title: Dioxin-like pollutants increase hepatic flavin containing monooxygenase (FMO3) expression to promote synthesis of the pro-atherogenic nutrient biomarker trimethylamine N-oxide from dietary precursors.
abstract: The etiology of cardiovascular disease (CVD) is impacted by multiple modifiable and non-modifiable risk factors including dietary choices, genetic predisposition, and environmental exposures. However, mechanisms linking diet, exposure to pollutants, and CVD risk are largely unclear. Recent studies identified a strong link between plasma levels of nutrient-derived Trimethylamine N-oxide (TMAO) and coronary artery disease. Dietary precursors of TMAO include carnitine and phosphatidylcholine, which are abundant in animal-derived foods. Dioxin-like pollutants can upregulate a critical enzyme responsible for TMAO formation, hepatic flavin containing monooxygenase 3 (FMO3), but a link between dioxin-like PCBs, upregulation of FMO3, and increased TMAO has not been reported. Here, we show that mice exposed acutely to dioxin-like PCBs exhibit increased hepatic FMO3 mRNA, protein, as well as an increase in circulating levels of TMAO following oral administration of its metabolic precursors. C57BL/6 mice were exposed to 5μmol PCB 126/kg mouse weight (1.63mg/kg). At 48h post-PCB exposure, mice were subsequently given a single gavage of phosphatidylcholine dissolved in corn oil. Exposure to 5 μmole/kg PCB 126 resulted in greater than 100-fold increase in FMO3 mRNA expression, robust induction of FMO3 protein, and a 5-fold increase in TMAO levels compared with vehicle treated mice. We made similar observations in mice exposed to PCB 77 (49.6mg/kg twice); stable isotope tracer studies revealed increased formation of plasma TMAO from an orally administered precursor trimethylamine (TMA). Taken together, these observations suggest a novel diet-toxicant interaction that results in increased production of a circulating biomarker of cardiovascular disease risk.
authors.affiliation: Superfund Research Center, University of Kentucky, Lexington, KY, 40536; Department of Animal and Food Sciences, College of Agriculture, Food and Environment, University of Kentucky, Lexington, KY, 40536; Lexington Veterans Affairs Medical Center, Lexington, KY, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Petriello
authors.affiliation: Superfund Research Center, University of Kentucky, Lexington, KY, 40536; Graduate Center for Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY, 40536.
authors.forename: Jessie B
authors.initials: JB
authors.lastname: Hoffman
authors.affiliation: Superfund Research Center, University of Kentucky, Lexington, KY, 40536; Division of Cardiovascular Medicine, College of Medicine, University of Kentucky, Lexington, KY, 40536.
authors.forename: Manjula
authors.initials: M
authors.lastname: Sunkara
authors.affiliation: Superfund Research Center, University of Kentucky, Lexington, KY, 40536; Department of Animal and Food Sciences, College of Agriculture, Food and Environment, University of Kentucky, Lexington, KY, 40536.
authors.forename: Banrida
authors.initials: B
authors.lastname: Wahlang
authors.affiliation: Superfund Research Center, University of Kentucky, Lexington, KY, 40536.
authors.forename: Jordan T
authors.initials: JT
authors.lastname: Perkins
authors.affiliation: Superfund Research Center, University of Kentucky, Lexington, KY, 40536; Lexington Veterans Affairs Medical Center, Lexington, KY, USA; Division of Cardiovascular Medicine, College of Medicine, University of Kentucky, Lexington, KY, 40536.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Morris
authors.affiliation: Superfund Research Center, University of Kentucky, Lexington, KY, 40536; Department of Animal and Food Sciences, College of Agriculture, Food and Environment, University of Kentucky, Lexington, KY, 40536. Electronic address: bhennig@uky.edu.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hennig
mesh_terms: D000284:Administration, Oral; D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology* / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D002794:Choline / Q000008:administration & dosage / Q000378:metabolism*; D003903:Deuterium; D004041:Dietary Fats / Q000378:metabolism; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000633:toxicity*; D004790:Enzyme Induction / Q000187:drug effects; D018565:Food-Drug Interactions; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008744:Methylamines / Q000008:administration & dosage / Q000097:blood* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D010105:Oxygenases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000008:administration & dosage / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000008:administration & dosage / Q000633:toxicity*; D011897:Random Allocation; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015415:Biomarkers; D004041:Dietary Fats; D004785:Environmental Pollutants; D008744:Methylamines; D010713:Phosphatidylcholines; D003903:Deuterium; D011078:Polychlorinated Biphenyls; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); C005855:trimethyloxamine; C023336:trimethylamine; D002794:Choline; C023035:3,4,5,3',4'-pentachlorobiphenyl
keywords: Cardiovascular disease; FMO3; Nutrition; PCB toxicity; TMAO