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ToxSci Advance Access originally published online on June 28, 2006
Toxicological Sciences 2006 93(2):382-389; doi:10.1093/toxsci/kfl052
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Methoxychlor Inhibits Growth and Induces Atresia of Antral Follicles through an Oxidative Stress Pathway

Rupesh K. Gupta, Kimberly P. Miller, Janice K. Babus and Jodi A. Flaws1

Program in Toxicology, Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, 660 West Redwood Street, Howard Hall 133B, Baltimore, Maryland 21201

Received May 19, 2006; accepted June 26, 2006

The mammalian ovary contains antral follicles, which are responsible for the synthesis and secretion of hormones that regulate estrous cyclicity and fertility. The organochlorine pesticide methoxychlor (MXC) causes atresia (follicle death via apoptosis) of antral follicles, but little is known about the mechanisms by which MXC does so. Oxidative stress is known to cause apoptosis in nonreproductive and reproductive tissues. Thus, we tested the hypothesis that MXC inhibits growth and induces atresia of antral follicles through an oxidative stress pathway. To test this hypothesis, antral follicles isolated from 39-day-old CD-1 mice were cultured with vehicle control (dimethylsulfoxide [DMSO]), MXC (1–100 µg/ml), or MXC + the antioxidant N-acetyl cysteine (NAC) (0.1–10mM). During culture, growth was monitored daily. At the end of culture, follicles were processed for quantitative real-time polymerase chain reaction of Cu/Zn superoxide dismutase (SOD1), glutathione peroxidase (GPX), and catalase (CAT) mRNA expression or for histological evaluation of atresia. The results indicate that exposure to MXC (1–100 µg/ml) inhibited growth of follicles compared to DMSO controls and that NAC (1–10mM) blocked the ability of MXC to inhibit growth. MXC induced follicular atresia, whereas NAC (1–10mM) blocked the ability of MXC to induce atresia. In addition, MXC reduced the expression of SOD1, GPX, and CAT, whereas NAC reduced the effects of MXC on their expression. Collectively, these data indicate MXC causes slow growth and increased atresia by inducing oxidative stress.

Key Words: methoxychlor; antral follicles; oxidative stress; ovary.


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