Organochlorine pesticides directly regulate gonadotropin-releasing hormone gene expression and biosynthesis in the GT1-7 hypothalamic cell line.
Environmental toxicants profoundly affect growth and developmental processes. In the present study, we hypothesized that hypothalamic gonadotropin-releasing hormone (GnRH) neurons, which regulate the reproductive axis, are targets of environmental endocrine disrupting chemicals. Two organochlorine pesticides (methoxychlor and chlorpyrifos) were tested for their effects on GnRH gene expression and biosynthesis in the immortalized hypothalamic GT1-7 cells, which synthesize and secrete GnRH. GT1-7 cells were treated with methoxychlor or chlorpyrifos for 24 h in dose-response experiments, and GnRH gene expression and peptide levels were quantified. In order to examine whether these pesticides affect GnRH biosynthesis through the estrogen receptor (ER), in other experiments their effects were compared to those of estrogen, or they were co-administered with the ER antagonist, ICI 182,780 (ICI). Both methoxychlor and chlorpyrifos had significant effects on GnRH gene transcription and GnRH mRNA levels. These effects were not consistently blocked by ICI, nor did the effects of these pesticides consistently mimic those of estrogen, suggesting a mechanism independent of the ER. Chlorpyrifos and methoxychlor slightly stimulated peptide levels, and this effect was blocked by ICI, suggesting that the ER may mediate effects of pesticides on GnRH release. These results indicate that chlorpyrifos and methoxychlor alter GnRH biosynthesis in this hypothalamic cell line in vitro, suggesting that they may have endocrine disrupting effects on GnRH neurons in vivo.
Gore
Andrea C
AC
Kastor Neurobiology of Aging Laboratories, Fishberg Research Center for Neurobiology, and Brookdale Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, Box 1639, New York, NY 10029, USA. andrea.gore@mssm.edu
D000818:Animals; D002461:Cell Line, Transformed / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004390:Chlorpyrifos / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology*; D000077267:Fulvestrant; D005786:Gene Expression Regulation / Q000187:drug effects*; D007987:Gonadotropin-Releasing Hormone / Q000096:biosynthesis* / Q000235:genetics; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007306:Insecticides / Q000494:pharmacology*; D008731:Methoxychlor / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D011960:Receptors, Estrogen / Q000187:drug effects / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects
D020847:Estrogen Receptor Modulators; D004968:Estrogens, Non-Steroidal; D007306:Insecticides; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D000077267:Fulvestrant; D007987:Gonadotropin-Releasing Hormone; D004958:Estradiol; D004390:Chlorpyrifos; D008731:Methoxychlor