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Gao X, Yu L, Castro L, Moore AB, Hermon T, Bortner C, Sifre M, Dixon D: An endocrine-disrupting chemical, fenvalerate, induces cell cycle progression and collagen type I expression in human uterine leiomyoma and myometrial cells. Toxicol Lett. 2010 Mar 15.
Fenvalerate (Fen), widely used for its high insecticidal potency and low mammalian toxicity, is classified as an endocrine-disrupting chemical. Recently, Fen has received great attention for its adverse effects on human reproductive health. In this study, we found that Fen (10muM) had a stimulatory effect on the growth of both cell lines at 24h compared with controls by MTS (p <0.01) and BrdU (p <0.01) assays by MTS colorimetric and bromodeoxyuridine (BrdU) uptake assays in hormonally responsive uterine leiomyoma (UtLM) cells and normal uterine smooth muscle cells (UtSMC). Flow cytometry results showed that Fen enhanced the escape of cells from the G (0)-G (1) checkpoint and promoted progression of both cell types into the S phase. An Annexin V assay showed that Fen had an anti-apoptotic effect on both cell types. By Real-time PCR, we found that collagen I mRNA expression increased (p <0.05) in Fen-treated cells compared to controls, although it was greater in UtLM tumor cells. Accordingly, Fen increased (p <0.05) collagen I protein level in both cell lysate and supernatant when compared to controls. To further test the mechanism of Fen's effects, transactivation and competitive binding assays were done. The results showed Fen did not significantly stimulate the luciferase activity at concentrations of 0.1muM, 1.0muM or 10.0muM in either of the cell types. Competitive binding assays revealed that the affinity of Fen binding to estrogen receptors (ERs) is non-detectable compared to E (2). Our data show that Fen can stimulate the growth of both UtLM cells and UtSMC, which involves a combination of enhanced cell cycle progression and inhibition of apoptosis. Also this compound can increase collagen I expression, at both mRNA and protein levels. Interestingly, ER is less likely involved in either the hyperplasia or extracellular matrix (ECM) overproduction induced by Fen. Our results indicate that Fen exposure could be considered a novel risk factor for uterine fibroids through molecular mechanisms that do not directly involve the ERs. |
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