Aryl-hydrocarbon receptor binding and the incidence of type 2 diabetes: the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)

Abstract

Background Persistent organic pollutants (POPs) may cause diabetes, in part through aryl hydrocarbon receptor (AhR) binding. Ensuing mitochondrial dysfunction is postulated to mediate this effect. We aim to investigate the association of POPs with incident diabetes indirectly by bio-assaying AhR ligand bioactivity and intracellular ATP level induced by participant serum samples. Methods In incident case-cohort analyses of one ELSA-Brasil center, 1605 eligible subjects without diabetes at baseline had incident diabetes ascertained by self-report, medication use, OGTT or HbA1c at follow-up 4 years later. We assayed AhR ligand bioactivity (AhRL) and intracellular ATP content, the latter reflecting the presence of mitochondria-inhibiting substances (MIS), following incubation of recombinant mouse Hepa1c1c7 cells with participant sera for 71 incident diabetes cases and 472 randomly selected controls. Results In multiply-adjusted proportional hazards regression analyses, those with above-median AhRL and below-median MIS-ATP had 69 and 226% greater risk of developing diabetes (HR = 1.69; 95%CI 1.01–2.83 and 3.26; 1.84–5.78), respectively. A strong interaction was seen between the two exposures (HRhigh AhRL/low MIS-ATP vs. low AhRL/high MIS-ATP = 8.15; 2.86–23.2). Conclusion The markedly increased incidence of diabetes seen in those with both higher AhR ligand bioactivity and increased mitochondrial inhibition supports the hypothesis that widespread POPs exposure contributes to the diabetes epidemic.

Effects of organic chemicals from diesel exhaust particles on adipocytes differentiated from human mesenchymal stem cells

“…AhR ligands such as TCDD and dioxin‐like PCBs have been reported to induce inflammatory reactions and/or glucose impairment in adipose cells and tissues in vitro and in vivo through AhR‐dependent mechanisms 30,31 . Furthermore, a marked incidence of diabetes has been reported in individuals with enhanced AhR bioactivity 57 . We also observed that DEP‐OC caused a dose‐dependent down‐regulation of the βAR genes ADRβ1 and ADRβ2.…”

“… 30 , 31 Furthermore, a marked incidence of diabetes has been reported in individuals with enhanced AhR bioactivity. 57 We also observed that DEP‐OC caused a dose‐dependent down‐regulation of the βAR genes ADRβ1 and ADRβ2. Previous studies have shown that PAHs can directly interact with β2AR, and down‐regulate β2AR levels both in vitro and in vivo, 32 , 33 , 58 and B[ a ]P has also been shown to impair adrenergic lipolysis, causing weight gain in mice at relatively low exposure levels.…”

Gender- and Age-Group Specific Association of Persistent Organic Pollutants (POPs) Exposure with Diabetes Mellitus: Korean National Environmental Health Survey (KoNEHS) 2015–2017

“…AhR has been employed to explain the relationship between POPs exposure and diabetes, because its activation may partially mediate the effect of POPs to develop diabetes, possibly by influencing glucose homeostasis and insulin secretion through influencing cytochrome P450 1A1 and 1B1 pathways . Indeed, a recent case-cohort study in Brazil (71 cases and 472 controls) reported increased prevalence of diabetes in the participants with higher AhR ligand bioactivity measured in the serum and increased mitochondrial inhibition . On the other hand, sex hormones are reported to interact with AhR, and AhR sensitivity differs by sex .…”

Synergistic effect of endurance training and nettle leaf extract on the IDO1-KYN-AHR pathway homeostasis and inhibiting of liver toxicity in rats with STZ-induced diabetes

“…KYN is a derivative of tryptophan (TRP) that functions as an endogenous agonist for the aryl hydrocarbon receptor (AHR) and regulates a variety of immune and physiological functions (6). AHR, in turn, is a cytoplasm-resident ligand-activated transcription factor with many functions in health and disease, including diabetes and liver diseases (7)(8)(9). TRP 2,3dioxygenase (TDO) and indoleamine 2,3-dioxygenase 1 (IDO1) and 2 (IDO2), whose expression is mediated by AHR signaling, catalyze the breakdown of TRP into KYN (10).…”