An endocrine-disrupting chemical, fenvalerate, induces cell cycle progression and collagen type I expression in human uterine leiomyoma and myometrial cells.
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 (10 microM) had a stimulatory effect on the growth of both cell lines at 24 h compared with controls by MTS (p < 0.01) and BrdU (p < 0.01) 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 levels 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 luciferase activity at concentrations of 0.1 microM, 1.0 microM or 10.0 microM in either of the cell types. Competitive binding assays revealed that the affinity of Fen binding to estrogen receptors (ERs) was 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, the 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.
Comparative Pathobiology Group, Cellular and Molecular Pathology Branch, NTP, National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park, NC 27709, United States.
Xiaohua
X
Gao
Linda
L
Yu
Lysandra
L
Castro
Alicia B
AB
Moore
Tonia
T
Hermon
Carl
C
Bortner
Maria
M
Sifre
Darlene
D
Dixon
D017209:Apoptosis / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics*; D052244:Endocrine Disruptors / Q000633:toxicity*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007889:Leiomyoma / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D009215:Myometrium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009570:Nitriles / Q000633:toxicity*; D011722:Pyrethrins / Q000633:toxicity*; D012333:RNA, Messenger / Q000032:analysis; D011960:Receptors, Estrogen / Q000502:physiology; D014594:Uterine Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology
D024042:Collagen Type I; D052244:Endocrine Disruptors; D009570:Nitriles; D011722:Pyrethrins; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D001973:Bromodeoxyuridine; C017690:fenvalerate