Perspective Cite This: J. Agric. Food Chem. 2018, 66, 10132−10138
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Insecticide Exposure and Development of Nonalcoholic Fatty Liver Disease Jason S. Yang and Yeonhwa Park*
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Department of Food Science, University of Massachusetts Amherst, 102 Holdsworth Way, Amherst, Massachusetts 01003, United States ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is the prevalent liver disease resulting from metabolic disorder, which is highly associated with obesity and type 2 diabetes. Emerging evidence has shown that insecticide exposure disrupts lipid and glucose metabolism and results in obesity and type 2 diabetes. However, the potential impact of insecticide exposure on the liver functions related to NAFLD development is largely unknown. Thus, this perspective focused on the current knowledge of the effect of insecticides on the liver functions, particularly lipid and glucose metabolism, as well as other liver functions to correlate insecticide exposure and the development of NAFLD. KEYWORDS: NAFLD, insecticides, lipid metabolism, glucose metabolism, oxidative stress
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is associated with metabolic diseases;1 however, its role in the development of NAFLD is still mostly unknown. On the basis of recent research that exposure to some insecticides can interrupt hepatic lipid metabolism and induce hepatic lipid peroxidation and oxidative stress,8−14 it is important to evaluate the role of environmental contaminants, particularly insecticides, in the liver function, including the development of NAFLD. In this perspective, current literature reporting the effects of insecticides on the liver functions, particularly in hepatic lipid and glucose metabolism, was reviewed. This perspective provides a brief summary of the current knowledge of the potential contribution of insecticides on NAFLD and initiates further studies to determine the role and mechanism of insecticides in the development of NAFLD. Currently, there are 84 publications on the effects of insecticides on lipid and glucose metabolism. Among those, publications with markers of hepatic lipid and glucose metabolism were summarized in Table 1.
INTRODUCTION Environmental chemicals, such as insecticides, have become a growing concern because they are known to be associated with several health issues, including obesity and type 2 diabetes.1 Common routes of insecticide exposure include residues in foods, accidental or occupational exposure during farming, textiles applied with insecticides, contacting livestock treated with insecticides, and contaminated drinking water.2 Levels of insecticide exposure from the environment are generally low enough to avoid any acute impacts on health and, thus, often ignored.1 However, the worldwide usage of insecticides was still estimated at over 1 billion pounds in 2012, even with about a 25% decrease since 1998.3,4 It is likely that insecticides are ubiquitous in daily life, and the effects of persistent lowlevel insecticide residues in humans may lead to irreversible health issues. Thus, elucidating the potential impact of insecticides on human health is imperative. The liver is a key organ in the human body controlling complex functions, including lipid and glucose metabolism as well as detoxification of harmful substances, such as insecticides. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease resulting from imbalanced lipid and glucose metabolism. It is estimated that around 25% of adults worldwide are currently subject to NAFLD.5 This disease has a wide spectrum ranging from benign, simple hepatic lipid accumulation to nonalcoholic steatosis hepatitis (NASH) and the irreversible late stages of fibrosis and cirrhosis.6 With the high prevalence of NAFLD and limited treatment strategy, it is important to identify the potential causes of NAFLD for disease prevention. Hydrophobic chemicals, such as insecticides, are often deposited into stored lipid droplets in the liver and adipose tissues, which may be less likely to be metabolized and result in prolonged exposure of insecticides, especially when ingested with a diet rich in fat.7 While the prevalence of pre-existing conditions continue to rise, including metabolic diseases that cause the liver to be more susceptible, chronic insecticide exposure may also impact liver functions. It is currently known that insecticide exposure © 2018 American Chemical Society
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INSECTICIDES AND HEPATIC LIPID METABOLISM The development of NAFLD is associated with abnormal liver functions, including altered hepatic lipid and glucose homeostasis. NAFLD is also marked by the physiological change of increased hepatic lipid deposits, which originate from dietary fat, lipolysis from adipose tissue, or de novo lipogenesis. It can result from the improper regulation of hepatic lipid metabolism by insecticide exposure, which includes lipogenesis, fatty acid (FA) uptake, FA β-oxidation, and lipid secretion. Hepatic Lipogenesis. There are a few key enzymes in lipogenesis in mammals: acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and stearoyl-CoA desaturase 1 (SCD-1).6 As rate-limiting steps of de novo lipogenesis, the activities of ACC and FAS are closely regulated by several nuclear Received: Revised: Accepted: Published: 10132
June 18, 2018 August 12, 2018 September 7, 2018 September 7, 2018 DOI: 10.1021/acs.jafc.8b03177 J. Agric. Food Chem. 2018, 66, 10132−10138
10133
a
1 ↓ glucokinase, ↑ hexokinase, ↓ glycogenolysis, 1, 19, 34, ↑ hepatic glycogen, and ↑ and 36 phosphoenolpyruvate carboxykinase 1 ↓ hexokinase 37 12
↑ hepatic TG and ↑ hepatic cholesterol ↑ or = blood cholesterol, ↑ blood TG, ↑ or = blood LDL, and = blood HDL ↑ blood TG in high-fat-diet-fed males and ↓ blood TG in females
dimethoate malathion
parathion phoxim profenofos Carbamates bendiocarb carbofuran carbendazim Pyrethroids allerthrin bifenthrin cypermethrin
↓ hepatic TG and ↓ hepatic lipogenesis
Avermectins ivermectin
15
1, 29, and 39
Abbreviations: ↑, increase; ↓, decrease; =, no change; FA, fatty acid; HDL, high-density lipoprotein; LDL, low-density lipoprotein; TG, triglycerides; and VLDL, very low density lipoprotein.
↑ or = blood TG, ↑ or = blood cholesterol, ↑ hepatic lipogenesis in a high-fat diet, and ↑ liver weight
deltamethrin permethrin prallethrin Neonicotinoids imidacloprid
↑ phosphoenolpyruvate carboxykinase
25 23 1, 22, and 26 27 30 and 44 25
↑ blood TG, ↓ blood cholesterol, ↑ blood VLDL, and = blood HDL and LDL ↓ hepatic FA oxidation ↑ blood cholesterol, TG, and LDL-C, ↑ blood VLDL, and ↓ blood HDL ↑ blood cholesterol, TG, LDL, and VLDL and ↓ blood HDL ↑ blood TG and cholesterol in high-fat-diet-fed males but not in a low-fat diet or females ↑ blood TG, ↓ blood cholesterol, ↑ blood VLDL, and = blood HDL and LDL
18 21 1
↑ hepatic TG ↑ blood TG ↑ blood TG
↑ hepatic glucose
↓ hepatic glycogen and ↑ gluconeogenesis ↑ glycogenolysis, ↑ glycogen synthesis, ↓ hepatic glycogen, ↓ glucokinase activity, and ↓ hepatic glycogen
↑ or = blood TG, ↑, ↓, or = cholesterol, ↓or = blood HDL, and ↑ blood LDL
diazinon dichlorvos
↑ blood VLDL
1 1, 17, and 20 1 1 and 33
2,2′-bis(4-chlorophenyl)-1,1,1-trichloroethane (DDT) dieldrin hexachlorobezene (HCB) β-hexachlorocyclohexane (β-HCH) γ-hexachlorocyclohexane (γ-HCH) oxychlordane trans-nonachlor (TNC) mirex Organophosphorus acephate chlorpyrifos ↓ hepatic glycogen
reference
↑ hepatic TG and ↑ hepatic cholesterol ↑ or = blood TG, ↑ blood cholesterol, and ↑ hepatic lipogenesis
glucose metabolism
1, 16, 28, and 42 1 and 43 1 42 16 42 1 and 42 42 42
lipid metabolism ↑ hepatic TG, ↑ hepatic FA uptake and oxidation in a high-fat diet, ↓ hepatic lipogenesis in a high-fat diet, ↓ gluconeogenesis in a high-fat diet ↑ or = blood TG and cholesterol, ↓ blood HDL, and ↑ VLDL (APO-B secretion) ↑ blood TG, ↓ blood cholesterol (in sedentary rats), and ↑ blood cholesterol (in exercised rats) ↑ hepatic TG and = blood cholesterol ↑ hepatic glycogen ↑ or = blood TG, ↑ blood cholesterol, ↓ or = blood HDL, and ↑ liver weight = blood TG, = blood HDL, ↑ blood VLDL, and ↑ hepatic TG and lipogenesis = blood TG and = blood HDL ↑ blood TG and = blood HDL = blood TG and = blood HDL = blood TG and = blood HDL
Organochlorines 2,2′-bis(4-chlorophenyl)-1,1-dichloroethylene (DDE)
insecticide
Table 1. Effects of Insecticide on Hepatic Lipid and Glucose Metabolisma
Journal of Agricultural and Food Chemistry Perspective
DOI: 10.1021/acs.jafc.8b03177 J. Agric. Food Chem. 2018, 66, 10132−10138
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increased plasma TG in humans, while cypermethrin and deltamethrin increased blood TG in rodents.1,22 Taken together, a wide range of insecticides have been reported to influence the balance of circulating TG, which may lead to increased hepatic FA uptake. FA β-Oxidation. The catabolic reaction of breakdown FAs to acetyl-CoA (FA β-oxidation) occurs to produce adenosine triphosphate (ATP) when there is an energy demand. Once FAs are converted into acyl-CoA forms in the cytosol, FA βoxidation can take place in the mitochondria, peroxisome, and/ or endoplasmic reticulum (ER). However, only short- and medium-chain FAs can cross the membranes of mitochondria freely. Long-chain FAs require the assistance of carnitine palmitoyltransferase I (CPT1) to cross the mitochondrial membranes for FA β-oxidation. Thus, the liver isoform CPT1α is considered as the rate-limiting enzyme of mitochondria FA β-oxidation in hepatocytes, and the activity of CPT1α can be allosterically inhibited by malonyl-CoA, an intermediate product from de novo lipogenesis.6 PPARα, which can be activated by FAs, is known to promote FA β-oxidation as it regulates the gene expression of CPT1α.6 There is no direct evidence suggesting the ability of insecticides to inhibit PPARα, while bifenthrin (a pyrethroid) was reported to decrease CPT1α gene expressions in HepG2 cells (Table 1).23 Because de novo lipogenesis is an inhibitory pathway for FA oxidation, we can infer that insecticides that increase hepatic de novo lipogenesis can potentially suppress FA β-oxidation,6 which then results in increased fat accumulation and steatosis. Hepatic Lipid Secretion. Stored hepatic lipid is repackaged into very low-density lipoprotein (VLDL), consisting of TG, cholesterol, and apolipoproteins (APOs) to carry TG in the bloodstream. Hepatic lipid secretion is a unique way of the liver to manage excessive lipid or a response to energy needs from other parts of the body. As the VLDL circulates in the body, lipids in VLDL can be transferred to peripheral tissues. The major APOs present in VLDL are APOE, APO-C1, APO-C2, and APO-B100, which not only contribute to the structure of VLDL as a result of their amphiphilic properties but also serve as important markers to be recognized by membrane receptors that are involved in several signaling pathways, especially those in maintaining lipid homeostasis.24 In NAFLD or NASH, dysregulation of hepatic lipid secretion can result in an overproduction of VLDL, which is considered as an atherogenic and inflammatory factor.24 Insecticide exposure has been demonstrated to disrupt normal circulatory lipid in several manners, as shown in Table 1. In human studies, it has been reported that pyrethroids, allethrin and prallethrin, increased the serum VLDL level.1,25 In addition, profenofos (an organophosphorus) and deltamethrin (a pyrethroid) treatments were reported to increase the level of blood VLDL, although cypermethrin (a pyrethroid) decreased blood VLDL in rats.12,26,27 It was also indicated that transgenic mice with human APO-E3 were more vulnerable to the exposure of an organophosphorus insecticide, chlorpyrifos.1 Consistently, others reported that DDE increased the secretion of APO-B, one of the major APOs present in VLDL in rodent hepatocytes, suggesting a potential role of DDE in increased hepatic lipid secretion through VLDL.28 VLDL secretion is known to be regulated by insulin, which suppresses lipid secretion from the liver.6 Thus, elevated levels of blood VLDL associated with insecticide exposure may be an indirect effect of insulin resistance and serve as an potential factor of NAFLD development.
receptors and transcriptional factors, including sterol response element-binding protein 1c (SREBP-1c), peroxisome proliferator-activated receptor γ (PPARγ), and farnesoid X receptor (FXR, the bile acid receptor).15 During lipogenesis, ACC and FAS elongate acetyl-CoA or malonyl-CoA into the hydrocarbons and SCD-1 desaturates to form monounsaturated FAs. Increased hepatic de novo lipogenesis, described as lipotoxicity, is known to be one of the major causes of increased hepatic fat accumulation in NAFLD.6 It is therefore considered as a critical factor of the pathogenesis of NAFLD. Various insecticides are known to affect nuclear receptors and transcription factors, including those for hepatic de novo lipogenesis (Table 1). Previously, pyrethrins were reported to mediate the activity of PPARα.1 Organochloride insecticides, β-hexachlorocyclohexane (β-HCH) and dichlorodiphenyldichloroethylene (DDE), increased hepatic lipogenesis by upregulating the mRNA expression of ACC and FAS.16 Others reported that an organophosphorus insecticide, chlorpyrifos, increased hepatic lipogenesis in hepatocytes17 and a carbamate insecticide, bendiocarb, increased the number of lipid droplets in the rabbit liver, suggesting elevated hepatic lipogenesis.18 In addition, it has been suggested that imidacloprid, a neonicotinoid insecticide, induced hepatic lipogenesis by increasing the activity of ACC in the mouse liver.1 Overall, research findings indicate that various insecticides may potentially alter hepatic de novo lipogenesis and, hence, may contribute to the pathogenesis of NAFLD. FA Uptake. In addition to hepatic lipogenesis, direct uptake of FAs from the plasma pool is another major source of hepatic FAs and can contribute to accumulating lipid droplets in the liver. Circulating FAs originate mainly from lipolysis of stored triglycerides (TG) in adipose tissues6 and can be elevated in response to the energy demands. The uptake of plasma FAs into the hepatocytes is a facilitated process that requires fatty acid transport proteins (FATPs), fatty-acid-binding proteins (FABPs), and fatty acid translocase (CD36/FAT, a scavenger receptor). FAs will then undergo oxidation for energy or reesterification to form TG. FA uptake is regulated by various signals based on the nutritional status, including two hormones, insulin and glucagon. In addition, hepatic FA uptake can be triggered by high levels of plasma lipids, such as TG. Therefore, hypertriglyceridemia is considered closely related to the induction of NAFLD, especially in patients with type 2 diabetes, as a result of dysregulation of peripheral lipolysis resulting from insulin resistance.6 Although there is no direct evidence suggesting that insecticides can promote the expression of FATPs, FABPs, and CD36, a number of studies reported that various insecticides are associated with hypertriglyceridemia that may lead to increased hepatic FA uptake (Table 1): low doses of organochlorine insecticides have been shown to be associated with the incidence of hypertriglyceridemia among healthy adults,1 while other organochlorine insecticides, including DDE, dichlorodiphenyltrichloroethane (DDT), hexachlorobenzene (HCB), and oxychlordane, were reported to be positively associated with blood TG levels in humans.1 Among organophosphorus insecticides, malathion treatment resulted in a higher level of blood TG in rats,19 chlorpyrifos elevated blood TG in male mice,20 and diazinon increased blood TG and cholesterol in mice.1 In addition, a carbamate insecticide, carbofuran, was found to increase plasma TG in mice,21 while pyrethroid insecticides have been reported to influence the blood TG level. In particular, allethrin and prallethrin 10134
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content in the liver.33 Another organophosphorus insecticide, malathion, has also been found to decrease hepatic glucokinase gene expression.34 Although it has been reported that glucokinase mRNA expression is associated with de novo lipogenesis and the liver triglyceride content,35 the activity of glucokinase is also associated with glycogen synthesis, where its suppression is connected to NAFLD.6 Overall, there is no direct evidence that the hepatic glucose uptake by GLUT2 is influenced by insecticide exposure, although downstream pathways in hepatic glucose metabolism may be influenced, which can thereby contribute to an altered glucose homeostasis. Glycogenosis. The liver is the major site of glycogen synthesis, a series of anabolic reactions that transform glucose into glycogen.6 It was suggested that hepatic fat accumulation decreased glycogen synthesis and a lack of glycogen could further contribute to the development of fatty liver diseases.6 A variety of hexokinases and glycogen synthases are involved in glycogen synthesis. Glucose-6-phosphate acts as an allosteric activator of glycogen synthase, and insulin signaling inhibits the activity of glycogen synthase kinase 3, a kinase that inactivates glycogen synthase, therefore resulting in glycogen synthesis. Inconsistent findings with regard to the effects of insecticides on hexokinases have been reported. In particular, among organophosphorus insecticides, malathion increased the activity of hexokinase,36 while phoxim decreased the activity of hexokinase in the rat liver.37 In several previous studies, insecticide exposure was recognized to cause insulin resistance and disrupt insulin signaling,1 which suggests that insecticide exposure may also affect the regulation of glycogenosis. Overall, these studies suggest that insecticide exposure can alter glycogenosis through directly regulating activities of key enzymes or indirectly through compromising insulin signaling. Glycogenolysis. Glycogenolysis, which refers to the breakdown of glycogen, is an important process to supply energy during an energy demand and before gluconeogenesis takes place in an extended fasting state (the next section). Glycogenolysis is tightly regulated by several enzymes, including glycogen phosphorylase, phosphoglucomutase, and glucose-6 phosphatase.6 Elevated glycogenolysis has been shown to be associated with fatty liver diseases.6 Previously, an organophosphorus insecticide, dichlorvos, has been reported to increase glycogenolysis and deplete the glycogen content in the rat liver.1 Consistently, several insecticide-induced disturbances of glycogenolysis in freshwater fish models were reported.38 These suggested the potential effect of insecticides on glycogenolysis, which may further contribute to NAFLD development. Gluconeogenesis. When stored glycogen is no longer sufficient to support the energy needs as well as maintain blood glucose levels, gluconeogenesis starts to produce glucose with alternative substrates to carbohydrates.6 This process mainly occurs in the liver but can also be found in the kidney.6 Phosphoenolpyruvate carboxykinase (PEPCK) plays an important role in gluconeogenesis because it participates in the conversion of oxaloacetate to phosphoenolpyruvate, and the activity of PEPCK generally represents gluconeogenesis. Hepatic gluconeogenesis was reported to increase in NAFLD patients and positively correlate to the accumulation of intrahepatic triglycerides.6 The elevated gluconeogenesis in NAFLD is considered as a complex result of lipotoxicity and insulin resistance, while insulin resistance also suppresses
Interactions between Insecticides and Dietary Fats. Most of the major insecticides in use are hydrophobic to facilitate penetrations into insect bodies. Thus, insecticide residues in foods are more likely to be associated with lipophilic components and absorbed along with dietary fats into the body. Therefore, a high-fat diet may enhance the absorption of lipophilic insecticides. This was supported by previous studies reporting that relatively low levels of insecticide exposure, including malathion, enhanced the effects of high-fat-diet-induced adiposity,1,29,30 hyperglycemia, insulin resistance, and hepatic lipid dysfunction, but not with a low-fat diet in mice (Table 1).1 The metabolism of insecticides mainly relies on the cytochrome P450 system in hepatocytes for phase I detoxification of insecticides, which is a complex enzyme system regulated by several extracellular signals, such as oxidative stress.31 Dietary fats are absorbed in the intestine and packed into nascent chylomicron to travel in the vascular system and arrive at the liver after the FAs are partially taken up by the extrahepatic tissues, including adipose tissues.6 Thus, it is more likely that hydrophobic insecticides are deposited in adipose tissues and less likely to be metabolized as a result of limited access for further metabolism. Moreover, it has been reported that gene expressions of the hepatic phase I and II enzymes were reduced by 30−60% in high-fat-diet-fed mice.31 Therefore, a high-fat diet can cause the liver to be more susceptible to further disruptions of hepatic metabolism induced by insecticides, elevating the risk of NAFLD associated with insecticide exposure.
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INSECTICIDES AND HEPATIC GLUCOSE METABOLISM Although the classic phenotypic manifestation of increased liver TG accumulations in NAFLD is primarily contributed to an imbalanced hepatic lipid metabolism, impairments in glucose metabolism also plays an important role in the disease development. NAFLD has been ranked as a top complication in patients with type 2 diabetes.32 The main functions of the liver in maintaining glucose homeostasis can be classified into glucose uptake, glycogenosis, glycogenolysis, and gluconeogenesis. These functions not only regulate the utilization and storage of glucose but also influence the lipid metabolism, as discussed in the previous section. Glucose Uptake. The liver regulates the blood glucose level by uptaking plasma glucose into hepatocytes mainly facilitated by glucose transporter type 2 (GLUT2), a highly expressed glucose transporter only in hepatocytes. The main function of GLUT2 is to respond to high postprandial blood sugar, which then transforms glucose into glycogen for storage that is independent of the insulin level. Although GLUT2 has a relatively low binding affinity to glucose, it has a high capacity for transporting glucose from circulation. Once in hepatocytes, glucokinase, a rate-limiting enzyme, converts glucose continuously to glucose-6-phosphate, which is subsequently used for energy production or glycogen synthesis.6 The activity of glucokinase is not influenced by feedback suppressions, unlike other forms of hexokinases that are critical for postprandial glycogen formation in the hepatocyte.6 Certain insecticides are known to disrupt insulin signaling and hepatic glucose metabolism by affecting glucokinase activities, as shown in Table 1. It has been reported that exposure to dichlorvos, an organophosphorus insecticide, results in reduced glucokinase activities and a lowered glycogen 10135
DOI: 10.1021/acs.jafc.8b03177 J. Agric. Food Chem. 2018, 66, 10132−10138
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the basis of the current literature, exposure to insecticides is linked to disruption of hepatic lipid and glucose metabolism as well as other liver functions, which may contribute to the development of NAFLD. This perspective may serve as a reference for the role of insecticides in the development of NAFLD, which will initiate future research to determine the pathophysiology of insecticides on hepatic dysfunctions and to develop potential prevention/treatment strategies of NAFLD.
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OTHER LIVER FUNCTIONS
AUTHOR INFORMATION
Corresponding Author
*Telephone: 413-545-1018. Fax: 413-545-1262. E-mail:
[email protected].
Besides lipid and glucose metabolism, the liver has several other critical functions, such as bile acid metabolism and generation of an endogenous antioxidant, which also contributes to modulating lipid and glucose metabolism. These liver functions may be altered during NAFLD as well as other NAFLD-related diseases, including hepatitis and hepatic carcinogenesis. Bile Acid Metabolism. The metabolism of bile acids is a unique function majorly performed by the liver. Most of the bile acids secreted for lipid digestion are reabsorbed in the intestine and return to the liver through the enterohepatic circulation. The bile acid receptor, farnesoid X receptor (FXR), is a nuclear receptor with the natural ligand of bile acids that is highly expressed in the liver and the intestine. FXR plays an essential role in both energy homeostasis and lipid metabolism because it regulates not only bile acid synthesis but also lipogenesis, FA oxidation, FA secretion, and gluconeogenesis.15 FXR−bile acid interaction represents lipid intakes and triggers corresponding responses. This includes an upregulation of PPARα that promotes FA oxidation and inhibits the transcriptional activity of SREBP-1c, which further results in reduced lipogenesis.15 Additionally, APO-C2, one of the key apolipoproteins of VLDL, was also increased by FXR, which can lead to increased hepatic lipid secretions. Certain insecticides have been discovered as specific agonists of FXR. Avermectins, a group of insecticides used for parasites and insects by targeting through the glutamate-gated chloride channel, act as an ligand of FXR, resulting in reduced fat accumulation in the mouse liver (Table 1).15 Thus, it is suggested to target FXR as a potential treatment of NAFLD; however, it is not known currently if other insecticides can influence FXR to alter hepatic lipid metabolism. Oxidative Stress and Liver Damage. As a major pathogenesis factor of NAFLD, FA overload would influence the cellular oxidative status. The alteration of FA oxidation during FA overload is considered an important mechanism of lipotoxicity, oxidative stress, ER stress, insulin resistance, lipogenesis, and apoptosis, which leads to an irreversible progression of hepatosteatosis to hepatitis in NAFLD.6 There are reports that insecticide exposure and increased oxidative stress, including the exposure of cypermethrin, deltamethrin, imidacloprid, profenofos, malathion, chlorpyrifos, and diazinon, all induced hepatic oxidative stress in rodents.1,10−14,40,41 Thus, insecticide-induced oxidative stress may contribute to their effects in the pathogenesis of NAFLD as well.
ORCID
Yeonhwa Park: 0000-0001-9727-0899 Funding
This project was supported in part by the Department of Food Science and the F. J. Francis Endowment at the University of Massachusetts Amherst. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors thank Stephanie Choi for assistance with manuscript preparation. REFERENCES
(1) Xiao, X.; Clark, J. M.; Park, Y. Potential contribution of insecticide exposure and development of obesity and type 2 diabetes. Food Chem. Toxicol. 2017, 105, 456−474. (2) Fenske, R. A.; Elkner, K. P. Multi-route exposure assessment and biological monitoring of urban pesticide applicators during structural control treatments with chlorpyrifos. Toxicol. Ind. Health 1990, 6, 349−71. (3) Donaldson, D.; Kiely, T.; Grube, A. Pesticides Industry Sales and Usage 1998−1999 Market Estimates; United States Environmental Protection Agency (U.S. EPA): Washington, D.C., 2002; EPA-733-R02-OOI, https://nepis.epa.gov/Exe/ZyPURL.cgi?Dockey= 200001G5.txt. (4) Atwood, D.; Paisley-Jones, C. Pesticides Industry Sales and Usage 2008−2012 Market Estimates; United States Environmental Protection Agency (U.S. EPA): Washington, D.C., 2017; https://www.epa. gov/sites/production/files/2017-01/documents/pesticides-industrysales-usage-2016_0.pdf. (5) Younossi, Z. M.; Koenig, A. B.; Abdelatif, D.; Fazel, Y.; Henry, L.; Wymer, M. Global epidemiology of nonalcoholic fatty liver diseaseMeta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016, 64, 73−84. (6) Bechmann, L. P.; Hannivoort, R. A.; Gerken, G.; Hotamisligil, G. S.; Trauner, M.; Canbay, A. The interaction of hepatic lipid and glucose metabolism in liver diseases. J. Hepatol. 2012, 56, 952−964. (7) Zhang, R. J.; Wu, W. H.; Zhang, Z. P.; Park, Y.; He, L. L.; Xing, B. S.; McClements, D. J. Effect of the Composition and Structure of Excipient Emulsion on the Bioaccessibility of Pesticide Residue in Agricultural Products. J. Agric. Food Chem. 2017, 65, 9128−9138. (8) Tuzmen, N.; Candan, N.; Kaya, E.; Demiryas, N. Biochemical effects of chlorpyrifos and deltamethrin on altered antioxidative defense mechanisms and lipid peroxidation in rat liver. Cell Biochem. Funct. 2008, 26, 119−24. (9) Mostafalou, S.; Eghbal, M. A.; Abdollahi, M.; Mohammadi, S. Oxidative stress and inflammation in malathion disrupted hepatic glucose metabolism. Toxicol. Lett. 2012, 211, S174−S174. (10) Giray, B.; Gurbay, A.; Hincal, F. Cypermethrin-induced oxidative stress in rat brain and liver is prevented by Vitamin E or allopurinol. Toxicol. Lett. 2001, 118, 139−146.
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CONCLUSION The development and progression of NAFLD are results from multiple factors, such as diet, life style, pre-existing health conditions, and/or diseases elevating the risk of NAFLD. On 10136
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DOI: 10.1021/acs.jafc.8b03177 J. Agric. Food Chem. 2018, 66, 10132−10138
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DOI: 10.1021/acs.jafc.8b03177 J. Agric. Food Chem. 2018, 66, 10132−10138
