Regulatory crosstalk and interference between the PCB 126 stimulated AHR and hypoxia stimulated HIF-1α signaling pathways

摘要

Polychlorinated biphenyls (PCBs) are synthetic organic chemicals that persist in the environment and are known to be carcinogenic to humans. Virtually all of the deleterious effects of PCB 126, the most potent dioxin-like PCB, are mediated by the aryl hydrocarbon receptor (AhR). By means of the common cofactor ARNT, the AhR signaling pathway can crosstalk with the hypoxia signaling pathway. Regulated by hypoxia-inducible factors (HIFs), the hypoxia pathway mediates responses to environments of reduced oxygen availability (hypoxia). This dissertation specifically examines the crosstalk and interference between these two pathways in the context of PCB 126 exposure. The results of this dissertation show that the antagonistic relationship between the AhR and hypoxia signaling pathways affects the function and responses of both AhR and HIF-1Α. We provide substantial evidence that ARNT is indeed a crucial factor in both the AhR and HIF-1Α signaling pathways. Furthermore, this dissertation examines regulatory mechanisms involved in AhR-mediated gene expression and identifies epigenetic regulation as a critical factor in AhR target gene expression. In summary, this dissertation helped to improve the understanding of mechanisms of PCB 126 toxicity. Understanding the detrimental biological effects of these ubiquitous environmental pollutants might ultimately have significant implications for human health.