title: A Mixture Reflecting Polybrominated Diphenyl Ether (PBDE) Profiles Detected in Human Follicular Fluid Significantly Affects Steroidogenesis and Induces Oxidative Stress in a Female Human Granulosa Cell Line.
abstract: Brominated flame retardants are incorporated into consumer products to prevent flame propagation. These compounds leach into the domestic environment, resulting in chronic exposure. Pregnancy failure is associated with high levels of polybrominated diphenyl ethers (PBDEs), a major class of brominated flame retardants, in human follicular fluid, raising serious questions regarding their impact on female fertility. Our goal was to elucidate the effects of a mixture of PBDEs, similar to the profile found in human follicular fluid, on an immortalized human granulosa cell line, the KGN cell line. We showed that cell viability was altered and oxidative stress was induced as reflected by increased reactive oxygen species formation at 100 μM of the PBDE mixture. Transcriptomic analysis revealed that PBDE treatments of 1, 5, and 20 μM altered the expression of several genes involved in the reactive oxygen species signaling pathway. Significant dose-dependent reductions in progesterone and estradiol levels in the culture medium were measured after PBDE treatment; in parallel, the expression of genes involved in estradiol metabolism, namely CYP1A1, was up-regulated by 5 and 20 μM of the PBDE mixture. Treatment with 20 μM PBDE also increased the expression and secretion of the proinflammatory factor, IL-6, into the KGN cell culture medium. Our results demonstrate that PBDEs can alter human granulosa cell functions by inducing oxidative stress and disrupting steroidogenesis. These results indicate that PBDEs may be detrimental to ovarian functions and thus may adversely affect female reproductive health after chronic exposure.
authors.affiliation: Departments of Pharmacology and Therapeutics (P.L.C.L., B.F.H., B.R.), Pediatrics (C.G.), and Obstetrics and Gynecology (B.R.), McGill University, and the Research Institute of the McGill University Health Centre, Montréal, Québec, Canada H3G 1Y6; and Environmental Health Science and Research Bureau (M.W.), Health Canada, Ottawa, Ontario, Canada K1A 0K9.
authors.forename: Pavine L C
authors.initials: PL
authors.lastname: Lefevre
authors.affiliation: Departments of Pharmacology and Therapeutics (P.L.C.L., B.F.H., B.R.), Pediatrics (C.G.), and Obstetrics and Gynecology (B.R.), McGill University, and the Research Institute of the McGill University Health Centre, Montréal, Québec, Canada H3G 1Y6; and Environmental Health Science and Research Bureau (M.W.), Health Canada, Ottawa, Ontario, Canada K1A 0K9.
authors.forename: Mike
authors.initials: M
authors.lastname: Wade
authors.affiliation: Departments of Pharmacology and Therapeutics (P.L.C.L., B.F.H., B.R.), Pediatrics (C.G.), and Obstetrics and Gynecology (B.R.), McGill University, and the Research Institute of the McGill University Health Centre, Montréal, Québec, Canada H3G 1Y6; and Environmental Health Science and Research Bureau (M.W.), Health Canada, Ottawa, Ontario, Canada K1A 0K9.
authors.forename: Cindy
authors.initials: C
authors.lastname: Goodyer
authors.affiliation: Departments of Pharmacology and Therapeutics (P.L.C.L., B.F.H., B.R.), Pediatrics (C.G.), and Obstetrics and Gynecology (B.R.), McGill University, and the Research Institute of the McGill University Health Centre, Montréal, Québec, Canada H3G 1Y6; and Environmental Health Science and Research Bureau (M.W.), Health Canada, Ottawa, Ontario, Canada K1A 0K9.
authors.forename: Barbara F
authors.initials: BF
authors.lastname: Hales
authors.affiliation: Departments of Pharmacology and Therapeutics (P.L.C.L., B.F.H., B.R.), Pediatrics (C.G.), and Obstetrics and Gynecology (B.R.), McGill University, and the Research Institute of the McGill University Health Centre, Montréal, Québec, Canada H3G 1Y6; and Environmental Health Science and Research Bureau (M.W.), Health Canada, Ottawa, Ontario, Canada K1A 0K9.
authors.forename: Bernard
authors.initials: B
authors.lastname: Robaire
mesh_terms: D002460:Cell Line; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D015571:Follicular Fluid / Q000737:chemistry*; D006107:Granulosa Cells / Q000187:drug effects* / Q000378:metabolism; D055768:Halogenated Diphenyl Ethers / Q000032:analysis / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011374:Progesterone / Q000378:metabolism*; D059467:Transcriptome; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D055768:Halogenated Diphenyl Ethers; D015850:Interleukin-6; D011374:Progesterone; D004958:Estradiol; D019363:Cytochrome P-450 CYP1A1