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ToxSci Advance Access published online on November 9, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfj044
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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@oxfordjournals.org
Received October 13, 2005
Accepted November 8, 2005

Reproductive and Developmental Toxicology

Effect of Methoxychlor and Estradiol on Cytochrome P450 Enzymes in the Mouse Ovarian Surface Epithelium

Daniel A. Symonds 1, Kimberly P. Miller 1, Dragana Tomic 1, and Jodi A. Flaws 1*

1 Program in Toxicology, Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, MD 21201

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


  Abstract

Although the ovarian surface epithelium (OSE) is responsive to hormones and endocrine disrupting chemicals, little information is available on the metabolizing capabilities of the OSE. Thus, we tested the hypothesis that the OSE is capable of expressing genes regulating phase I metabolism of estrogen and the estrogenic endocrine disruptor, methoxychlor (MXC). To test this hypothesis, we isolated mouse OSE cells and cultured them with vehicle (dimethylsulfoxide; DMSO), 3µM MXC, or 0.1µM 17{beta}-estradiol (E2) ± the anti-estrogen ICI 182,780 (1µM) for 14 days. After culture, the cells were subjected to quantitative real time polymerase chain reaction for cytochrome P450s (CYPs) 1A1, 1B1, 2C29, and 1A2, and estrogen receptor {alpha} (ER{alpha}). Our results indicate that E2 and MXC did not alter the expression of CYP1A1 or CYP1A2. In contrast, E2 significantly increased expression of CYP1B1 compared to controls (DMSO=0.93±0.1, E2=3.12±0.64 genomic equivalents (GE), n=4, p≤0.01). The E2-induced increase in CYP1B1 was abolished by co-treatment with ICI 182,780 (0.41±0.17 GE). MXC treatment did not affect CYP1B1 expression. Both MXC and E2 increased expression of CYP2C29 (DMSO=0.02±0.003; MXC=0.04±0.008; E2=0.46±0.03 GE, n=4, p≤0.05). MXC- and E2-induced elevations in CYP2C29 were abolished by co-treatment with ICI 182,780 (0.02±0.005; 0.02±0.07 GE). In addition, E2 increased ER{alpha} expression 15-fold compared to controls (DMSO=1.10±0.09, E2= 15.0±3.60 GE, n=3, p≤ 0.05) and ICI 182,780 abolished the E2-induced increase in ER{alpha} expression (1.85±1.09 GE). MXC treatment did not affect ER{alpha} expression. These data indicate that the OSE expresses enzymes known to metabolize native and xenoestrogens and that MXC and E2 modulate expression of some of them through ER-linked mechanisms.

Keywords: ovarian surface epithelium; methoxychlor; estradiol; cytochrome P450; estrogen receptor.
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