Tebuconazole Fungicide Induces Lipid Accumulation and Oxidative Stress in HepG2 Cells.

Hyuk-Cheol Kwon,Yea-Ji Kim,Dong-Wook Kim,Do-Hyun Kim,Chang-Hee Jeong,Jong-Hyun Han,Sung-Gu Han,Dong-Min Shin,Su-Jin Lim

doi:10.3390/foods10102242

Abstract

Tebuconazole (TEB), a triazole fungicide, is frequently applied to agriculture for the increase of food production. Although TEB causes liver toxicity, its effects on cellular lipid accumulation are rarely investigated. Therefore, this study aimed to study the effects of TEB on lipid metabolism and accumulation in HepG2 cells. HepG2 cells were exposed to 0–320 µM TEB for 1–24 h. TEB (20–80 µM, 24 h)-treated cells showed lipid accumulation. Further, TEB (20–80 µM, 1–12 h) increased the nuclear translocation of peroxisome proliferator-activated receptors and the expression of lipid uptake and oxidation-related markers such as cluster of differentiation 36, fatty acid transport protein (FATP) 2, FATP5, and carnitine palmitoyltransferase 1. Oxidative stress levels in TEB-treated cells (20–80 µM, 24 h) were higher, compared to those in the control. TEB (20–80 µM, 24 h) also induced the loss of mitochondrial membrane potential and lower levels of microsomal triglyceride transfer protein in the cells. Thus, TEB can induce lipid accumulation by altering the expression of lipid-metabolizing molecules and can therefore impair lipid metabolism. Our data suggest that human exposure to TEB may be a risk factor for non-alcoholic fatty liver disease.

Highlights

Tebuconazole (TEB), a triazole fungicide, is often applied to agriculture for the increases of crop yield and food production [1]
A previous study showed that insecticide exposure impaired lipid metabolism, thereby resulting in the development of non-alcoholic fatty liver disease (NAFLD) [21]
Recent studies have reported that fungicides such as propiconazole, flutriafol, cyproconazole, dazomet, fluazinam, hexaconazole, pyrasulfotole metabolite, and myclobutanil can cause NAFLD pathogenesis [22,23,24,25]

Summary

Introduction

Tebuconazole (TEB), a triazole fungicide, is often applied to agriculture for the increases of crop yield and food production [1]. Previous studies have reported that TEB residues were detected in stream and surface water at concentrations of up to 175–200 μg/L and that the risk value for the consumer chronically exposed to TEB residues in agricultural and animal origin commodities had reached up to 9.65 mg/kg [4,5] Considering that both the acceptable daily intake and acute reference dose for TEB are 0.03 mg/kg body weight, and that human exposure to TEB residues may be frequent, TEB has the potential to cause toxicity in the human body, including hepatotoxicity [4]. CYP catalytic cycles for xenobiotic biotransformation (e.g., TEB) generate various reactive oxygen species (ROS), including hydrogen peroxide and superoxide anion [7] Such ROS generation causes a redox imbalance and oxidative stress in the liver [7]. An imbalance of hepatic lipid homeostasis has induced lipid accumulation in the liver and subsequently caused pathogenic conditions, such as NAFLD [10]

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