Modulation of gene expression and DNA-adduct formation in precision-cut liver slices exposed to polycyclic aromatic hydrocarbons of different carcinogenic potency.
Polycyclic aromatic hydrocarbons (PAHs) differ markedly in their carcinogenic potencies. Differences in transcriptomic responses upon PAH exposures might improve our current understanding of the differences in carcinogenicity, and therefore gene expression modulation by six PAHs in precision-cut rat liver slices was investigated. Gene expression modulation by benzo[a]pyrene (B[a]P), dibenzo[a,l]pyrene (DB[a,l]P), benzo[b]fluoranthene (B[b]F), fluoranthene (FA), dibenzo[a,h]anthracene (DB[a,h]A) and 1-methylphenanthrene (1-MPA) was assessed after 6- (B[a]P, DB[a,l]P) and 24-h (all compounds) exposure, using oligonucleotide arrays. DNA-adduct formation was determined using (32)P-post-labelling. The effects of PAHs on gene expression and on DNA-adduct formation were much more pronounced after 24-h exposure than after a 6-h exposure. Each compound induced gene expression changes dose-dependently and gene expression profiles were generally compound-specific. B[a]P, B[b]F and DB[a,h]A displayed comparable gene expression profiles, and so did DB[a,l]P, FA and 1-MPA. Only the carcinogenic PAHs (B[a]P, B[b]F, DB[a,l]P and DB[a,h]A) induced the oxidative stress pathway. DNA-adduct levels were: DB[a,l]P >> B[a]P > B[b]F > or = DB[a,h]A > FA > or = 1-MPA. The expression of only a few genes was found to correlate significantly with DNA-adduct formation, carcinogenic potency or Ah-receptor binding capacity (the last two taken from literature). These genes differed between the parameters. Our results indicate that PAHs generally induce a compound-specific response on gene expression and that discrimination of carcinogenic from non-carcinogenic compounds is partly feasible using this approach. Only at a specific pathway level, namely oxidative stress response, PAHs with high and low carcinogenic potency could be discriminated.
Staal
Yvonne C M
YC
Department of Health Risk Analysis and Toxicology, Maastricht University, 6200 MD Maastricht, The Netherlands.
van Herwijnen
Marcel H M
MH
Pushparajah
Daphnee S
DS
Umachandran
Meera
M
Ioannides
Costas
C
van Schooten
Frederik J
FJ
van Delft
Joost H M
JH
D000818:Animals; D015197:Carcinogenicity Tests; D016000:Cluster Analysis; D018736:DNA Adducts / Q000096:biosynthesis*; D004210:Dissection; D004353:Drug Evaluation, Preclinical; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
D018736:DNA Adducts; D011084:Polycyclic Aromatic Hydrocarbons