Novel Cell-Based Assay Reveals Associations of Circulating Serum AhR-ligands With Metabolic Syndrome and Mitochondrial Dysfunction

Biofactors. Jul-Aug 2013;39(4):494-504. doi: 10.1002/biof.1092. Epub 2013 Jan 30.

Abstract

Serum concentrations of environmental pollutants have been positively correlated with diabetes and metabolic syndrome in epidemiologic studies. In turn, abnormal mitochondrial function has been associated with the diseases. The relationships between these variables, however, have not been studied. We developed novel cell-based aryl hydrocarbon receptor (AhR) agonist bioassay system without solvent extraction process and analyzed whether low-dose circulating AhR ligands in human serum are associated with parameters of metabolic syndrome and mitochondrial function. Serum AhR ligand activities were measured as serum 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalent (sTCDDeq) in pM using 10 μL human sera from 97 Korean participants (47 with glucose intolerance and 50 matched controls, average age of 46.6 ± 9.9 years, 53 male and 45 female). sTCDDeq were higher in participants with glucose intolerance than normal controls and were positively associated (P < 0.01) with obesity, blood pressure, serum triglyceride, and fasting glucose, but not with HDL-cholesterol. Body mass index was in a positive linear relationship with serum AhR ligands in healthy participants. When myoblast cells were incubated with human sera, ATP generating power of mitochondria became impaired in an AhR ligand concentration-dependent manner. Our results support that circulating AhR ligands may directly reduce mitochondrial function in tissues, leading to weight gain, glucose intolerance, and metabolic syndrome. Our rapid cell-based assay using minute volume of human serum may provide one of the best monitoring systems for circulating AhR ligands, good clinical biomarkers for the progress of disease and therapeutic efficacy.

Keywords: POPs; alternative test method development; aryl hydrocarbon receptor; dioxins; insulin resistance; metabolic syndrome; mitochondrial dysfunction; obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Biological Assay
  • Blood Glucose
  • Case-Control Studies
  • Cell Line, Tumor
  • Diabetes Mellitus, Type 2 / blood
  • Environmental Pollutants / blood
  • Environmental Pollutants / pharmacology
  • Environmental Pollutants / toxicity*
  • Female
  • Glucose Intolerance / blood
  • Glucose Intolerance / chemically induced
  • Humans
  • Male
  • Metabolic Syndrome / blood*
  • Metabolic Syndrome / chemically induced
  • Mice
  • Middle Aged
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Obesity / blood
  • Polychlorinated Dibenzodioxins / blood
  • Polychlorinated Dibenzodioxins / pharmacology
  • Polychlorinated Dibenzodioxins / toxicity*
  • Receptors, Aryl Hydrocarbon / agonists
  • Receptors, Aryl Hydrocarbon / metabolism
  • Triglycerides / blood

Substances

  • Blood Glucose
  • Environmental Pollutants
  • Polychlorinated Dibenzodioxins
  • Receptors, Aryl Hydrocarbon
  • Triglycerides