Effect of a complex environmental mixture from coal tar containing polycyclic aromatic hydrocarbons (PAH) on the tumor initiation, PAH–DNA binding and metabolic activation of carcinogenic PAH in mouse epidermis

Abstract

Human exposure to polycyclic aromatic hydrocarbons (PAH) occurs through complex mixtures such as coal tar. The effect of complex PAH mixtures on the activation of carcinogenic PAH to DNA-binding derivatives and carcinogenesis were investigated in mice treated topically with NIST (National Institute of Standards and Technology) Standard Reference Material 1597 (SRM), a complex mixture of PAH extracted from coal tar, and either additional benzo[a]pyrene (B[a]P) or dibenzo[a,l]pyrene (DB[a,l]P). In an initiation-promotion study using 12-O-tetradecanoylphorbol-13-acetate as the promoter for 25 weeks, the SRM and B[a]P co-treated mice had a similar incidence of papillomas per mouse compared with the group exposed to B[a]P alone as the initiator. PAH-DNA adduct analysis of epidermal DNA by 33P-post-labeling and reversed-phase high-performance liquid chromatography found the SRM co-treatment led to a significant decrease in the total level of DNA adducts and B[a]P-DNA adducts to less than that observed in mice treated with B[a]P alone at 6, 12 and 72 h exposure. After 24 and 48 h exposure, there was no significant difference in the levels of adducts between these groups. In the DB[a,l]P initiation-promotion study, the co-treated group had significantly fewer papillomas per mouse than mice treated with DB[a,l]P alone as initiator. Averaging over the times of exposure gave strong evidence that mice co-treated with SRM and DB[a,l]P had a significantly lower level of PAH-DNA adducts than mice treated with DB[a,l]P alone. Western immunoblots showed that both cytochrome P450 (CYP) 1A1 and 1B1 were induced by the SRM. These results are consistent with the hypothesis that two major factors determining the carcinogenic activity of PAH within a complex mixture are (i) the persistence of certain PAH-DNA adducts as well as total adduct levels, and (ii) the ability of the components present in the mixture to inhibit the activation of carcinogenic PAH by the induced CYP enzymes.

Understanding the human health effects of chemical mixtures.

“…PAHs are invariably found as mixtures in the environment (e.g., products of partial combustion, coal tars, environmental cigarette smoke), and the interactions among PAHs may be quite complex. The toxicity and carcinogenicity of a PAH mixture may depend on the net activities of CYP inducers (AhR agonists or antagonists), the prevalence of enzyme inhibitors versus substrates for bioactivation, and the activation or inhibition of metabolic pathways leading to nontoxic/noncarcinogenic metabolites (275)(276)(277)(278)(279). Results of recent studies indicate that the formation of diol epoxides may not be the only metabolic pathway involved in PAH-induced carcinogenesis.…”

A novel degradation pathway in the assimilation of phenanthrene by Staphylococcus sp. strain PN/Y via meta-cleavage of 2-hydroxy-1-naphthoic acid: formation of trans-2,3-dioxo-5-(2′-hydroxyphenyl)-pent-4-enoic acid

“…Polycyclic aromatic hydrocarbons (PAHs) constitute a group of priority environmental pollutants, which are ubiquitous contaminants in soils and sediments and are of environmental concern because of their toxic, mutagenic and/or carcinogenic effects (Mastrangelo et al, 1996;Marston et al, 2001;Xue & Warshawsky, 2005). In recent years, the biodegradation of PAHs has received considerable attention and a variety of micro-organisms have been reported to play important roles in the process (Pothuluri & Cerniglia, 1994;Shuttleworth & Cerniglia, 1995;Kanaly & Harayama, 2000;Habe & Omori, 2003;Tortella et al, 2005).…”

A screen for Benzo(a)pyrene in Fish Samples From Crude Oil Polluted Environments

“…Benzo(a)pyrene induced carcinogenesis involves 3 stages. First is the enzymatic activation of the compound into metabolites [8] . The second stage in the carcinogenesis of benzo(a)pyrene is the covalent bonding of anti-BPDE to DNA to form BPDE-DNA adduct [9] .…”