Correlation between gene expression in human cells and tumor initiation in sencar mice on exposure to a standardized complex mixture derived from diesel exhaust.
Courter LA; Mahadevan B; Keshava C; Musafia-Jeknic T; Fischer K; Brooks E; Bildfell R; Weston A; Baird WM
Toxicologist 2006 Mar; 90(1):11
Human exposures to polycyclic aromatic hydrocarbons (PAH) occur as complex mixtures of PAH, some of which are carcinogenic. Standardized Reference Material (SRM) 1650a (diesel particulate) and SRM 1975 (diesel exhaust extract), was obtained from the National Institute of Standards and Technology. Gene expression patterns were investigated in MCF-7 cells exposed to SRM 1650a alone or in combination with individual PAH (24h). Gene expression was monitored using high density oligonucleotide arrays (U133A, Affymetrix). Global gene expression analyses revealed alterations in at least 223 RNA transcript species by at least 2 fold. Among several other genes, increase in expression of CYP1A1 and CYP1B1 was observed in response to benzo[a]pyrene (BP) exposure. Additive induction of similar genes was noticed on co-treatment with SRM 1650a plus BP. Unlike BP and SRM 1650a, no change in expression of CYP1A1 and CYP1B1 was observed when MCF-7 cells were exposed to Dibenzo[a,l]pyrene (DBP). To study the effect of complex PAH mixtures on the metabolic activation of carcinogenic PAH to DNA-binding derivatives and to relate the results with gene expression studies in human cells, mouse skin initiation-promotion tumorigenesis model was utilized. Results indicate that although SRM 1975 had a weak tumor-initiating activity, on co-treatment with BP an increase in tumors per tumor bearing animal was observed. On the contrary, SRM 1975 did not cause any modification in the tumor-initiating activity of DBP. These results not only provide a transcriptional signature to chemical carcinogen exposure but also suggest that understanding the relationship between tumor induction and gene expression may allow the prediction of early carcinogenic effects of these environmental mixtures.
Genes; Laboratory-animals; Animal-studies; Animals; Diesel-exhausts; Polycyclic-aromatic-hydrocarbons; Carcinogens; Carcinogenesis; Carcinogenicity; Exposure-levels; Exposure-assessment; Tumors; Tumorigenesis; Tumorigens
The Toxicologist. Society of Toxicology 45th Annual Meeting and ToxExpo, March 5-9, 2006, San Diego, California