Staying alive

Pi3k pathway promotes primordial follicle activation and survival in response to 3MC-induced ovotoxicity

Alexander P. Sobinoff, Brett Nixon, Shaun D. Roman, Eileen A. Mclaughlin

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

3-Methylcholanthrene (3MC) is a potent ovotoxicant capable of causing premature ovarian failure through primordial follicle depletion. Despite 3MCs ovotoxicity having been established for 30 years, relatively little information exists on the mechanisms. In this study, we examined the effects of 3MC exposure on the immature ovarian follicle population. Microarray analysis revealed a complex mechanism of 3MC-induced ovotoxicity involving a number of cellular processes associated with xenobiotic metabolism, ovarian cancer, cell cycle progression, and cell death. 3MC exposure was also found to induce developing follicle atresia and aberrant primordial follicle activation via the stimulation of PI3K/Akt and mammalian target of rapamycin (mTOR) signaling pathways. Inhibition of PI3K/Akt signaling resulted in the severe depletion of the primordial follicle pool, with further analysis identifying increased Akt1-stimulated Bad phosphoinhibition in 3MC-treated primordial follicles. Our results suggest that the primordial follicle pool enters a "prosurvival" state upon 3MC exposure and that its depletion is due to a vicious cycle of primordial follicle activation in an attempt to replace developing follicles undergoing follicular atresia.

Original languageEnglish
Pages (from-to)258-271
Number of pages14
JournalToxicological Sciences
Volume128
Issue number1
DOIs
Publication statusPublished - 1 Jul 2012
Externally publishedYes

Fingerprint

Methylcholanthrene
Chemical activation
Phosphatidylinositol 3-Kinases
Follicular Atresia
Primary Ovarian Insufficiency
Ovarian Follicle
Xenobiotics
Cell death
Sirolimus
Microarray Analysis
Microarrays
Metabolism
Ovarian Neoplasms
Cell Cycle
Cell Death
Cells
Population

Cite this

Sobinoff, Alexander P. ; Nixon, Brett ; Roman, Shaun D. ; Mclaughlin, Eileen A. / Staying alive : Pi3k pathway promotes primordial follicle activation and survival in response to 3MC-induced ovotoxicity. In: Toxicological Sciences. 2012 ; Vol. 128, No. 1. pp. 258-271.
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Staying alive : Pi3k pathway promotes primordial follicle activation and survival in response to 3MC-induced ovotoxicity. / Sobinoff, Alexander P.; Nixon, Brett; Roman, Shaun D.; Mclaughlin, Eileen A.

In: Toxicological Sciences, Vol. 128, No. 1, 01.07.2012, p. 258-271.

Research output: Contribution to journalArticle

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