The methoxychlor metabolite, HPTE, directly inhibits the catalytic activity of cholesterol side-chain cleavage (P450scc) in cultured rat ovarian cells
| Autor: | K. Murali Krishna Rao, Eisuke P. Murono, Raymond C. Derk, Yucel Akgul, Terence Meighan |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
endocrine system
medicine.medical_specialty Gonadotropins Equine medicine.drug_class Biology Toxicology Gene Expression Regulation Enzymologic Flutamide Rats Sprague-Dawley chemistry.chemical_compound Phenols Catalytic Domain Internal medicine medicine Animals Cholesterol Side-Chain Cleavage Enzyme RNA Messenger Benzhydryl Compounds Enzyme Inhibitors Ovarian follicle Fulvestrant Oxazoles Cells Cultured Progesterone Dose-Response Relationship Drug Estradiol Cholesterol side-chain cleavage enzyme Ovary Estrogen Antagonists Androgen Antagonists Estrogens Methoxychlor Androgen Antiestrogen Rats Androgen receptor medicine.anatomical_structure Endocrinology Receptors Estrogen chemistry Receptors Androgen Estrogen Female hormones hormone substitutes and hormone antagonists |
| Zdroj: | Reproductive Toxicology. 25:67-75 |
| ISSN: | 0890-6238 |
| DOI: | 10.1016/j.reprotox.2007.10.007 |
| Popis: | Exposure to the pesticide methoxychlor in rodents is linked to impaired steroid production, ovarian atrophy and reduced fertility. Following in vivo administration, it is rapidly converted by the liver to 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), the reported active metabolite. Both methoxychlor and HPTE have weak estrogenic and antiandrogenic activities, and these effects are thought to be mediated through the estrogen and androgen receptors, respectively. Previous in vivo studies on methoxychlor exposure to female animals have demonstrated decreased progesterone production but no change in serum estrogen levels. We recently showed that HPTE specifically inhibits the P450 cholesterol side-chain cleavage (P450scc, CYP11A1) step resulting in decreased androgen production by cultured rat testicular Leydig cells. The current studies examined the mechanism of action of HPTE on progesterone production by cultured ovarian cells (granulosa and theca-interstitial) from pregnant mare serum gonadotropin-primed immature rats. In addition, we evaluated whether the effects of HPTE on rat ovarian cell progesterone biosynthesis were mediated through the estrogen or androgen receptors. Exposure to HPTE (0, 10, 50 or 100 nM) alone progressively inhibited progesterone formation in cultured theca-interstitial and granulosa cells and the P450scc catalytic activity in theca-interstitial cells in a dose-dependent manner with significant declines starting at 50 nM. However, HPTE did not change mRNA levels of the P450scc system (P450scc, adrenodoxin reductase and adrenodoxin) as well as P450scc protein levels. Of interest, estradiol, xenoestrogens (bisphenol-A or 4-tert-octylphenol), a pure antiestrogen (ICI 182,780), or antiandrogens (4-hydroxyflutamide or the vinclozolin metabolite M-2), had no effect on progesterone production even at 1000 nM. Co-treatment of HPTE with ICI 182,780 did not block the effect of HPTE on progesterone formation. These studies suggest that the decline in progesterone formation following exposure to HPTE in cultured ovarian cells is associated with the inhibition of catalytic activity of P450scc at least in theca-interstitial cells. This action does not appear to be mediated through the estrogen or androgen receptor signaling pathways, and other chemicals exhibiting estrogenic, antiestrogenic or antiandrogenic properties do not mimic its effect on ovarian steroid production. |
| Databáze: | OpenAIRE |
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