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ToxSci Advance Access published online on August 4, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi276
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received June 14, 2005
Accepted August 1, 2005

Reproductive and Developmental Toxicology

Methoxychlor Directly Affects Ovarian Antral Follicle Growth and Atresia Through Bcl-2- and Bax-Mediated Pathways

Kimberly P. Miller 1, Rupesh K. Gupta 1, Chuck R. Greenfeld 2, Janice K. Babus 1, and Jodi A. Flaws 1*

1 Program in Toxicology and Department of Epidemiology and Preventive Medicine, Baltimore, Maryland 21201
2 Department of Physiology, University of Maryland, Baltimore, Maryland 21201

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


  Abstract

Methoxychlor (MXC) is an organochlorine pesticide and reproductive toxicant. While in vivo studies indicate that MXC exposure increases antral follicle atresia, in part by altering apoptotic regulators (Bcl-2 and Bax), they do not distinguish whether MXC does so via direct or indirect mechanisms. Therefore, we utilized an in-vitro follicle culture system to test the hypothesis that MXC is directly toxic to antral follicles, and that overexpression of anti-apoptotic Bcl-2, or deletion of pro-apoptotic Bax, protects antral follicles from MXC-induced toxicity. Antral follicles were isolated from wild-type (WT), Bcl-2 overexpressing (Bcl-2 OE), or Bax deficient (BaxKO) mice, and exposed to dimethylsulfoxide (control) or MXC (1-100µg/ml) for 96h. Follicle diameters were measured every 24h to assess growth. After 96h, follicles were histologically evaluated for atresia or collected for quantitative PCR analysis of Bcl-2 and Bax mRNA levels. MXC (10-100µg/ml) significantly inhibited antral follicle growth at 72 and 96h, and increased atresia (100µg/ml) compared to controls at 96h. Furthermore, MXC increased Bax mRNA levels between 48-96h and decreased Bcl-2 mRNA levels at 96h. While MXC inhibited growth of WT antral follicles beginning at 72h, it did not inhibit growth of Bcl-2 OE or BaxKO follicles until 96h. MXC also increased atresia of small and large WT and BaxKO antral follicles over controls, but it did not increase atresia of large Bcl-2 OE antral follicles over controls. These data suggest that MXC directly inhibits follicle growth partly by Bcl-2 and Bax pathways, and increases atresia partly through Bcl-2 pathways.

Keywords: methoxychlor; antral follicles; ovary; Bcl-2; Bax.
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