Lindane may modulate the female reproductive development through the interaction with ER-β: an in vivo– in vitro approach

Abstract

Lindane (γ-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-α and -β) have shown to be target for endocrine disruption, we investigated the role of γ-HCH on the development of female reproductive system. For an in vivo evaluation of γ-HCH effects during prenatal period, pregnant CD1 mice were treated p.o. on gestational days 9–16 with 15 mg/kg bw/day of γ-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, γ-HCH elicited subtle effects on female reproductive development likely mediated by ER-β-mediated pathway(s), without a concurrent impairment of steroid hormone metabolism. Furthermore, to verify whether the endocrine interference of γ-HCH is attributable to stimulation of ER-β-mediated pathway(s), its effect has been evaluated in vitro on a cell line, LNCaP, expressing only functional ER-β. 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 γ-HCH effects indicating an ER-β-mediated action. Our findings indicate that γ-HCH may act as endocrine disruptor during the female reproductive system development and ER-β as a potential target for this compound and other endocrine disrupting chemicals as well.