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林丹对宫内暴露雄性小鼠 CYP 介导的类固醇激素代谢的影响。

Effect of lindane on CYP-mediated steroid hormone metabolism in male mice following in utero exposure.

机构信息

Environment and Primary Prevention Department, Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161 Rome, Italy.

出版信息

J Appl Toxicol. 2009 Nov;29(8):648-55. doi: 10.1002/jat.1452.

Abstract

A wide number of pesticides, including highly persistent organochlorinated compounds, such as lindane (LIN), may induce reproductive and developmental alterations by directly binding to the estrogen/androgen receptors or altering steroid hormone metabolism. In the present work, we have investigated whether LIN in utero exposure of CD1 mice affects the reproductive system in male offspring by causing an impairment of the CYP-dependent steroid hormone metabolism. Dam exposure to 25 mg kg(-1) b.w. LIN occurred during critical developmental periods, from gestational days 9 to 16. Effects on hepatic CYP-mediated testosterone (TST) hydroxylase, aromatase activities and testicular parameters were tested at postnatal days (PND 50, 65-69, 100) that are critical for sexual maturation in CD1 mice. In the adult F1 mice significant changes of male reproductive endpoints (testis weight, spermatid number) as well as dramatic effects on CYP-mediated TST metabolism were observed on PND 65-69, in the absence of any of systemic toxicity. The levels of TST 6beta- and 2alpha-hydroxylation and dehydrogenation showed the highest level of reduction, suggesting CYP 3A and 2C families as the major target of LIN induced effects. All changes were almost recovered on PND 100. No effects on aromatase activity were evidenced. Overall, these findings provide useful information for a better characterization of the LIN mode of action. They suggest that LIN-induced toxicity in males is linked to an impairment of steroid hormone homeostasis, due to CYP-mediated TST catabolism modulation and differs from LIN receptor-mediated mechanism previously reported in females.

摘要

大量的农药,包括高度持久的有机氯化合物,如林丹(LIN),可能通过直接与雌激素/雄激素受体结合或改变类固醇激素代谢来诱导生殖和发育改变。在本工作中,我们研究了 CD1 小鼠在宫内暴露于林丹是否通过破坏 CYP 依赖性类固醇激素代谢来影响雄性后代的生殖系统。母体在妊娠第 9 至 16 天的关键发育期暴露于 25mgkg(-1)b.w.LIN。在 CD1 小鼠性成熟的关键时期(出生后第 50、65-69、100 天)测试了对肝 CYP 介导的睾酮(TST)羟化酶、芳香酶活性和睾丸参数的影响。在没有任何全身毒性的情况下,在成年 F1 小鼠中,在 PND65-69 时观察到雄性生殖终点(睾丸重量、精子数量)的显著变化,以及对 CYP 介导的 TST 代谢的剧烈影响。TST6β-和 2α-羟化和脱氢水平显示出最高水平的降低,表明 CYP3A 和 2C 家族是 LIN 诱导作用的主要靶标。所有变化在 PND100 时几乎恢复。没有证据表明芳香酶活性受到影响。总的来说,这些发现为更好地描述 LIN 的作用模式提供了有用的信息。它们表明,雄性中的 LIN 诱导毒性与类固醇激素动态平衡的破坏有关,这是由于 CYP 介导的 TST 分解代谢调节所致,与先前在雌性中报道的 LIN 受体介导的机制不同。

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