Effect of phosphatidylinositol-3 kinase inhibition on ovotoxicity caused by 4-vinylcyclohexene diepoxide and 7, 12-dimethylbenz[a]anthracene in neonatal rat ovaries

Aileen F. Keating, Connie J. Mark, Nivedita Sen, I. Glenn Sipes, Patricia B Hoyer

Research output: Contribution to journalArticle

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Abstract

4-vinylcyclohexene diepoxide (VCD) is an ovotoxicant that specifically destroys primordial and small primary follicles in the ovaries of mice and rats. In contrast, 7,12-dimethylbenz[a]anthracene (DMBA) is ovotoxic to all ovarian follicle classes. This study investigated phosphatidylinositol-3 kinase signaling involvement in VCD- and DMBA-induced ovotoxicity. Postnatal day (PND) 4 Fischer 344 (F344) rat whole ovaries were cultured for 2-12 days in vehicle control, VCD (30 μM), or DMBA (1 μM), ± PI3 kinase inhibitor LY294002 (20 μM) or its inactive analog LY303511 (20 μM). Following culture, ovaries were histologically evaluated, and healthy follicles were classified and counted. PI3 kinase inhibition had no effect on primordial follicle number, but reduced (P < 0.05) small primary and larger follicles beginning on day 4. VCD caused primordial and small primary follicle loss (P < 0.05) beginning on day 6. With PI3 kinase inhibition, VCD did not affect primordial follicles (P > 0.05) at any time, but did cause loss (P < 0.05) of small primary follicles. DMBA exposure caused primordial and small primary follicle loss (P < 0.05) on day 6. Further, DMBA-induced primordial and small primary follicle loss was greater with PI3 kinase inhibition (P < 0.05) than with DMBA alone. These results support that (1) PI3 kinase mediates primordial to small primary follicle recruitment, (2) VCD, but not DMBA, enhances ovotoxicity by increasing primordial to small primary follicle recruitment, and (3) in addition to xenobiotic-induced ovotoxicity, VCD is also a useful model chemical with which to elucidate signaling mechanisms involved in primordial follicle recruitment.

Original languageEnglish (US)
Pages (from-to)127-134
Number of pages8
JournalToxicology and Applied Pharmacology
Volume241
Issue number2
DOIs
StatePublished - Dec 1 2009

Fingerprint

Phosphatidylinositol 3-Kinase
9,10-Dimethyl-1,2-benzanthracene
Rats
Ovary
Phosphatidylinositol 3-Kinases
LY 303511
Chemical Models
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Ovarian Follicle
Inbred F344 Rats
Xenobiotics
anthracene
4-vinyl-1-cyclohexene dioxide

Keywords

  • 4-vinylcyclohexene diepoxide
  • Follicle activation
  • Ovary
  • Ovotoxicity
  • Phosphatidylinositol-3 kinase

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Effect of phosphatidylinositol-3 kinase inhibition on ovotoxicity caused by 4-vinylcyclohexene diepoxide and 7, 12-dimethylbenz[a]anthracene in neonatal rat ovaries. / Keating, Aileen F.; J. Mark, Connie; Sen, Nivedita; Sipes, I. Glenn; Hoyer, Patricia B.

In: Toxicology and Applied Pharmacology, Vol. 241, No. 2, 01.12.2009, p. 127-134.

Research output: Contribution to journalArticle

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