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ToxSci Advance Access published online on June 28, 2006
Toxicological Sciences, 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
Received May 19, 2006
Accepted June 26, 2006

Reproductive and Developmental Toxicology

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

Rupesh K. Gupta 1, Kimberly P. Miller 1, Janice K. Babus 1, and Jodi A. Flaws 1 *

1 Program in Toxicology, Department of Epidemiology and Preventive Medicine, University of Maryland, Baltimore, MD USA

* To whom correspondence should be addressed.
Jodi A. Flaws, E-mail: jflaws{at}epi.umaryland.edu


  Abstract

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 non-reproductive 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 CD1 mice were cultured with vehicle control (DMSO), MXC (1-100 µg/ml), or MXC + the antioxidant N-acetyl cysteine (NAC) (0.1-10 mM). During culture, growth was monitored daily. At the end of culture, follicles were processed for real-time polymerase chain reaction (qPCR) 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) inhibits growth of follicles compared to DMSO controls and that NAC (1-10 mM) blocked the ability of MXC to inhibit growth. MXC induced follicular atresia, whereas NAC (1-10 mM) 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.

Keywords: methoxychlor; antral follicles; oxidative stress; ovary.
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