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Carcinogenesis Advance Access published online on December 19, 2003
Carcinogenesis, doi:10.1093/carcin/bgh048
© 2003 by Oxford University Press
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© 2003 Oxford University Press

CARCINOGENESIS

Low-dose induction of micronuclei by lindane

Olga I. Kalantzi 1, Rebecca Hewitt 2, Kirstie J. Ford 3, Lee Cooper 2, Ruth E. Alcock 4, Gareth O. Thomas 1, James A. Morris 3, Trevor J. McMillan 2, Kevin C. Jones 1, and Francis L. Martin 2*

1 Department of Environmental Science, IENS, Lancaster University, Lancaster LA1 4YQ, UK
2 Department of Biological Sciences, IENS, Lancaster University, Lancaster LA1 4YQ, UK
3 Department of Histopathology, Royal Lancaster Infirmary, Ashton Road, Lancaster LA1 4RP, UK
4 Environmental Research Solutions, Ghyll Cottage, Mill Side, Witherslack, Nr Grange-over-Sands, Cumbria LA11 6SG, UK

* Corresponding author. E-mail: f.martin{at}lancaster.ac.uk.

Received 8 August 2003 ; revised 21 November 2003 ; accepted 30 November 2003

Abstract

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 (P21WAF1/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 P21WAF1/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 p21Waf1/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.


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