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]
