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Acute 7,12-dimethylbenz[a]anthracene exposure causes differential concentration dependent follicle depletion and gene expression in neonatal rat ovaries.

Madden, JA and Hoyer, PB and Devine, Pj and Keating, AF (2013) Acute 7,12-dimethylbenz[a]anthracene exposure causes differential concentration dependent follicle depletion and gene expression in neonatal rat ovaries. Toxicology and Applied Pharmacology.

Abstract

7,12-dimethylbenz[a]anthracene (DMBA), a polycyclic aromatic hydrocarbon, is generated during combustion of organic matter, including cigarette smoke. Chronic DMBA exposure depletes all ovarian follicle types in the mouse and rat, and in vitro models mimic this effect. To investigate the mechanisms involved in follicular depletion during acute DMBA exposure, two concentrations of DMBA at which follicle depletion has (75 nM) and has not (12.5 nM) been observed were investigated. Postnatal day four F344 rat ovaries were maintained in culture for four days before a single exposure to vehicle control (1% DMSO; CT) or DMBA (12 nM; low-dose or 75 nM; high-dose). After eight additional days of culture, DMBA-induced follicle depletion was evaluated via follicle enumeration. Relative to control, DMBA induced large primary follicle loss at both concentrations; however, only low-dose DMBA caused secondary follicle depletion. Neither dose affected primordial or small primary follicle number. RNA was isolated and quantitative RT-PCR performed prior to follicle loss to measure mRNA levels of genes involved in xenobiotic metabolism (Cyp 2e1, Gstm, Gstp, Ephx1), autophagy (Atg7, Becn1), oxidative stress response (Sod1, Sod2) and the phosphatidylinositol 3-kinase (PI3K) pathway (Kitlg, cKit, Akt1) four days after treatment. Compared to CT and DMBA high-dose treated ovaries, single low-dose DMBA exposure increased mRNA expression of all genes investigated. Also, BECN1 and pAKTThr308 were increased at the 12.5 nM DMBA exposure, relative to control and 75 nM DMBA. These results add to understanding the mechanisms involved in DMBA-induced ovotoxicity and raise concern regarding female low dose DMBA exposures.

Item Type: Article
Additional Information: Part of a collaboration from before joining Novartis
Keywords: DMBA, ovary, follicle
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/11219

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