失的小鼠中未观察到，提示2,4- d诱导的毒性作用与PPAR α有关。我们还研究了2,4- d对间质细胞中参与胆固醇新生合成和睾酮合成的蛋白表达的影响。2,4- d治疗轻微影响了与睾酮合成有关的蛋白质的表达，但明显降低了胆固醇水平和与胆固醇从头合成有关的酶的表达。提示2,4- d治疗后睾酮水平的降低可能导致半分叶上皮和支持细胞的组织学改变。五氯酚（PCP）对雄性野生型小鼠和芳烃受体（AhR）缺失小鼠甲状腺激素（T4）的影响。PCP在野生型小鼠中增加AhR- mrna，而在AhR-缺失小鼠中没有增加，提示PCP是AhR的配体。PCP处理增加了udp -葡萄糖醛酸糖基转移酶（UGT） 1A1-mRNA和UGT1A6-mRNA。PCP处理也增加了1-萘酚作为UGT1A6底物的代谢率，但不影响胆红素作为UGT1A1底物在野生型小鼠中的代谢率。然而，在ahr缺失小鼠中，这些在野生型小鼠中观察到的变化无法观察到。这些结果表明PCP通过AhR诱导UGT1A6。PCP治疗使野生型小鼠和AhR缺失小鼠的T4水平降低，提示PCP治疗对T4水平的降低不依赖于AhR。

2,4-Dichlorophenoxyacetic Acid(2,4-D) clearly decreased serum and testicular testosterone level、and caused damage of seminiferous tubules and vacuolar of Sertoli cells in the wild-type mice. These changes could not be observed in peroxisome proliferators-activated receptor α(PPAR α)-null mice, suggesting that 2,4-D-induced toxic effects are related to PPAR α. We also investigated the effects of 2,4-D on the expression of protein involved in cholesterol de novo synthesis and testosterone synthesis in Leydig cells. 2,4-D treatment slightly influenced the expression of proteins involved in testosterone synthesis, but clearly decreased cholesterol level and also the expression ofenzymes involved in cholesterol de novo synthesis. These results suggest that decreased in testosterone by 2,4-D treatment may result in the histopathological change of semoiniferous epithelium and Sertoli cells.The effects of pentachlorophenol(PCP) on thyroid hormone (T4) using male wild-type and aromatic hydrocarbon receptor(AhR)-null mice. PCP increase AhR-mRNA in the wild-type mice, but not in AhR-null mice, suggesting a ligand of PCP for AhR. PCP treatment increased UDP-glucuronosyltransferase(UGT) 1A1-mRNA and UGT1A6-mRNA. PCP treatment also increased the metabolic rate of 1-naphtol as a substrate for UGT1A6, but did not affect that of bilirubin as a substrate of UGT1A1 in the wild-type mice. In the AhR-null mice, however, these changes observed in the wild-type mice could not be observed. These results indicate that PCP induces UGT1A6 via AhR. PCP treatment decreased T4 level in either wild-type mice or AhR-null mice, suggesting that decrease in T4 level by PCP treatment is not dependent on AhR.