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Evaluation of ovotoxicity induced by 7, 12-dimethylbenz[a]anthracene and its 3,4-diol metabolite utilizing a rat in vitro ovarian culture system.

ABSTRACT: The polycyclic aromatic hydrocarbon 7, 12-dimethylbenz[a]anthracene, (DMBA), targets and destroys all follicle types in rat and mouse ovaries. DMBA requires bioactivation to DMBA-3,4-diol-1,2-epoxide for ovotoxicity via formation of the intermediate, DMBA-3,4-diol (catalyzed by microsomal epoxide hydrolase; mEH). mEH was shown to be involved in DMBA bioactivation for ovotoxicity induction in B6C3F(1) mouse ovaries. The current study compared DMBA and DMBA-3,4-diol mediated ovotoxicity, and investigated mEH involvement in DMBA-3,4-diol bioactivation in Fischer 344 (F344) rat ovary. F344 postnatal day (PND) 4 rat ovaries were cultured in vehicle control or media containing 1) DMBA or DMBA-3,4-diol (12.5 nM - 1 muM; 15 days); 2) DMBA (1 muM; 6 h - 15 days); and 3) DMBA (1 muM) or DMBA-3,4-diol (75 nM)+/-the mEH activity inhibitor cyclohexene oxide (CHO; 2 mM; 4 days). Ovaries were histologically evaluated and mEH mRNA and protein were measured by reverse transcriptase PCR or Western blotting, respectively. Ovotoxicity following 15 days of culture occurred (P<0.05) at lower concentrations of DMBA-3,4-diol (12.5 nM - primordial; 75 nM - primary) than DMBA (75 nM - primordial; 375 nM - primary). The temporal pattern of mEH expression following DMBA exposure showed mRNA up-regulation (P<0.05) on day 2, with increased protein (P<0.05) on day 4, the earliest time of observed follicle loss (P<0.05). mEH inhibition prevented DMBA-induced, but not DMBA-3,4-diol-induced ovotoxicity. These results demonstrate a conserved response in mice and rats for ovarian mEH involvement in DMBA bioactivation to its ovotoxic, 3,4-diol-1,2-epoxide form.

SUBMITTER: Igawa Y

PROVIDER: S-EPMC2666049 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Evaluation of ovotoxicity induced by 7, 12-dimethylbenz[a]anthracene and its 3,4-diol metabolite utilizing a rat in vitro ovarian culture system.

Igawa Yoshiyuki Y Keating Aileen F AF Rajapaksa Kathila S KS Sipes I Glenn IG Hoyer Patricia B PB

Toxicology and applied pharmacology 20081105 3

The polycyclic aromatic hydrocarbon 7, 12-dimethylbenz[a]anthracene, (DMBA), targets and destroys all follicle types in rat and mouse ovaries. DMBA requires bioactivation to DMBA-3,4-diol-1,2-epoxide for ovotoxicity via formation of the intermediate, DMBA-3,4-diol (catalyzed by microsomal epoxide hydrolase; mEH). mEH was shown to be involved in DMBA bioactivation for ovotoxicity induction in B6C3F(1) mouse ovaries. The current study compared DMBA and DMBA-3,4-diol mediated ovotoxicity, and inves ...[more]

PMID: 19027032

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Project description:PurposeOvarian cancer is the most lethal malignancy of the female reproductive system, and the prevention and treatment of ovarian carcinoma are still far from optimal. Epidemiological studies reported that ovarian cancer risk was inversely associated with low level of 25-hydroxy vitamin D [25(OH)]. Therefore, this study focuses on exploring the chemoprevention of vitamin D on epithelial ovarian cancer induced by 7, 12-dimethylbenz [a] anthracene (DMBA).MethodsThe mouse ovarian surface epithelial cells were isolated from estrus mice by mild trypsinization and maintained in completed culture medium by repeated passaging. The malignant transformation of mouse ovarian surface epithelial cells was induced by DMBA in vitro. DMBA was directly injected into the bursa of mouse ovary to produce optimized in vivo ovarian cancer model.ResultsThe results indicate that 1α,25 dihydroxyvitamin D3 may delay malignant transformation of mouse ovarian surface epithelial cells induced by DMBA and significantly decreased the colony formation rate from 18.4% to 3.2% (P<0.05). There was a negative correlation between incidence of DMBA-induced tumor and 25-hydroxy vitamin D level (R (2)=0.978, P<0.05). Vitamin D3 can delay the progression of ovarian cancer induced by DMBA, and the administration of vitamin D3 during the whole process worked more effectively than the administration only during tumor initiation or promotion. Moreover, we found the vitamin D3 increased the expression of E-cadherin and vitamin D receptor while it decreased the expression of β-catenin.ConclusionWe succeeded in establishment of epithelial ovarian cancer models both in vitro and in vivo. The DMBA-implanted model in mice yields high incidence and specificity of epithelial derived tumors. We also found that vitamin D delays the progression of ovarian cancer. However, spontaneous epithelial ovarian carcinoma models are still to be explored for testing the preventive effects of vitamin D on epithelial ovarian cancer.

Dataset Information

Evaluation of ovotoxicity induced by 7, 12-dimethylbenz[a]anthracene and its 3,4-diol metabolite utilizing a rat in vitro ovarian culture system.

Publications

Evaluation of ovotoxicity induced by 7, 12-dimethylbenz[a]anthracene and its 3,4-diol metabolite utilizing a rat in vitro ovarian culture system.

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