Maranghi Francesca, Rescia Michele, Macrì Caterina, Di Consiglio Emma, De Angelis Giovanna, Testai Emanuela, Farini Donatella, De Felici Massimo, Lorenzetti Stefano, Mantovani Alberto
Department of Food Safety and Veterinary Public Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
Chem Biol Interact. 2007 Aug 15;169(1):1-14. doi: 10.1016/j.cbi.2007.04.008. Epub 2007 Apr 22.
Lindane (gamma-HCH) is a persistent environmental pollutant that may act as endocrine disrupter, affecting the nervous, immune and reproductive system, possibly through endocrine-mediated mechanisms. Since both estrogen receptors (ER-alpha and -beta) have shown to be target for endocrine disruption, we investigated the role of gamma-HCH on the development of female reproductive system. For an in vivo evaluation of gamma-HCH effects during prenatal period, pregnant CD1 mice were treated p.o. on gestational days 9-16 with 15 mg/kg bw/day of gamma-HCH and vehicle. The in vivo findings in treated F1 pups - in the absence of signs of systemic toxicity - included increase in the absolute and relative and absolute uterus weight revealed on post-natal day 22, earlier vaginal patency and reduced diameters of primary oocytes at fully sexual maturity. No effects on steroid hormone metabolism (aromatase, testosterone catabolism) were observed. Thus, gamma-HCH elicited subtle effects on female reproductive development likely mediated by ER-beta-mediated pathway(s), without a concurrent impairment of steroid hormone metabolism. Furthermore, to verify whether the endocrine interference of gamma-HCH is attributable to stimulation of ER-beta-mediated pathway(s), its effect has been evaluated in vitro on a cell line, LNCaP, expressing only functional ER-beta. In vitro treatments revealed a concentration-related effect on LNCaP cell viability and proliferation. Significantly, the contemporary addition of a pure anti-estrogen, the ER antagonist ICI 182,780, completely reversed gamma-HCH effects indicating an ER-beta-mediated action. Our findings indicate that gamma-HCH may act as endocrine disruptor during the female reproductive system development and ER-beta as a potential target for this compound and other endocrine disrupting chemicals as well.
林丹（γ-六氯环己烷）是一种持久性环境污染物，可能作为内分泌干扰物，可能通过内分泌介导的机制影响神经、免疫和生殖系统。由于两种雌激素受体（ER-α和-β）均已显示为内分泌干扰的靶点，我们研究了γ-六氯环己烷对雌性生殖系统发育的作用。为了在体内评估γ-六氯环己烷在孕期的影响，将怀孕的CD1小鼠在妊娠第9至16天经口给予15 mg/kg体重/天的γ-六氯环己烷和赋形剂。在处理后的F1幼崽中，在没有全身毒性迹象的情况下，体内研究结果包括出生后第22天显示的绝对和相对子宫重量增加以及子宫绝对重量增加、阴道开口提前和完全性成熟时初级卵母细胞直径减小。未观察到对类固醇激素代谢（芳香化酶、睾酮分解代谢）的影响。因此，γ-六氯环己烷对雌性生殖发育产生了微妙影响，可能由ER-β介导的途径介导，而同时类固醇激素代谢未受损。此外，为了验证γ-六氯环己烷的内分泌干扰是否归因于对ER-β介导途径的刺激，已在体外对仅表达功能性ER-β的细胞系LNCaP评估了其作用。体外处理显示对LNCaP细胞活力和增殖有浓度相关的影响。值得注意的是，同时添加一种纯抗雌激素、ER拮抗剂ICI 182,780，完全逆转了γ-六氯环己烷的作用，表明是由ER-β介导的作用。我们的研究结果表明，γ-六氯环己烷可能在雌性生殖系统发育过程中作为内分泌干扰物起作用，并且ER-β是该化合物以及其他内分泌干扰化学物质的潜在靶点。
