Crosstalk between the aryl hydrocarbon receptor and hypoxia inducible factor 1α pathways impairs downstream dioxin response in human islet models

Abstract

The incidence of type 2 diabetes (T2D) is increasing globally at a rate that cannot be explained solely by genetic predisposition, diet, or lifestyle. Epidemiology studies report positive associations between exposure to persistent organic pollutants, such as dioxins, and T2D. We previously showed that 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) activates the xenobiotic-sensitive aryl hydrocarbon receptor (AHR) in pancreatic islets. The AHR is known to crosstalk with the hypoxia inducible factor 1 (HIF1) in hepatocytes but whether this crosstalk occurs in islet cells remains unknown. We assessed AHR-HIF1 pathway crosstalk by treating human donor islets and stem cell-derived islets (SC-islets) with TCDD +/- hypoxia and examined the changes in downstream targets of both AHR (e.g., CYP1A1) and HIF1 (e.g., HMOX1). SC-islets showed consistent crosstalk between AHR and HIF1 pathways; co-treatment of SC-islets with TCDD + hypoxia robustly suppressed the magnitude of CYP1A1 induction compared with TCDD treatment alone. In human islets, only 2 of 6 donors showing suppressed CYP1A1 induction following TCDD + hypoxia co-treatment. In both SC-islets and human donor islets we observed an unexpected hypoxia-mediated suppression of glucose-6-phosphate catalytic subunit 2 (G6PC2) expression. Our study shows AHR-HIF1 crosstalk occurs in both SC-islets and primary human donor islets, but the response of human islets varied between donors. In both models, the HIF1 pathway dominated over the AHR pathway during TCDD + hypoxia co-treatment. Our study is the first to examine whether AHR-HIF1 crosstalk occurs in islet cells and presents novel data on the impact of hypoxia on G6PC2 gene expression.