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ToxSci Advance Access published online on June 7, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl034
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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 March 23, 2006
Accepted June 5, 2006

Reproductive and Developmental Toxicology

Methoxychlor Metabolites May Cause Ovarian Toxicity Through Estrogen Regulated Pathways

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

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

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


  Abstract

The pesticide methoxychlor (MXC) is a reproductive toxicant that targets antral follicles of the mammalian ovary. Cytochrome P450 (CYP) enzymes metabolize MXC to mono-OH MXC (mono-OH) and bis-OH MXC (HPTE), two compounds that are proposed to be more toxic than the parent compound, can interact with the estrogen receptor (ER), and are proposed to be responsible for ovarian toxicity. Thus, this work tested the hypothesis that MXC metabolites may be responsible for inducing antral follicle specific toxicities in the ovary, and that this toxicity may be mediated through ER-regulated pathways. Mouse antral follicles were isolated and exposed to mono-OH (0.01-10µg/ml), HPTE (0.01-10µg/ml), or MXC (100µg/ml) alone or in combination with ICI 182,780 (ICI; 1µM) or 17{beta}-estradiol (E2; 10nM, 50nM) for 96h. Follicle diameters were measured at 24h intervals. After culture, follicles were morphologically evaluated for atresia. Both mono-OH and HPTE (10µg/ml) inhibited follicle growth and increased follicle atresia. The antiestrogen, ICI, did not protect antral follicles from MXC or metabolite toxicity in regards to follicle growth or atresia, but E2 decreased MXC- and mono-OH-induced atresia in small antral follicles. These data suggest that MXC metabolites inhibit follicle growth and induce atresia, and that ER-regulated pathways may mediate the ovarian toxicity of MXC and its metabolites.

Keywords: methoxychlor; metabolites; antral follicles; ovary; ICI 182;780; estradiol.
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