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1: Carcinogenesis. 2003 Dec 19  
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Low-dose induction of micronuclei by lindane.

Kalantzi OI, Hewitt R, Ford KJ, Cooper L, Alcock RE, Thomas GO, Morris JA, McMillan TJ, Jones KC, Martin FL.

Department of Environmental Science, IENS, Lancaster University, Lancaster LA1 4YQ, UK.

Environmental contaminants possessing hormonal activity have long been suspected of playing a role in cancer causation. What is unclear is whether such agents elicit their effects through genotoxic and/or epigenetic mechanisms. gamma-Hexachlorocyclohexane (gamma-HCH) (lindane) was tested in the 10(-12) M-10(-4) M range. Chromosomal damage in MCF-7 breast cells and PC-3 prostate cells was assessed using the cytokinesis-block micronucleus assay. Micronuclei (MNi) were scored in 1,000 binucleate cells per treatment. Cell viability and cell cycle kinetics were also assessed along with immunocytochemical and quantitative gene expression analyses of CDKN1A (P21(WAF1/CIP1)), BCL-2 and BAX. Following 24-h treatment, lindane (10(-12) M-10(-10) M) induced increases (up to 5-fold) in MNi in both cell lines. Increases in MNi occurred in the absence of DNA singlestrand breaks or cytotoxicity and, compared to benzo[a]pyrene or 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, at low concentrations. Lindane induced more MNi than the a or b stereoisomers of HCH. Low-dose lindane (10(-12) M-10(-10) M) significantly elevated the %age of MCF-7 cells staining positive for Bcl-2 and of PC-3 cells staining positive for Bax. Only high-dose lindane (10(-4) M) disrupted cell cycle kinetics with increases in %age of cells in G1 and decreases in %age of cells in G2-M. Despite a comparable high-dose lindane induction of cell cycle arrest, marked increases in expression of P21(WAF1/CIP1) were observed only in MCF-7 cells, although in PC-3 cells a significant increase (P < 0.0005) in the %age of cells staining positive for p21(Waf1/Cip1) was seen. These results suggest that "environmental" concentrations of lindane can induce a number of subtle alterations in breast and prostate cells in the absence of cytotoxicity.

PMID: 14688026 [PubMed - as supplied by publisher]


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