Journal Article

Modulation of gene expression and DNA adduct formation in HepG2 cells by polycyclic aromatic hydrocarbons with different carcinogenic potencies

Yvonne C.M. Staal, Marcel H.M. van Herwijnen, Frederik J. van Schooten and Joost H.M. van Delft

in Carcinogenesis

Volume 27, issue 3, pages 646-655
Published in print March 2006 | ISSN: 0143-3334
Published online November 2005 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/bgi255
Modulation of gene expression and DNA adduct formation in HepG2 cells by polycyclic aromatic hydrocarbons with different carcinogenic potencies

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Polycyclic aromatic hydrocarbons (PAHs) can occur in relatively high concentrations in the air, and many PAHs are known or suspected carcinogens. In order to better understand differences in carcinogenic potency between PAHs, we investigated modulation of gene expression in human HepG2 cells after 6 h incubation with varying doses of benzo[a]pyrene (B[a]P), benzo[b]fluoranthene (B[b]F), fluoranthene (FA), dibenzo[a,h]anthracene (DB[a,h]A), 1-methylphenanthrene (1-MPA) or dibenzo[a,l]pyrene (DB[a,l]P), by using cDNA microarrays containing 600 toxicologically relevant genes. Furthermore, DNA adduct levels induced by the compounds were assessed with 32P-post-labeling, and carcinogenic potency was determined by literature study. All tested PAHs, except 1-MPA, induced gene expression changes in HepG2 cells, although generally no dose–response relationship could be detected. Clustering and principal component analysis showed that gene expression changes were compound specific, since for each compound all concentrations grouped together. Furthermore, it showed that the six PAHs can be divided into three groups, first FA and 1-MPA, second B[a]P, B[b]F and DB[a,h]A, and third DB[a,l]P. This grouping corresponds with the carcinogenic potencies of the individual compounds. Many of the modulated genes are involved in biological pathways like apoptosis, cholesterol biosynthesis and fatty acid synthesis. The order of DNA adduct levels induced by the PAHs was: B[a]P ≫ DB[a,l]P > B[b]F > DB[a,h]A > 1-MPA ≥ FA. When comparing the expression change of individual genes with DNA adduct levels, carcinogenic potency or Ah-receptor antagonicity (the last two were taken from literature), several highly correlated genes were found, of which CYP1A1, PRKCA, SLC22A3, NFKB1A, CYP1A2 and CYP2D6 correlated with all parameters. Our data indicate that discrimination of high and low carcinogenic PAHs by gene expression profiling is feasible. Also, the carcinogenic PAHs induce several pathways that were not affected by the least carcinogenic PAHs.

Keywords: 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; EROD assay, 7-ethoxyresorufin-O-deethylase assay; FA, fluoranthene; FAS, fatty acid synthase; IEF, induction equivalency factor; 1-MPA, 1-methylphenanthrene; PAH, Polycyclic aromatic hydrocarbons; PEF, potency equivalency factor; TEF, toxic equivalency factor

Journal Article.  5923 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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