| 18174961 |
Hewitt R, Forero A, Luncsford PJ, Martin FL: Enhanced micronucleus formation and modulation of BCL-2:BAX in MCF-7 cells after exposure to binary mixtures. Environ Health Perspect. 2007 Dec;115 Suppl 1:129-36.
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 (P21 (WAF1/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, p21 (Waf1/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 17beta-estradiol (E (2)). Although treatment with B [a] P alone was found to elevate expression of P21 (WAF1/CIP1) and 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 E (2) 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 E (2) 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. |
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