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 5 μmol PCB 126/kg mouse weight (1.63 mg/kg). At 48 h 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 (49.6 mg/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.

A compromised liver alters polychlorinated biphenyl-mediated toxicity

“…Furthermore, studies on PCB exposure and hypertension are scarce, with only a few epidemiologic studies showing associations between plasma PCBs and increased risk for hypertension (Donat-Vargas et al 2015; Park et al 2016). Recently, a study by our group has reported an increase in hepatic Fmo3 expression with “dioxin-like” PCBs, thereby implicating these pollutants as risk factors for CVD (Petriello et al 2016). To reiterate those previous findings, Fmo3 was measured in our study and it was upregulated with chronic PCB126 exposure.…”

Trimethylamine N-oxide and incident atherosclerotic events in high-risk individuals with diabetes: an ACCORD trial post hoc analysis

“…After thawing, samples underwent methanol protein precipitation, filtration, and dilution in 0.1% formic acid before being passed through an Imtakt Scherzo SM-C18 column (100 mm×1 mm, 3 µm particle size, 38°C) at a flow rate of 50 µL/minute. Separation of TMAO was accomplished using an isocratic flow of 80% solvent A (H 2 O with 0.1% formic acid) and 20% solvent B (acetonitrile) for 4 min, as published by Petriello et al 21. Sample injection volume was 1 µL.…”

Benefits of basic research from the Superfund Research Program

“…UK SRP Center researchers also reported that mice exposed to PCBs had increased blood levels of trimethylamine N-oxide (TMAO), a biological marker of cardiovascular disease that is produced when the body metabolizes certain foods (185). Their work suggested a novel diet-toxicant interaction that results in increased production of TMAO (185), providing evidence that exposure to PCBs may contribute to inter-individual variability in blood TMAO levels. Based on these findings, the team analyzed a human population and observed a link between exposure to dioxin-like PCBs and elevated TMAO levels (186).…”