ToxSci Advance Access originally published online on November 3, 2004
Toxicological Sciences 2005 83(2):355-362; doi:10.1093/toxsci/kfi024
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Toxicological Sciences vol. 83 no. 2 © Society of Toxicology 2005; all rights reserved.
Methoxychlor Induces Proliferation of the Mouse Ovarian Surface Epithelium
Program in Toxicology and Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201
Received September 3, 2004; accepted October 25, 2004
While the pesticide methoxychlor (MXC) has a variety of adverse effects on the female reproductive system, the effects of MXC on the ovarian surface epithelium (OSE) are unknown. Thus, this study tested the hypothesis that MXC alters the growth of the OSE. Mouse OSE cells were isolated by enzymatic digestion and cultured with vehicle, 3 µM of MXC, or 3 µM of 2,2-bis[p-hydroxyphenyl]-1,1,1,-trichloroethane (HPTE) for 14 days. After culture, proliferation and apoptosis were assessed by measurement of cell density, immunohistochemistry, and real-time polymerase chain reaction. Cell density was 66% greater for MXC-treated cells and 95% greater for HPTE-treated cells than controls (p 
0.05). The estrogen receptor blocker ICI 182,780 abolished MXC- and HPTE-induced increases in cell density. Proliferating cell nuclear antigen (PCNA) staining was positive in only 22 ± 2.3% of controls, compared to 35 ± 2.4% of MXC-treated cells and 40 ± 2.4% of HPTE-treated cells (p 0.05). The cell cycle regulators, cyclinD2 and cdk4, were significantly increased in MXC- and HPTE-treated cells compared to controls. The ApopTag assay demonstrated apoptotic cells in 4.8 ± 0.45% of controls, 2.2 ± 0.56% of MXC-treated cells, and 2.1 ± 0.33% of HPTE-treated cells (p 0.005). Expression of bcl-2 was significantly increased in MXC- and HPTE-treated cells, while bax was decreased in MXC- and HPTE-treated cells compared to controls. Collectively, these data indicate that MXC and HPTE stimulate OSE cell growth by increasing proliferation and inhibiting apoptosis. Further, since ICI 182,780 blocked MXC- and HPTE-induced OSE growth, these data suggest that the effects of MXC and HPTE on the OSE are mediated by estrogen receptors.
Key Words: methoxychlor; ovarian surface epithelium; proliferation; cell cycle; apoptosis; estrogen receptor.
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