Increased sensitivity of estrogen receptor alpha overexpressing antral follicles to methoxychlor and its metabolites.
Methoxychlor (MXC), an organochlorine pesticide, and its metabolites, mono-hydroxy MXC (MOH) and bis-hydroxy MXC (HPTE) are known ovarian toxicants and can cause inhibition of antral follicle growth. Since these chemicals bind to estrogen receptor alpha (ESR1), we hypothesized that ovaries overexpressing ESR1 (ESR1 OE) would be more susceptible to toxicity induced by MXC and its metabolites because the chemicals can bind to more ESR1 in the antral follicles. We cultured antral follicles from controls and ESR1 OE mouse ovaries with either the vehicle dimethylsulfoxide (DMSO), MXC, MOH, or HPTE. The data show that at 96 h, the cultured antral follicles from ESR1 OE antral follicles are more susceptible to toxicity induced by MXC, MOH, and HPTE because low doses of these chemicals cause follicle growth inhibition in ESR1 OE mice but not in control mice. On comparing gene expression levels of nuclear receptors in the cultured antral follicles of ESR1 OE and control follicles, we found differential messenger RNA (mRNA) expression of Esr1, estrogen receptor beta (Esr2), androgen receptor (Ar), progesterone receptor (Pr), and aryl hydrocarbon receptor (Ahr) between the genotypes. We also analyzed mRNA levels of Cyp3a41a, the enzyme metabolizing MOH and HPTE, in the cultured follicles and found that Cyp3a41a was significantly lower in DMSO-treated ESR1 OE follicles compared with controls. In ESR1 OE livers, we found that Cyp3a41a levels were significantly lower compared with control livers. Collectively, these data suggest that MXC and its metabolites cause differential gene expression in ESR1 OE mice compared with controls. The results also suggest that the increased sensitivity of ESR1 OE mouse ovaries to toxicity induced by MXC and its metabolites is due to low clearance of the metabolites by the liver and ovary.
Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, Illinois 61802, USA.
Tessie
T
Paulose
Isabel
I
Hernández-Ochoa
Mallikarjuna S
MS
Basavarajappa
Jackye
J
Peretz
Jodi A
JA
Flaws
D000818:Animals; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000502:physiology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D008731:Methoxychlor / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D051379:Mice; D008822:Mice, Transgenic; D006080:Ovarian Follicle / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010636:Phenols / Q000378:metabolism / Q000633:toxicity*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D047628:Estrogen Receptor alpha; D010636:Phenols; D003577:Cytochrome P-450 Enzyme System; C086292:Cyp2c29 protein, mouse; D019388:Cytochrome P-450 CYP1A2; D000072467:Cytochrome P450 Family 2; C404910:2,2-bis(4-hydroxyphenyl)-1,1,1-trichloroethane; D008731:Methoxychlor; C495657:1,1,1-trichloro-2-(4-hydroxyphenyl)-2-(4-methoxyphenyl)ethane
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