title: Lindane may modulate the female reproductive development through the interaction with ER-beta: an in vivo-in vitro approach.
abstract: 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.
authors.affiliation: Department of Food Safety and Veterinary Public Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. francesca.maranghi@iss.it
authors.forename: Francesca
authors.initials: F
authors.lastname: Maranghi
authors.forename: Michele
authors.initials: M
authors.lastname: Rescia
authors.forename: Caterina
authors.initials: C
authors.lastname: Macrì
authors.forename: Emma
authors.initials: E
authors.lastname: Di Consiglio
authors.forename: Giovanna
authors.initials: G
authors.lastname: De Angelis
authors.forename: Emanuela
authors.initials: E
authors.lastname: Testai
authors.forename: Donatella
authors.initials: D
authors.lastname: Farini
authors.forename: Massimo
authors.initials: M
authors.lastname: De Felici
authors.forename: Stefano
authors.initials: S
authors.lastname: Lorenzetti
authors.forename: Alberto
authors.initials: A
authors.lastname: Mantovani
mesh_terms: D000818:Animals; D001141:Aromatase / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D001556:Hexachlorocyclohexane / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D046468:Sexual Development / Q000187:drug effects*; D012741:Sexual Maturation / Q000187:drug effects; D013739:Testosterone / Q000378:metabolism
chemical_list: D047629:Estrogen Receptor beta; D012739:Gonadal Steroid Hormones; D013739:Testosterone; D001556:Hexachlorocyclohexane; D001141:Aromatase