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J Nutr Biochem. 2016 Jul;33:145-53. doi: 10.1016/j.jnutbio.2016.03.016. Epub 2016 Apr 1.

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.

Author information

1
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.
2
Superfund Research Center, University of Kentucky, Lexington, KY, 40536; Graduate Center for Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY, 40536.
3
Superfund Research Center, University of Kentucky, Lexington, KY, 40536; Division of Cardiovascular Medicine, College of Medicine, University of Kentucky, Lexington, KY, 40536.
4
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.
5
Superfund Research Center, University of Kentucky, Lexington, KY, 40536.
6
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.
7
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.

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.

KEYWORDS:

Cardiovascular disease; FMO3; Nutrition; PCB toxicity; TMAO

PMID:
27155921
PMCID:
PMC4893916
DOI:
10.1016/j.jnutbio.2016.03.016
[Indexed for MEDLINE]
Free PMC Article

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