Carcinogenesis Advance Access originally published online on August 8, 2007
Carcinogenesis 2007 28(12):2632-2640; doi:10.1093/carcin/bgm182
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Binary PAH mixtures cause additive or antagonistic effects on gene expression but synergistic effects on DNA adduct formation
1 Department of Health Risk Analysis and Toxicology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands
2 Present address: TNO Quality of Life, Department of Toxicology and Applied Pharmacology, PO box 360, 3700 AJ Zeist, The Netherlands
* To whom correspondence should be addressed. Tel: +31 43 388 1092; Fax: +31 43 388 4146;Email: j.vandelft{at}grat.unimaas.nl
Polycyclic aromatic hydrocarbons (PAHs) cover a wide range of structurally related compounds which differ greatly in their carcinogenic potency. PAH exposure usually occurs through mixtures rather than individual compounds. Therefore, we assessed whether the effects of binary PAH mixtures on gene expression, DNA adduct formation, apoptosis and cell cycle are additive compared with the effects of the individual compounds in human hepatoma cells (HepG2). Equimolar and equitoxic mixtures of benzo[a]pyrene (B[a]P) with either dibenzo[a,l]pyrene (DB[a,l]P), dibenzo[a,h]anthracene (DB[a,h]A), benzo[b]fluoranthene (B[b]F), fluoranthene (FA) or 1-methylphenanthrene (1-MPA) were studied. DB[a,l]P, B[a]P, DB[a,h]A and B[b]F dose-dependently increased apoptosis and blocked cells cycle in S-phase. PAH mixtures showed an additive effect on apoptosis and on cell cycle blockage. DNA adduct formation in mixtures was higher than expected based on the individual compounds, indicating a synergistic effect of PAH mixtures. Equimolar mixtures of B[a]P and DB[a,l]P (0.1, 0.3 and 1.0 µM) were assessed for their effects on gene expression. Only at 1.0 µM, the mixture showed antagonism. All five compounds were also tested as a binary mixture with B[a]P in equitoxic concentrations. The combinations of B[a]P with B[b]F, DB[a,h]A or FA showed additivity, whereas B[a]P with DB[a,l]P or 1-MPA showed antagonism. Many individual genes showed additivity in mixtures, but some genes showed mostly antagonism or synergism. Our results show that the effects of binary mixtures of PAHs on gene expression are generally additive or slightly antagonistic, suggesting no effect or decreased carcinogenic potency, whereas the effects on DNA adduct formation show synergism, which rather indicates increased carcinogenic potency.
Abbreviations: B[a]P, benzo[a]pyrene; B[b]F, benzo[b]fluoranthene; DB[a,h]A, dibenzo[a,h]anthracene; DB[a,l]P, dibenzo[a,l]pyrene; DMSO, dimethyl sulfoxide; FA, fluoranthene; PAH, polycyclic aromatic hydrocarbon; PCR, polymerase chain reaction; RT, real-time; 1-MPA, 1-methylphenanthrene
Received January 9, 2007; revised August 2, 2007; accepted August 2, 2007.
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