Organic Chemicals Adsorbed onto Diesel Exhaust Particles Directly Alter the Differentiation of Fetal Thymocytes Through Arylhydrocarbon Receptor but Not Oxidative Stress Responses

Abstract

Diesel exhaust particles (DEP) were reported to have adverse effects on the immune system of laboratory animals and to induce thymic involution, particularly when exposure occurred during the fetal or lactational period. DEP consist of a carbon core to which many organic compounds are adsorbed, including polyaromatic hydrocarbons (PAHs) and their derivatives (e.g., dioxins and quinones). Although it has been suggested that these organic compounds were responsible for mediating the effects of DEP through their regulation of gene expression, the molecular mechanism of action of DEP has not been fully elucidated. In this study, we examined the direct effect of DEP extracts and their constituents on gene expression and phenotype in the fetal thymus. Fetal thymuses from C57BL/6 mice were exposed to DEP extracts for 24 hrs, after which their gene expression was analyzed using an Affymetrix GeneChip system. DEP extracts up-regulated several genes known as arylhydrocarbon receptor (AhR)-target genes, including cytochrome P450 1a1 (Cyp1a1), 1b1 (Cyp1b1), TCDD-inducible poly(ADP-ribose) polymerase (Tiparp), and scinderin (Scin). Similarly, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and benzo[a]pyrene (B[a]P), which are AhR ligands, induced remarkably similar changes in gene expression compared to DEP extracts. In addition, our data showed little contribution of quinones to DEP extracts-induced changes in gene expression in fetal thymus through oxidative stress responses. These changes in gene expression were also confirmed by semi-quantitative RT-PCR. Furthermore, DEP extracts skewed thymic T-cell differentiation in favor of the production of CD8 T-cells, which was also observed when exposed to AhR ligands. Our results suggest that organic compounds adsorbed onto DEP alter thymic gene expression and directly affect thymocyte development by activating the AhR.