Novel cell-based assay reveals associations of circulating serum AhR-ligands with metabolic syndrome and mitochondrial dysfunction.
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.
Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Korea; Department of Neuroscience, College of Medicine, Kyung Hee University, Seoul, Korea.
Wook-Ha
WH
Park
Dae Won
DW
Jun
Jin Taek
JT
Kim
Jae Hoon
JH
Jeong
Hyokeun
H
Park
Yoon-Seok
YS
Chang
Kyong Soo
KS
Park
Hong Kyu
HK
Lee
Youngmi Kim
YK
Pak
D000328:Adult; D000818:Animals; D001681:Biological Assay; D001786:Blood Glucose; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000097:blood; D004785:Environmental Pollutants / Q000097:blood / Q000494:pharmacology / Q000633:toxicity*; D005260:Female; D018149:Glucose Intolerance / Q000097:blood / Q000139:chemically induced; D006801:Humans; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood* / Q000139:chemically induced; D051379:Mice; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000097:blood; D000072317:Polychlorinated Dibenzodioxins / Q000097:blood / Q000494:pharmacology / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D014280:Triglycerides
POPs; alternative test method development; aryl hydrocarbon receptor; dioxins; insulin resistance; metabolic syndrome; mitochondrial dysfunction; obesity