Gene Expression Analysis of PCB Exposed Children: Understanding Toxicity and Disease Process

O-29A5-2 Background/Aims: To understand the molecular mechanism of PCB-related toxicities and the basics of pathophysiology in association with high PCB exposure, we studied the differential global gene expression profile of children (mean age, 45 month) of East European descent from Slovakian Republic in a well-defined study cohort. Methods: An unsupervised microarray based gene expression analysis was performed on the subset of children having high blood PCB concentration (>75 percentile) against their low PCB counterpart (<25 percentile). The mean lipid adjusted PCB values in 2 groups were 3.16 ± 1.2 and 0.06 ± 0.03 ng/g of serum lipid, respectively. Total RNA from peripheral blood mononuclear cells were isolated and the microarray was conducted using Affymetrix platform (GeneChip Human genome U133 Plus 2.0 Array). The data obtained from microarray were analyzed by Genespring GX10. Results: A highly significant set of 162 differentially expressed genes between high PCB and low PCB group was observed (P < 0.00001). The subsequent Ingenuity Pathway Analysis on this set of genes implicated different compromised molecular and cellular function in higher PCB exposure included: Cell-to-Cell Signaling and Interaction, Cellular Movement, Cellular Assembly and Organization, Cellular Function and Maintenance, and Carbohydrate Metabolism. The analysis conducted on children with high PCB exposure also indicated perturbed expression of genetic pathways related to cardiotoxicity, hepatotoxicity, and nephrotoxicity. These uncharacteristic effects on gene expression may play a role in development of major diseases and disorders in population, including cancer. Some of the relevant genes reported in relation to PCB-related toxicities were subsequently validated through quantitative RT-PCR. Conclusion: Our results provided a molecular insight in understanding the associated mechanism of this complex gene environment interaction. The future endeavor of supervised genotyping of pathway-specific molecular epidemiological study would reveal the individual risk factor in PCB exposure.