The Methoxychlor Metabolite, HPTE, Directly Inhibits the Catalytic Activity of Cholesterol Side-Chain Cleavage (P450scc) in Cultured Rat Ovarian Cells

Details

• Personal Author:
  Akgul Y ; Derk RC ; Meighan T ; Murono EP ; Rao KMK
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Biological Products Environmental Monitoring Insecticides Laboratories Occupational Health Safety Toxicology Urogenital Diseases Urogenital System
• Keywords:
  Biological-agents Biological-monitoring Exposure-assessment Laboratory-animals Pesticides-and-agricultural-chemicals Reproduction Reproductive-effects Reproductive-hazards Reproductive-system-disorders Toxicopathology
• ISSN:
  0890-6238
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  67-75
• Volume:
  25
• Issue:
  1
• NIOSHTIC Number:
  nn:20033374
• Citation:
  Reprod Toxicol 2008 Jan; 25(1):67-75
• Contact Point Address:
  Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown, WV
• Email:
  yakgul@hsc.wvu.edu
• CAS Registry Number:
  Methoxychlor (CAS RN 72-43-5)
• Federal Fiscal Year:
  2008
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  True
• Source Full Name:
  Reproductive Toxicology
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:ff3598b579c568c47fb6ea3c589ffd752bf9c0fd5be545fb41b64614016d7a635d1ac18bdb226eeabbd1946aff9776311c456f15a607e7e7038a8b2fb6ce859b
• Download URL:
  https://stacks.cdc.gov/view/cdc/188984/cdc_188984_DS1.pdf
• File Type:
  [PDF - 646.42 KB ]