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Enhanced micronucleus formation and modulation of Bcl-2 : Bax in MCF-7 cells after exposure to binary mixtures.

Hewitt, Rebecca and Forero, Albert and Luncsford, Paz J. and Martin, Frank L. (2007) Enhanced micronucleus formation and modulation of Bcl-2 : Bax in MCF-7 cells after exposure to binary mixtures. Environmental Health Perspectives, 115 (Supple). pp. 129-136. ISSN 0091-6765

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Abstract

Background: Within mixtures, interactions between different xenobiotics may occur to give rise to additive, synergistic, inhibitory and/or stimulatory effects in target cells. The role that xenobiotics individually or in mixtures, and at environmental concentrations, play in the etiology of common human diseases often remains obscure. Methods: In the presence or absence of lindane, chromosomal aberrations were detected in MCF-7 cells after 24-hr treatment with benzo[a]pyrene (B[a]P) or 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) using the cytokinesis-block micronucleus assay. Micronuclei were scored in 1,000 binucleate cells/treatment. We investigated intracellular responses using quantitative gene expression analyses of cyclin-dependent kinase inhibitor 1A [CDKN1A (P21WAF1/CIP1) ], B-cell leukemia/lymphoma 2 (BCL-2) , BCL-2–associated X (BAX) , and isoforms of cytochrome P450 (CYP) , CYP1A1, CYP1A2, and CYP1B1. Immunocytochemical analyses of p53, p21Waf1/Cip1, Bcl-2 and Bax protein expression in MCF-7 cells were also carried out. Results: After exposure to binary mixtures of B[a]P plus lindane or PhIP plus lindane, a 10-fold increase in micronucleus formation resulted ; these test agents individually induced 2- to 5-fold increases. Lindane increased the ratio of Bcl-2:Bax, as did 17β-estradiol (E2) . Although treatment with B[a]P alone was found to elevate expression of P21WAF1/CIP1and CYP isoenzymes, it reduced the ratio of BCL-2:BAX mRNA transcripts. Treatment with a binary mixture of 10–8 M B[a]P plus 10–12 M lindane or 10–10 M E2 reversed B[a]P-induced reductions in the ratio of Bcl-2– to Bax-positive cells. In contrast, treatments with PhIP (known to possess hormonelike properties) plus lindane or E2 resulted in profound reductions in Bcl-2:Bax ratio. Conclusions: Our results suggest that low-dose treatments (i.e., close to environmental levels) may increase DNA damage while influencing survival in exposed cells and that these effects may depend on the endocrine activity of test agents.

Item Type: Article
Journal or Publication Title: Environmental Health Perspectives
Uncontrolled Keywords: 17β-estradiol ; BAX ; Bcl-2 ; benzo[a]pyrene ; binary mixture ; clonogenic assay ; cytokinesis-block micronucleus assay ; lindane ; micronucleus ; PhIP.
Subjects: G Geography. Anthropology. Recreation > GE Environmental Sciences
Departments: Faculty of Science and Technology > Lancaster Environment Centre
ID Code: 31373
Deposited By: Mr Richard Ingham
Deposited On: 14 Jan 2010 10:16
Refereed?: Yes
Published?: Published
Last Modified: 26 Jul 2012 16:56
Identification Number:
URI: http://eprints.lancs.ac.uk/id/eprint/31373

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