title: Low dose induction of micronuclei by lindane.
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)-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 1000 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)-10(-10) M) induced increases (up to 5-fold) in MNi in both cell lines. Increases in MNi occurred in the absence of DNA single-strand breaks or cytotoxicity and, compared with benzo[a]pyrene and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, at low concentrations. Lindane induced more MNi than the alpha or beta stereoisomers of HCH. Low dose lindane (10(-12)-10(-10) M) significantly elevated the percentage 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 percentage of cells in G1 and decreases in percentage 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 percentage 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.
authors.affiliation: Department of Environmental Science, Lancaster University, Lancaster LA1 4YQ, UK.
authors.forename: Olga I
authors.initials: OI
authors.lastname: Kalantzi
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hewitt
authors.forename: Kirstie J
authors.initials: KJ
authors.lastname: Ford
authors.forename: Lee
authors.initials: L
authors.lastname: Cooper
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Alcock
authors.forename: Gareth O
authors.initials: GO
authors.lastname: Thomas
authors.forename: James A
authors.initials: JA
authors.lastname: Morris
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: McMillan
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Jones
authors.forename: Francis L
authors.initials: FL
authors.lastname: Martin
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms; D015197:Carcinogenicity Tests; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D017931:DNA Primers; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D001556:Hexachlorocyclohexane / Q000633:toxicity*; D006801:Humans; D007700:Kinetics; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects / Q000473:pathology*; D015162:Micronucleus Tests; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D001556:Hexachlorocyclohexane