PCB 126 perturbs hypoxia-induced HIF-1α activity and glucose consumption in human HepG2 cells

Abstract

Aerobic organisms strongly depend on the availability of oxygen for respiration and countless other metabolic processes to maintain cellular homeostasis. Under certain conditions, the amount of available oxygen can be limited. To support survival in environments with limited oxygen supply, hypoxia-inducible factors (HIFs) reprogram vital components of cellular metabolism. HIF-1α is an important mediator of acute and adaptive responses to hypoxic stress. Interestingly, the heterodimeric partner required by HIF-1α to function as transcription factor, known as ARNT, is also an essential part of the aryl hydrocarbon receptor (AhR) transcription factor complex. Thus, via ARNT a crosstalk exists between these two pathways that might affect HIF-1α-mediated processes. In this study we sought to assess the effect of the AhR agonist PCB 126 on HIF-1α activity as well as on HIF-1α-regulated targets involved in cellular metabolism in human HepG2 cells. Our results show that PCB 126 reduced HIF-1α localization to the nucleus. Furthermore, in an in vivo setting, rats exposed to parenteral PCB 126 also displayed reduced hepatocyte nuclear localization of HIF-1α. Additionally, HepG2 cells exposed to PCB126 displayed reduced hypoxia-regulated HRE-luciferase reporter gene expression as well as a reduction in glucose consumption in conditions of hypoxia. In summary, this study reveals that HIF-1α-regulated cellular metabolic processes are negatively affected by PCB 126 which might ultimately affect adaptive responses and cell survival in hypoxic environments.

Reoxygenation induces reactive oxygen species production and ferroptosis in renal tubular epithelial cells by activating aryl hydrocarbon receptor

“…However, activated AhR also associates with HIF-1β ( 33 , 34 ). In certain experimental models, this competition between AhR and HIF-α for HIF-1β results in reduced HIF-1α transcriptional activity in the case of AhR activation, or to decreased AhR transcriptional activity in the case of HIF-1α activation ( 38 – 40 ). However, the interaction between AhR and HIF-1 has not been evaluated during the reperfusion phase of I-R injury.…”

“…However, activated AhR also forms a heterodimer with HIF-1β (33, 34). In certain experimental models of AhR activation, the competition between AhR and HIF-1α for HIF-1β results in reduced HIF-1α transcriptional activity, and vice versa ( 38 – 40 ). However, this interaction between AhR and HIF-1α has not been evaluated in models of I-R injury.…”

Interactive effects of hypoxia and PCB co‐exposure on expression of CYP1A and its potential regulators in Atlantic croaker liver

“…Upon activation by PAHs and PHAHs, the AhR is translocated to the nucleus where it forms a transcriptionally heterodimer with ARNT to regulate transcription of numerous genes, including CYP1A1 . In vitro studies with mammalian and fish cell lines have shown that there is cross‐talk between the HIF‐1α/ARNT and AhR/ARNT pathways during co‐exposure to hypoxia and AhR agonists resulting in attenuation of AhR agonist‐induced CYP1A1 expression and enzymatic activity . However, an analysis of AhR‐mediated signaling induced by dioxin in mammalian hepatoma cell lines during hypoxia exposure revealed a lack of competition for ARNT, even though CYP1A1 mRNA was down‐regulated .…”

Polychlorinated Biphenyls (PCBs) Inhibit Hepcidin Expression through an Estrogen-Like Effect Associated with Disordered Systemic Iron Homeostasis

“…In the current study, we verified estrogen-like activity for both PCB126 and PCB153, in support of previous reports. 10,23,64,65 We also discovered that PCB126 exerted a stronger estrogenic activity than that of PCB153 in HepG2 cells. Importantly, we demonstrated that PCB153 and PCB126 significantly inhibited hepatic hepcidin expression through ERdependent signaling, independent of oxidative stress, BMP-6, and IL-6.…”