The diverse mechanism of action of dichlorodiphenyldichloroethylene (DDE) and methoxychlor in ovarian cells in vitro.
Dichlorodiphenyldichloroethylene (DDE), the most stable metabolite of the organochlorine insecticide dichlorodiphenyltrichloroethane (DDT), and the DDT analog methoxychlor can have adverse effects on reproduction. These chemicals have been identified as having estrogenic activity. The aim of the current study was to examine the effects of dichlorodiphenyldichloroethylene (DDE), methoxychlor, and estradiol-17 beta on steroidogenesis and FSH responsiveness in ovarian cells in vitro. Experiments were performed on a primary culture of porcine granulosa cells and a culture of Chinese hamster ovary (CHO) cells, the latter stably transfected with the FSH receptor (CHO-FSH-R). DDE (10 microM) and estradiol-17 beta (0.1 microM) but not methoxychlor (10 microM), increased proliferation of the granulosa cells. DDE (100 and 10 microM, respectively) decreased FSH-stimulated cAMP synthesis in the granulosa and CHO-FSH-R cells. DDE also decreased progesterone synthesis in the granulosa cells. Methoxychlor (10 microM) inhibited progesterone synthesis in the granulosa cells, but it did not affect the generation of cAMP in either type of cells studied. However, methoxychlor inhibited estradiol-17 beta-stimulated progesterone synthesis in the granulosa cells. We conclude that DDE primarily inhibited the generation of cAMP, while methoxychlor suppressed progesterone synthesis through a mechanism distal to cAMP generation. The present results indicate that DDE and methoxychlor are not limited to a mimicking of the endocrine effects of estradiol-17 beta in cultured ovarian cells. Therefore, a non-estrogenic component of the endocrine disrupting activities of DDE and methoxychlor must be considered in evaluating their reproductive toxicity.
Chedrese
P J
PJ
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Saskatchewan, Saskatoon, SK, Canada. chedresj@duke.usask.ca
Feyles
F
F
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D003633:Dichlorodiphenyl Dichloroethylene / Q000633:toxicity*; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D006107:Granulosa Cells / Q000187:drug effects* / Q000378:metabolism; D006727:Hormone Antagonists / Q000633:toxicity*; D007306:Insecticides / Q000633:toxicity*; D008731:Methoxychlor / Q000633:toxicity*; D011374:Progesterone / Q000096:biosynthesis; D013552:Swine
D006727:Hormone Antagonists; D007306:Insecticides; D011374:Progesterone; D003633:Dichlorodiphenyl Dichloroethylene; D004958:Estradiol; D005640:Follicle Stimulating Hormone; D000242:Cyclic AMP; D008731:Methoxychlor