Unraveling the divergent biological effects of 3,3',4,4',5-pentachloro biphenyl (PCB 126): toward understanding the role of gene expression

Abstract

Expression of genetic information encoded within DNA underpins the existence of life. Adaptive responses to chemical stressors may alter the levels and activity of gene-products and modify molecular interactions leading to downstream health effects. One mechanism by which chemicals can alter the activity of genes is by altering transcription of mRNA. Humans, in particular breast-fed infants, continue to be exposed to polychlorinated biphenyls (PCBs), specifically to the congener 3 ,3',4 ,4',5-pentachloro biphenyl (PCB 126, CAS # 57465-28-8, molecular weight 326.44) from environmental sources. PCB 126, and other related compounds such as the prototype halogenated aromatic hydrocarbon 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are persistent environmental chemicals known to potently induce the activity of several important xenobiotic metabolizing enzymes in liver and other tissues. An important step in the cascade of events leading to enzyme induction is the transcriptional activation of genes encoding these enzymes. While it is unclear if the increased activity of these particular enzymes following transcriptional activation is directly responsible for toxicity, their induction is highly correlated with numerous toxic responses including events that increase the risk of cancer. The aim of this dissertation is to identify, on a transcriptome-wide basis, genes selectively activated or suppressed by PCB 126, and then connect these genes to previously observed biological effects of PCB 126. Knowledge of these linkages should then provide additional weight-of-evidence for conclusions about human health risks from exposure to PCB 126 and other similar chemicals such as TCDD. Following a comprehensive literature review presented in this dissertation, it is clear that biochemical effects of PCB 126 in liver are well characterized and comparable to those of TCDD. Although epidemiological studies of PCB mixtures implicate PCB 126 as having a role in adverse neurodevelopment outcomes, experimental data to support this role are equivocal. For these reasons, it was decided to compare gene expression profiles of PCB 126 in xenobiotic-metabolizing liver and brain tissues using two methods capable of interrogating genome-wide transcriptional responses. The results of this research clearly demonstrate transcriptional responses to PCB 126 are unique between liver and brain tissues, a finding that points to the need for organ-specific risk assessment.