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

Authors :
I. Glenn Sipes
Patricia B. Hoyer
Nivedita Sen
Aileen F. Keating
Connie J. Mark
Source :
Toxicology and Applied Pharmacology. 241:127-134
Publication Year :
2009
Publisher :
Elsevier BV, 2009.

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 microM), or DMBA (1 microM), +/-PI3 kinase inhibitor LY294002 (20 microM) or its inactive analog LY303511 (20 microM). 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 (P0.05) small primary and larger follicles beginning on day 4. VCD caused primordial and small primary follicle loss (P0.05) beginning on day 6. With PI3 kinase inhibition, VCD did not affect primordial follicles (P0.05) at any time, but did cause loss (P0.05) of small primary follicles. DMBA exposure caused primordial and small primary follicle loss (P0.05) on day 6. Further, DMBA-induced primordial and small primary follicle loss was greater with PI3 kinase inhibition (P0.05) 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.

Details

ISSN :
0041008X
Volume :
241
Database :
OpenAIRE
Journal :
Toxicology and Applied Pharmacology
Accession number :
edsair.doi.dedup.....947cdd91e96c02a7939bf1419de602e9
Full Text :
https://doi.org/10.1016/j.taap.2009.08.012