ToxSci Advance Access originally published online on June 7, 2006
Toxicological Sciences 2006 93(1):180-188; doi:10.1093/toxsci/kfl034
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Methoxychlor Metabolites May Cause Ovarian Toxicity Through Estrogen-Regulated Pathways
Program in Toxicology and Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201
Received March 23, 2006; accepted June 5, 2006
The pesticide methoxychlor (MXC) is a reproductive toxicant that targets antral follicles of the mammalian ovary. Cytochrome P450 enzymes metabolize MXC to mono-OH MXC (1,1,1-trichloro-2-(4-hydroxyphenyl)-2-(4-methoxyphenyl)ethane [mono-OH]) and bis-OH MXC (1,1,1-trichloro-2,2-bis(4-hydroxyphenyl)ethane [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 (0.01–10 µg/ml), HPTE (0.01–10 µg/ml), or MXC (100 µg/ml) alone or in combination with ICI 182,780 (ICI; 1µM) or 17ß-estradiol (E2; 10 and 50nM) for 96 h. Follicle diameters were measured at 24-h intervals. After culture, follicles were morphologically evaluated for atresia. Both mono-OH and HPTE (10 µg/ml) inhibited follicle growth and increased follicle atresia. The antiestrogen, ICI, did not protect antral follicles from MXC or metabolite toxicity in regard 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.
Key Words: methoxychlor; metabolites; antral follicles; ovary; ICI 182,780; estradiol.
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