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

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<mark>Journal publication date</mark>2007
<mark>Journal</mark>Environmental Health Perspectives
Issue numberSupple
Number of pages8
Pages (from-to)129-136
<mark>Original language</mark>English


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.