SpringerLink
Log in

Mechanisms of Environmental Contributions to Fatty Liver Disease

  • Mechanisms of Toxicity (JR Richardson, Section Editor)
  • Published:
Current Environmental Health Reports Aims and scope Submit manuscript

Abstract

Purpose

Fatty liver disease (FLD) affects over 25% of the global population and may lead to liver-related mortality due to cirrhosis and liver cancer. FLD caused by occupational and environmental chemical exposures is termed “toxicant-associated steatohepatitis” (TASH). The current review addresses the scientific progress made in the mechanistic understanding of TASH since its initial description in 2010.

Recent Findings

Recently discovered modes of actions for volatile organic compounds and persistent organic pollutants include the following: (i) the endocrine-, metabolism-, and signaling-disrupting chemical hypotheses; (ii) chemical-nutrient interactions and the “two-hit” hypothesis. These key hypotheses were then reviewed in the context of the steatosis adverse outcome pathway (AOP) proposed by the US Environmental Protection Agency.

Summary

The conceptual understanding of the contribution of environmental exposures to FLD has progressed significantly. However, because this is a new research area, more studies including mechanistic human data are required to address current knowledge gaps.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

ACHS:

Anniston Community Health Survey

AhR:

aryl hydrocarbon receptor

ALT:

alanine aminotransferase

AMPK:

AMP-activated protein kinase

AOP:

adverse outcome pathway

ASH:

alcoholic steatohepatitis

ATSDR:

Agency for Toxic Substances and Disease Registry

CAR:

constitutive androstane receptor

CK2:

casein kinase 2

CREB-1:

cyclic AMP-responsive element-binding protein 1

EDCs:

endocrine-disrupting chemicals

EGFR:

epidermal growth factor receptor

EPA:

Environmental Protection Agency

ER:

endoplasmic reticulum

FLD:

fatty liver disease

FXR:

farnesoid × receptor

FGF-21:

fibroblast growth factor-21

GLP-1:

glucagon-like peptide-1

HNF4α:

hepatocyte nuclear factor 4-alpha

IR:

insulin resistance

MCD:

methionine-choline deficient

MDCs:

metabolism-disrupting chemicals

MIEs:

molecular initiating events

mTOR:

mammalian target of rapamycin

NAFLD:

nonalcoholic fatty liver disease

NASH:

nonalcoholic steatohepatitis

NDL:

non-dioxin like

NIOSH:

National Institute for Occupational Safety and Health

NPL:

National Priority List

NRF2:

nuclear factor-erythroid 2–related factor

PCBs:

polychlorinated biphenyls

PCE:

perchloroethylene

PFAS:

perfluoroalkyl substances

POPs:

persistent organic pollutants

PNPLA3:

patatin-like phospholipase domain-containing protein 3

PPARα:

peroxisome proliferator-activated receptor α

PVC:

polyvinyl chloride

PXR:

pregnane × receptor

ROS:

reactive oxygen species

SDCs:

signaling-disrupting chemicals

STAT3:

signal transducer and activator of transcription 3

TASH:

toxicant-associated steatohepatitis

TCDD:

2,3,7,8-tetrachlorodibenzodioxin

TGF-β:

transforming growth factor β

UPR:

unfolded protein response

VOCs:

volatile organic compounds

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Tapper EB, Parikh ND. Mortality due to cirrhosis and liver cancer in the United States, 1999-2016: observational study. BMJ. 2018;362:k2817. https://doi.org/10.1136/bmj.k2817.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Fabbrini E, Magkos F. Hepatic steatosis as a marker of metabolic dysfunction. Nutrients. 2015;7(6):4995–5019. https://doi.org/10.3390/nu7064995.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology (Baltimore, Md). 2016;64(1):73–84. https://doi.org/10.1002/hep.28431.

    Article  Google Scholar 

  4. Cave M, Falkner KC, Ray M, Joshi-Barve S, Brock G, Khan R, et al. Toxicant-associated steatohepatitis in vinyl chloride workers. Hepatology (Baltimore, Md). 2010;51(2):474–81. https://doi.org/10.1002/hep.23321.

    Article  CAS  Google Scholar 

  5. Al-Eryani L, Wahlang B, Falkner KC, Guardiola JJ, Clair HB, Prough RA, et al. Identification of environmental chemicals associated with the development of toxicant-associated fatty liver disease in rodents. Toxicol Pathol. 2014. https://doi.org/10.1177/0192623314549960.

  6. Shan Q, Huang F, Wang J, Du Y. Effects of co-exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin and polychlorinated biphenyls on nonalcoholic fatty liver disease in mice. Environ Toxicol. 2015;30(12):1364–74. https://doi.org/10.1002/tox.22006.

    Article  CAS  PubMed  Google Scholar 

  7. Kopec AK, Boverhof DR, Nault R, Harkema JR, Tashiro C, Potter D, et al. Toxicogenomic evaluation of long-term hepatic effects of TCDD in immature, ovariectomized C57BL/6 mice. Toxicol Sci. 2013;135(2):465–75. https://doi.org/10.1093/toxsci/kft156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Matsubara T, Tanaka N, Krausz KW, Manna SK, Kang DW, Anderson ER, et al. Metabolomics identifies an inflammatory cascade involved in dioxin- and diet-induced steatohepatitis. Cell Metab. 2012;16(5):634–44. https://doi.org/10.1016/j.cmet.2012.10.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Angrish MM, Mets BD, Jones AD, Zacharewski TR. Dietary fat is a lipid source in 2,3,7,8-tetrachlorodibenzo-rho-dioxin (TCDD)-elicited hepatic steatosis in C57BL/6 mice. Toxicol Sci. 2012;128(2):377–86. https://doi.org/10.1093/toxsci/kfs155.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Han M, Liu X, Liu S, Su G, Fan X, Chen J, et al. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces hepatic stellate cell (HSC) activation and liver fibrosis in C57BL6 mouse via activating Akt and NF-kappaB signaling pathways. Toxicol Lett. 2017;273:10–9. https://doi.org/10.1016/j.toxlet.2017.03.013.

    Article  CAS  PubMed  Google Scholar 

  11. Duval C, Teixeira-Clerc F, Leblanc AF, Touch S, Emond C, Guerre-Millo M, et al. Chronic exposure to low doses of dioxin promotes liver fibrosis development in the C57BL/6J diet-induced obesity mouse model. Environ Health Perspect. 2017;125(3):428–36. https://doi.org/10.1289/EHP316.

    Article  CAS  PubMed  Google Scholar 

  12. Kumar J, Lind L, Salihovic S, van Bavel B, Ingelsson E, Lind PM. Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample of men and women. Environ Res. 2014;134:251–6. https://doi.org/10.1016/j.envres.2014.07.023.

    Article  CAS  PubMed  Google Scholar 

  13. Yorita Christensen KL, Carrico CK, Sanyal AJ, Gennings C. Multiple classes of environmental chemicals are associated with liver disease: NHANES 2003-2004. Int J Hyg Environ Health. 2013;216(6):703–9. https://doi.org/10.1016/j.ijheh.2013.01.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lee DH, Jacobs DR Jr. Association between serum concentrations of persistent organic pollutants and gamma glutamyltransferase: results from the National Health and Examination Survey 1999-2002. Clin Chem. 2006;52(9):1825–7. https://doi.org/10.1373/clinchem.2006.071563.

    Article  CAS  PubMed  Google Scholar 

  15. • Shi H, Jan J, Hardesty JE, Falkner KC, Prough RA, Balamurugan AN, et al. Polychlorinated biphenyl exposures differentially regulate hepatic metabolism and pancreatic function: implications for nonalcoholic steatohepatitis and diabetes. Toxicol Appl Pharmacol. 2019;363:22–33. https://doi.org/10.1016/j.taap.2018.10.011 This study demonstrated how PCBs elicited varying effects on the liver and pancreas depending on their dioxin-like or non-dioxin-like nature.

    Article  CAS  PubMed  Google Scholar 

  16. Wahlang B, Song M, Beier JI, Cameron Falkner K, Al-Eryani L, Clair HB, et al. Evaluation of Aroclor 1260 exposure in a mouse model of diet-induced obesity and non-alcoholic fatty liver disease. Toxicol Appl Pharmacol. 2014;279(3):380–90. https://doi.org/10.1016/j.taap.2014.06.019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gadupudi GS, Klaren WD, Olivier AK, Klingelhutz AJ, Robertson LW. PCB126-induced disruption in gluconeogenesis and fatty acid oxidation precedes fatty liver in male rats. Toxicol Sci. 2016;149(1):98–110. https://doi.org/10.1093/toxsci/kfv215.

    Article  CAS  PubMed  Google Scholar 

  18. Wahlang B, Falkner KC, Gregory B, Ansert D, Young D, Conklin DJ, et al. Polychlorinated biphenyl 153 is a diet-dependent obesogen that worsens nonalcoholic fatty liver disease in male C57BL6/J mice. J Nutr Biochem. 2013;24(9):1587–95. https://doi.org/10.1016/j.jnutbio.2013.01.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wahlang B, Barney J, Thompson B, Wang C, Hamad OM, Hoffman JB, et al. Editor’s highlight: PCB126 exposure increases risk for peripheral vascular diseases in a liver injury mouse model. Toxicol Sci. 2017;160(2):256–67. https://doi.org/10.1093/toxsci/kfx180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wahlang B, Perkins JT, Petriello MC, Hoffman JB, Stromberg AJ, Hennig B. A compromised liver alters polychlorinated biphenyl-mediated toxicity. Toxicology. 2017;380:11–22. https://doi.org/10.1016/j.tox.2017.02.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. •• Wahlang B, Prough RA, Falkner KC, Hardesty JE, Song M, Clair HB, et al. Polychlorinated biphenyl-xenobiotic nuclear receptor interactions regulate energy metabolism, behavior, and inflammation in non-alcoholic-steatohepatitis. Toxicol Sci. 2016;149(2):396–410. https://doi.org/10.1093/toxsci/kfv250 This manuscript demonstrated that CAR and PXR knockout mice were not protected against non-dioxin-like PCB exposures, suggesting other PCB-mediated targets.

    Article  CAS  PubMed  Google Scholar 

  22. •• Clair HB, Pinkston CM, Rai SN, Pavuk M, Dutton ND, Brock GN, et al. Liver disease in a residential cohort with elevated polychlorinated biphenyl exposures. Toxicol Sci. 2018;164(1):39–49. https://doi.org/10.1093/toxsci/kfy076 This cohort study reported that PCB exposures were associated with a high prevalence of necrotic liver disease, insulin resistance, and pro-inflammatory cytokines, consistent with TASH.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Cave M, Appana S, Patel M, Falkner KC, McClain CJ, Brock G. Polychlorinated biphenyls, lead, and mercury are associated with liver disease in American adults: NHANES 2003-2004. Environ Health Perspect. 2010;118(12):1735–42. https://doi.org/10.1289/ehp.1002720.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Serdar B, LeBlanc WG, Norris JM, Dickinson LM. Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides (OCPs) on immune cells and blood biochemistry measures: a cross-sectional assessment of the NHANES 2003-2004 data. Environ Health. 2014;13:114. https://doi.org/10.1186/1476-069X-13-114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yu ML, Guo YL, Hsu CC, Rogan WJ. Increased mortality from chronic liver disease and cirrhosis 13 years after the Taiwan “yucheng” (“oil disease”) incident. Am J Ind Med. 1997;31(2):172–5.

    Article  CAS  Google Scholar 

  26. Li MC, Tsai PC, Chen PC, Hsieh CJ, Leon Guo YL, Rogan WJ. Mortality after exposure to polychlorinated biphenyls and dibenzofurans: 30 years after the “Yucheng accident”. Environ Res. 2013;120:71–5. https://doi.org/10.1016/j.envres.2012.09.003.

    Article  CAS  PubMed  Google Scholar 

  27. Li MC, Chen PC, Tsai PC, Furue M, Onozuka D, Hagihara A, et al. Mortality after exposure to polychlorinated biphenyls and polychlorinated dibenzofurans: a meta-analysis of two highly exposed cohorts. Int J Cancer. 2015;137(6):1427–32. https://doi.org/10.1002/ijc.29504.

    Article  CAS  PubMed  Google Scholar 

  28. Tan X, **e G, Sun X, Li Q, Zhong W, Qiao P, et al. High fat diet feeding exaggerates perfluorooctanoic acid-induced liver injury in mice via modulating multiple metabolic pathways. PLoS One. 2013;8(4):e61409. https://doi.org/10.1371/journal.pone.0061409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Beggs KM, McGreal SR, McCarthy A, Gunewardena S, Lampe JN, Lau C, et al. The role of hepatocyte nuclear factor 4-alpha in perfluorooctanoic acid- and perfluorooctanesulfonic acid-induced hepatocellular dysfunction. Toxicol Appl Pharmacol. 2016;304:18–29. https://doi.org/10.1016/j.taap.2016.05.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Das KP, Wood CR, Lin MT, Starkov AA, Lau C, Wallace KB, et al. Perfluoroalkyl acids-induced liver steatosis: effects on genes controlling lipid homeostasis. Toxicology. 2017;378:37–52. https://doi.org/10.1016/j.tox.2016.12.007.

    Article  CAS  PubMed  Google Scholar 

  31. Wu X, **e G, Xu X, Wu W, Yang B. Adverse bioeffect of perfluorooctanoic acid on liver metabolic function in mice. Environ Sci Pollut Res Int. 2018;25(5):4787–93. https://doi.org/10.1007/s11356-017-0872-7.

    Article  CAS  PubMed  Google Scholar 

  32. Darrow LA, Groth AC, Winquist A, Shin HM, Bartell SM, Steenland K. Modeled perfluorooctanoic acid (PFOA) exposure and liver function in a mid-Ohio Valley community. Environ Health Perspect. 2016;124(8):1227–33. https://doi.org/10.1289/ehp.1510391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gallo V, Leonardi G, Genser B, Lopez-Espinosa MJ, Frisbee SJ, Karlsson L, et al. Serum perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) concentrations and liver function biomarkers in a population with elevated PFOA exposure. Environ Health Perspect. 2012;120(5):655–60. https://doi.org/10.1289/ehp.1104436.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. •• Bassler J, Ducatman A, Elliton M, Wen S, Wahlang B, Barnett J, et al. Environmental perfluoroalkyl acid exposures are associated with liver disease characterized by apoptosis and altered serum adipocytokines. Environ Pollut. 2019;247:1055–63. https://doi.org/10.1016/j.envpol.2019.01.064 This cohort study reported that environmental PFAS exposures were associated with the novel combination of increased biomarkers of hepatocyte apoptosis and decreased inflammation.

    Article  CAS  PubMed  Google Scholar 

  35. Yamaguchi M, Arisawa K, Uemura H, Katsuura-Kamano S, Takami H, Sawachika F, et al. Consumption of seafood, serum liver enzymes, and blood levels of PFOS and PFOA in the Japanese population. J Occup Health. 2013;55(3):184–94.

    Article  CAS  Google Scholar 

  36. Gleason JA, Post GB, Fagliano JA. Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the US population (NHANES), 2007-2010. Environ Res. 2015;136:8–14. https://doi.org/10.1016/j.envres.2014.10.004.

    Article  CAS  PubMed  Google Scholar 

  37. Lin CY, Lin LY, Chiang CK, Wang WJ, Su YN, Hung KY, et al. Investigation of the associations between low-dose serum perfluorinated chemicals and liver enzymes in US adults. Am J Gastroenterol. 2010;105(6):1354–63. https://doi.org/10.1038/ajg.2009.707.

    Article  CAS  PubMed  Google Scholar 

  38. Zhang L, Krishnan P, Ehresman DJ, Smith PB, Dutta M, Bagley BD, et al. Perfluorooctane sulfonate-choline ion pair formation: a potential mechanism modulating hepatic steatosis and oxidative stress in mice. Toxicol Sci. 2016. https://doi.org/10.1093/toxsci/kfw120.

  39. Fai Tse WK, Li JW, Kwan Tse AC, Chan TF, Hin Ho JC, Sun Wu RS, et al. Fatty liver disease induced by perfluorooctane sulfonate: novel insight from transcriptome analysis. Chemosphere. 2016;159:166–77. https://doi.org/10.1016/j.chemosphere.2016.05.060.

    Article  CAS  PubMed  Google Scholar 

  40. Cheng J, Lv S, Nie S, Liu J, Tong S, Kang N, et al. Chronic perfluorooctane sulfonate (PFOS) exposure induces hepatic steatosis in zebrafish. Aquat Toxicol. 2016;176:45–52. https://doi.org/10.1016/j.aquatox.2016.04.013.

    Article  CAS  PubMed  Google Scholar 

  41. Wan HT, Zhao YG, Wei X, Hui KY, Giesy JP, Wong CK. PFOS-induced hepatic steatosis, the mechanistic actions on beta-oxidation and lipid transport. Biochim Biophys Acta. 2012;1820(7):1092–101. https://doi.org/10.1016/j.bbagen.2012.03.010.

    Article  CAS  PubMed  Google Scholar 

  42. Lv Z, Li G, Li Y, Ying C, Chen J, Chen T, et al. Glucose and lipid homeostasis in adult rat is impaired by early-life exposure to perfluorooctane sulfonate. Environ Toxicol. 2013;28(9):532–42. https://doi.org/10.1002/tox.20747.

    Article  CAS  PubMed  Google Scholar 

  43. Bruchajzer E, Frydrych B, Sporny S, Szymanska JA. The effect of short-term intoxication of rats with pentabromodiphenyl ether (in mixture mimic commercial products). Hum Exp Toxicol. 2011;30(5):363–78. https://doi.org/10.1177/0960327110371261.

    Article  CAS  PubMed  Google Scholar 

  44. Chen H, Zhang W, Rui BB, Yang SM, Xu WP, Wei W. Di(2-ethylhexyl) phthalate exacerbates non-alcoholic fatty liver in rats and its potential mechanisms. Environ Toxicol Pharmacol. 2016;42:38–44. https://doi.org/10.1016/j.etap.2015.12.016.

    Article  CAS  PubMed  Google Scholar 

  45. Ito Y, Nakamura T, Yanagiba Y, Ramdhan DH, Yamagishi N, Naito H, et al. Plasticizers may activate human hepatic peroxisome proliferator-activated receptor alpha less than that of a mouse but may activate constitutive androstane receptor in liver. PPAR Res. 2012;2012:201284. https://doi.org/10.1155/2012/201284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Maranghi F, Lorenzetti S, Tassinari R, Moracci G, Tassinari V, Marcoccia D, et al. In utero exposure to di-(2-ethylhexyl) phthalate affects liver morphology and metabolism in post-natal CD-1 mice. Reprod Toxicol. 2010;29(4):427–32. https://doi.org/10.1016/j.reprotox.2010.03.002.

    Article  CAS  PubMed  Google Scholar 

  47. Kaiser JP, Lipscomb JC, Wesselkamper SC. Putative mechanisms of environmental chemical-induced steatosis. Int J Toxicol. 2012;31(6):551–63. https://doi.org/10.1177/1091581812466418.

    Article  CAS  PubMed  Google Scholar 

  48. Rodriguez-Alcala LM, Sa C, Pimentel LL, Pestana D, Teixeira D, Faria A, et al. Endocrine disruptor DDE associated with a high-fat diet enhances the impairment of liver fatty acid composition in rats. J Agric Food Chem. 2015;63(42):9341–8. https://doi.org/10.1021/acs.jafc.5b03274.

    Article  CAS  PubMed  Google Scholar 

  49. Liu Q, Wang Q, Xu C, Shao W, Zhang C, Liu H, et al. Organochloride pesticides impaired mitochondrial function in hepatocytes and aggravated disorders of fatty acid metabolism. Sci Rep. 2017;7:46339. https://doi.org/10.1038/srep46339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. ** Y, Lin X, Miao W, Wu T, Shen H, Chen S, et al. Chronic exposure of mice to environmental endocrine-disrupting chemicals disturbs their energy metabolism. Toxicol Lett. 2014;225(3):392–400. https://doi.org/10.1016/j.toxlet.2014.01.006.

    Article  CAS  PubMed  Google Scholar 

  51. Lim S, Ahn SY, Song IC, Chung MH, Jang HC, Park KS, et al. Chronic exposure to the herbicide, atrazine, causes mitochondrial dysfunction and insulin resistance. PLoS One. 2009;4(4):e5186. https://doi.org/10.1371/journal.pone.0005186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhang XF, Zhang CH, Zheng J, Li LX, Geng TQ, Zhang Y. Potential biomarkers for monitoring the toxicity of long-term exposure to atrazine in rat by metabonomic analysis. Xenobiotica. 2018;48(3):241–9. https://doi.org/10.1080/00498254.2017.1303221.

    Article  CAS  PubMed  Google Scholar 

  53. Anders LC, Lang AL, Anwar-Mohamed A, Douglas AN, Bushau AM, Falkner KC, et al. Vinyl chloride metabolites potentiate inflammatory liver injury caused by LPS in mice. Toxicol Sci. 2016;151(2):312–23. https://doi.org/10.1093/toxsci/kfw045.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Anders LC, Yeo H, Kaelin BR, Lang AL, Bushau AM, Douglas AN, et al. Role of dietary fatty acids in liver injury caused by vinyl chloride metabolites in mice. Toxicol Appl Pharmacol. 2016;311:34–41. https://doi.org/10.1016/j.taap.2016.09.026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. •• Lang AL, Chen L, Poff GD, Ding WX, Barnett RA, Arteel GE, et al. Vinyl chloride dysregulates metabolic homeostasis and enhances diet-induced liver injury in mice. Hepatol Commun. 2018;2(3):270–84. https://doi.org/10.1002/hep4.1151 This study demonstrated how vinyl chloride exacerbated liver injury caused by high-fat diet feeding by inducing endoplasmic reticulum stress, leading to mitochondrial damage and altered metabolic homeostasis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. •• Guardiola JJ, Beier JI, Falkner KC, Wheeler B, McClain CJ, Cave M. Occupational exposures at a polyvinyl chloride production facility are associated with significant changes to the plasma metabolome. ToxicolApplPharmacol. 2016;313:47–56 This cohort study utilized plasma metabolomics to identify key protein targets that play a role in vinyl chloride toxicity including AMPK and Akt.

    CAS  Google Scholar 

  57. Boue S, Tarasov K, Janis M, Lebrun S, Hurme R, Schlage W, et al. Modulation of atherogenic lipidome by cigarette smoke in apolipoprotein E-deficient mice. Atherosclerosis. 2012;225(2):328–34. https://doi.org/10.1016/j.atherosclerosis.2012.09.032.

    Article  CAS  PubMed  Google Scholar 

  58. Yuan H, Shyy JY, Martins-Green M. Second-hand smoke stimulates lipid accumulation in the liver by modulating AMPK and SREBP-1. J Hepatol. 2009;51(3):535–47. https://doi.org/10.1016/j.jhep.2009.03.026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lin C, Rountree CB, Methratta S, LaRusso S, Kunselman AR, Spanier AJ. Secondhand tobacco exposure is associated with nonalcoholic fatty liver disease in children. Environ Res. 2014;132:264–8. https://doi.org/10.1016/j.envres.2014.04.005.

    Article  CAS  PubMed  Google Scholar 

  60. Liu Y, Dai M, Bi Y, Xu M, Xu Y, Li M, et al. Active smoking, passive smoking, and risk of nonalcoholic fatty liver disease (NAFLD): a population-based study in China. J Epidemiol. 2013;23(2):115–21.

    Article  Google Scholar 

  61. Zuo Z, Chen S, Wu T, Zhang J, Su Y, Chen Y, et al. Tributyltin causes obesity and hepatic steatosis in male mice. Environ Toxicol. 2011;26(1):79–85. https://doi.org/10.1002/tox.20531.

    Article  CAS  PubMed  Google Scholar 

  62. Chamorro-Garcia R, Sahu M, Abbey RJ, Laude J, Pham N, Blumberg B. Transgenerational inheritance of increased fat depot size, stem cell reprogramming, and hepatic steatosis elicited by prenatal exposure to the obesogen tributyltin in mice. Environ Health Perspect. 2013;121(3):359–66. https://doi.org/10.1289/ehp.1205701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhang J, Sun P, Kong T, Yang F, Guan W. Tributyltin promoted hepatic steatosis in zebrafish (Danio rerio) and the molecular pathogenesis involved. Aquat Toxicol. 2016;170:208–15. https://doi.org/10.1016/j.aquatox.2015.11.028.

    Article  CAS  PubMed  Google Scholar 

  64. Lyssimachou A, Santos JG, Andre A, Soares J, Lima D, Guimaraes L, et al. The mammalian “obesogen” tributyltin targets hepatic triglyceride accumulation and the transcriptional regulation of lipid metabolism in the liver and brain of zebrafish. PLoS One. 2015;10(12):e0143911. https://doi.org/10.1371/journal.pone.0143911.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Zheng Z, Xu X, Zhang X, Wang A, Zhang C, Huttemann M, et al. Exposure to ambient particulate matter induces a NASH-like phenotype and impairs hepatic glucose metabolism in an animal model. J Hepatol. 2013;58(1):148–54. https://doi.org/10.1016/j.jhep.2012.08.009.

    Article  CAS  PubMed  Google Scholar 

  66. Tomaru M, Takano H, Inoue K, Yanagisawa R, Osakabe N, Yasuda A, et al. Pulmonary exposure to diesel exhaust particles enhances fatty change of the liver in obese diabetic mice. Int J Mol Med. 2007;19(1):17–22.

    CAS  PubMed  Google Scholar 

  67. Tan HH, Fiel MI, Sun Q, Guo J, Gordon RE, Chen LC, et al. Kupffer cell activation by ambient air particulate matter exposure may exacerbate non-alcoholic fatty liver disease. J Immunotoxicol. 2009;6(4):266–75. https://doi.org/10.1080/15476910903241704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Vesterdal LK, Danielsen PH, Folkmann JK, Jespersen LF, Aguilar-Pelaez K, Roursgaard M, et al. Accumulation of lipids and oxidatively damaged DNA in hepatocytes exposed to particles. Toxicol Appl Pharmacol. 2014;274(2):350–60. https://doi.org/10.1016/j.taap.2013.10.001.

    Article  CAS  PubMed  Google Scholar 

  69. Cho SJ, Echevarria GC, Lee YI, Kwon S, Park KY, Tsukiji J, et al. YKL-40 is a protective biomarker for fatty liver in world trade center particulate matter-exposed firefighters. J Mol Biomark Diagn. 2014;5. https://doi.org/10.4172/2155-9929.1000174.

  70. Regnault C, Willison J, Veyrenc S, Airieau A, Meresse P, Fortier M, et al. Metabolic and immune impairments induced by the endocrine disruptors benzo[a]pyrene and triclosan in Xenopus tropicalis. Chemosphere. 2016;155:519–27. https://doi.org/10.1016/j.chemosphere.2016.04.047.

    Article  CAS  PubMed  Google Scholar 

  71. Ortiz L, Nakamura B, Li X, Blumberg B, Luderer U. In utero exposure to benzo[a]pyrene increases adiposity and causes hepatic steatosis in female mice, and glutathione deficiency is protective. Toxicol Lett. 2013;223(2):260–7. https://doi.org/10.1016/j.toxlet.2013.09.017.

    Article  CAS  PubMed  Google Scholar 

  72. Arteel GE, Guo L, Schlierf T, Beier JI, Kaiser JP, Chen TS, et al. Subhepatotoxic exposure to arsenic enhances lipopolysaccharide-induced liver injury in mice. Toxicol Appl Pharmacol. 2008;226(2):128–39. https://doi.org/10.1016/j.taap.2007.08.020.

    Article  CAS  PubMed  Google Scholar 

  73. Tan M, Schmidt RH, Beier JI, Watson WH, Zhong H, States JC, et al. Chronic subhepatotoxic exposure to arsenic enhances hepatic injury caused by high fat diet in mice. Toxicol Appl Pharmacol. 2011;257(3):356–64. https://doi.org/10.1016/j.taap.2011.09.019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Shi X, Wei X, Koo I, Schmidt RH, Yin X, Kim SH, et al. Metabolomic analysis of the effects of chronic arsenic exposure in a mouse model of diet-induced fatty liver disease. J Proteome Res. 2014;13(2):547–54. https://doi.org/10.1021/pr400719u.

    Article  CAS  PubMed  Google Scholar 

  75. Bambino K, Zhang C, Austin C, Amarasiriwardena C, Arora M, Chu J, et al. Inorganic arsenic causes fatty liver and interacts with ethanol to cause alcoholic liver disease in zebrafish. Dis Model Mech. 2018;11(2). https://doi.org/10.1242/dmm.031575.

  76. Hu Y, Yu C, Yao M, Wang L, Liang B, Zhang B, et al. The PKCdelta-Nrf2-ARE signalling pathway may be involved in oxidative stress in arsenic-induced liver damage in rats. Environ Toxicol Pharmacol. 2018;62:79–87. https://doi.org/10.1016/j.etap.2018.05.012.

    Article  CAS  PubMed  Google Scholar 

  77. Ditzel EJ, Nguyen T, Parker P, Camenisch TD. Effects of arsenite exposure during fetal development on energy metabolism and susceptibility to diet-induced fatty liver disease in male mice. Environ Health Perspect. 2016;124(2):201–9. https://doi.org/10.1289/ehp.1409501.

    Article  CAS  PubMed  Google Scholar 

  78. Islam K, Haque A, Karim R, Fajol A, Hossain E, Salam KA, et al. Dose-response relationship between arsenic exposure and the serum enzymes for liver function tests in the individuals exposed to arsenic: a cross sectional study in Bangladesh. Environ Health. 2011;10:64. https://doi.org/10.1186/1476-069x-10-64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Poursafa P, Ataee E, Motlagh ME, Ardalan G, Tajadini MH, Yazdi M, et al. Association of serum lead and mercury level with cardiometabolic risk factors and liver enzymes in a nationally representative sample of adolescents: the CASPIAN-III study. Environ Sci Pollut Res Int. 2014;21(23):13496–502. https://doi.org/10.1007/s11356-014-3238-4.

    Article  CAS  PubMed  Google Scholar 

  80. Chang LW, Yamaguchi S. Ultrastructural changes of the liver after long-term diet of mercury-contaminated tuna. Environ Res. 1974;7:16.

    Article  Google Scholar 

  81. Hazelhoff MH, Torres AM. Gender differences in mercury-induced hepatotoxicity: potential mechanisms. Chemosphere. 2018;202:330–8. https://doi.org/10.1016/j.chemosphere.2018.03.106.

    Article  CAS  PubMed  Google Scholar 

  82. Go YM, Sutliff RL, Chandler JD, Khalidur R, Kang BY, Anania FA, et al. Low-dose cadmium causes metabolic and genetic dysregulation associated with fatty liver disease in mice. Toxicol Sci. 2015;147(2):524–34. https://doi.org/10.1093/toxsci/kfv149.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Zhang S, ** Y, Zeng Z, Liu Z, Fu Z. Subchronic exposure of mice to cadmium perturbs their hepatic energy metabolism and gut microbiome. Chem Res Toxicol. 2015;28(10):2000–9. https://doi.org/10.1021/acs.chemrestox.5b00237.

    Article  CAS  PubMed  Google Scholar 

  84. Sarmiento-Ortega VE, Trevino S, Flores-Hernandez JA, Aguilar-Alonso P, Moroni-Gonzalez D, Aburto-Luna V, et al. Changes on serum and hepatic lipidome after a chronic cadmium exposure in Wistar rats. Arch Biochem Biophys. 2017;635:52–9. https://doi.org/10.1016/j.abb.2017.10.003.

    Article  CAS  PubMed  Google Scholar 

  85. Kang MY, Cho SH, Lim YH, Seo JC, Hong YC. Effects of environmental cadmium exposure on liver function in adults. Occup Environ Med. 2013;70(4):268–73. https://doi.org/10.1136/oemed-2012-101063.

    Article  CAS  PubMed  Google Scholar 

  86. Kelishadi R, Askarieh A, Motlagh ME, Tajadini M, Heshmat R, Ardalan G, et al. Association of blood cadmium level with cardiometabolic risk factors and liver enzymes in a nationally representative sample of adolescents: the CASPIAN-III study. J Environ Public Health. 2013;2013:142856. https://doi.org/10.1155/2013/142856.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Garcia-Arevalo M, Alonso-Magdalena P, Rebelo Dos Santos J, Quesada I, Carneiro EM, Nadal A. Exposure to bisphenol-A during pregnancy partially mimics the effects of a high-fat diet altering glucose homeostasis and gene expression in adult male mice. PLoS One. 2014;9(6):e100214. https://doi.org/10.1371/journal.pone.0100214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Jiang Y, **a W, Zhu Y, Li X, Wang D, Liu J, et al. Mitochondrial dysfunction in early life resulted from perinatal bisphenol A exposure contributes to hepatic steatosis in rat offspring. Toxicol Lett. 2014;228(2):85–92. https://doi.org/10.1016/j.toxlet.2014.04.013.

    Article  CAS  PubMed  Google Scholar 

  89. Wei J, Sun X, Chen Y, Li Y, Song L, Zhou Z, et al. Perinatal exposure to bisphenol A exacerbates nonalcoholic steatohepatitis-like phenotype in male rat offspring fed on a high-fat diet. J Endocrinol. 2014;222(3):313–25. https://doi.org/10.1530/JOE-14-0356.

    Article  CAS  PubMed  Google Scholar 

  90. Strakovsky RS, Wang H, Engeseth NJ, Flaws JA, Helferich WG, Pan YX, et al. Developmental bisphenol A (BPA) exposure leads to sex-specific modification of hepatic gene expression and epigenome at birth that may exacerbate high-fat diet-induced hepatic steatosis. Toxicol Appl Pharmacol. 2015;284(2):101–12. https://doi.org/10.1016/j.taap.2015.02.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Abdelhadya DH, El-Magd MA, Elbialy ZI, Saleh AA. Bromuconazole-induced hepatotoxicity is accompanied by upregulation of PXR/CYP3A1 and downregulation of CAR/CYP2B1 gene expression. Toxicol Mech Methods. 2017;27(7):544–50. https://doi.org/10.1080/15376516.2017.1333555.

    Article  CAS  PubMed  Google Scholar 

  92. Mesnage R, Renney G, Seralini GE, Ward M, Antoniou MN. Multiomics reveal non-alcoholic fatty liver disease in rats following chronic exposure to an ultra-low dose of roundup herbicide. Sci Rep. 2017;7:39328. https://doi.org/10.1038/srep39328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Vandenberg LN, Blumberg B, Antoniou MN, Benbrook CM, Carroll L, Colborn T, et al. Is it time to reassess current safety standards for glyphosate-based herbicides? J Epidemiol Community Health. 2017;71(6):613–8. https://doi.org/10.1136/jech-2016-208463.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Salla GBF, Bracht L, de Sa-Nakanishi AB, Parizotto AV, Bracht F, Peralta RM, et al. Distribution, lipid-bilayer affinity and kinetics of the metabolic effects of dinoseb in the liver. Toxicol Appl Pharmacol. 2017;329:259–71. https://doi.org/10.1016/j.taap.2017.06.013.

    Article  CAS  PubMed  Google Scholar 

  95. Tolman KG, Sirrine R. Occupational hepatotoxicity. Clin Liver Dis. 1998;2(3):26.

    Article  Google Scholar 

  96. Wahlang B, Beier JI, Clair HB, Bellis-Jones HJ, Falkner KC, McClain CJ, et al. Toxicant-associated steatohepatitis. Toxicol Pathol. 2013;41(2):343–60. https://doi.org/10.1177/0192623312468517.

    Article  CAS  PubMed  Google Scholar 

  97. Joshi-Barve S, Kirpich I, Cave MC, Marsano L, McClain CJ. Alcoholic, non-alcoholic and toxicant-associated steatohepatitis: mechanistic similarities and differences. Cell Mol Gastroenterol Hepatol. 2015;1(4):356–67.

    Article  Google Scholar 

  98. Cave MC, Clair HB, Hardesty JE, Falkner KC, Feng W, Clark BJ, et al. Nuclear receptors and nonalcoholic fatty liver disease. Biochim Biophys Acta. 2016;(9):1083–99. https://doi.org/10.1016/j.bbagrm.2016.03.002.

  99. Klaunig JE, Li X, Wang Z. Role of xenobiotics in the induction and progression of fatty liver disease. Toxicol Res (Camb). 2018;7(4):664–80. https://doi.org/10.1039/c7tx00326a.

    Article  CAS  Google Scholar 

  100. Foulds CE, Trevino LS, York B, Walker CL. Endocrine-disrupting chemicals and fatty liver disease. Nat Rev Endocrinol. 2017;13(8):445–57. https://doi.org/10.1038/nrendo.2017.42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Heindel JJ, Blumberg B, Cave M, Machtinger R, Mantovani A, Mendez MA, et al. Metabolism disrupting chemicals and metabolic disorders. Reprod Toxicol. 2017;68:3–33. https://doi.org/10.1016/j.reprotox.2016.10.001.

    Article  CAS  PubMed  Google Scholar 

  102. Angrish MM, Kaiser JP, McQuene C, Chorley B. Tip** the balance: hepatotoxicity and the four apical key events of hepatic steatosis. Toxicol Sci. 2016;150(2):261–8.

    Article  CAS  Google Scholar 

  103. Angrish MM, McQueen CA, Cohen-Hubal E, Bruno M, Ge Y, Chorley BN. Editor’s highlight: mechanistic toxicity tests based on an adverse outcome pathway network for hepatic steatosis. Toxicol Sci. 2017;159(1):159–69. https://doi.org/10.1093/toxsci/kfx121.

    Article  CAS  PubMed  Google Scholar 

  104. Knapen D, Angrish MM, Fortin MC, Katsiadaki I, Leonard M, Margiotta-Casaluci L, et al. Adverse outcome pathway networks I: development and applications. Environ Toxicol Chem. 2018;37(6):1723–33. https://doi.org/10.1002/etc.4125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Hardesty JE, Wahlang B, Falkner KC, Clair HB, Clark BJ, Ceresa BP, et al. Polychlorinated biphenyls disrupt hepatic epidermal growth factor receptor signaling. Xenobiotica. 2017;47(9):807–20. https://doi.org/10.1080/00498254.2016.1217572.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. •• Hardesty JE, Al-Eryani L, Wahlang B, Falkner KC, Shi H, ** J, et al. Epidermal growth factor receptor signaling disruption by endocrine and metabolic disrupting chemicals. Toxicol Sci. 2018;162(2):622–34. https://doi.org/10.1093/toxsci/kfy004 This study demonstrated mechanisms by which POPs antagonized the EGFR to cause signaling disruption.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Hardesty JE, Wahlang B, Falkner KC, Shi H, ** J, Wilkey D, et al. Hepatic signalling disruption by pollutant polychlorinated biphenyls in steatohepatitis. Cell Signal. 2019;53:132–9. https://doi.org/10.1016/j.cellsig.2018.10.004.

    Article  CAS  PubMed  Google Scholar 

  108. • Hardesty JE, Wahlang B, Falkner KC, Shi H, ** J, Zhou Y, et al. Proteomic analysis reveals novel mechanisms by which polychlorinated biphenyls compromise the liver promoting diet-induced steatohepatitis. J Proteome Res. 2019;18(4):1582–94. https://doi.org/10.1021/acs.jproteome.8b00886 This study demonstrated how PCBs acted as a first “hit” to compromise the liver, making it suceptible to a second “hit” such as high-fat diet.

    Article  CAS  PubMed  Google Scholar 

  109. Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998;114(4):842–5.

    Article  CAS  Google Scholar 

  110. Fedeli U, Girardi P, Gardiman G, Zara D, Scoizzato L, Ballarin MN, et al. Mortality from liver angiosarcoma, hepatocellular carcinoma, and cirrhosis among vinyl chloride workers. Am J Ind Med. 2019;62(1):14–20. https://doi.org/10.1002/ajim.22922.

    Article  CAS  PubMed  Google Scholar 

  111. Jacobsen AV, Norden M, Engwall M, Scherbak N. Effects of perfluorooctane sulfonate on genes controlling hepatic fatty acid metabolism in livers of chicken embryos. Environ Sci Pollut Res Int. 2018;25(23):23074–81. https://doi.org/10.1007/s11356-018-2358-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Frawley RP, Smith M, Cesta MF, Hayes-Bouknight S, Blystone C, Kissling GE, et al. Immunotoxic and hepatotoxic effects of perfluoro-n-decanoic acid (PFDA) on female Harlan Sprague-Dawley rats and B6C3F1/N mice when administered by oral gavage for 28 days. J Immunotoxicol. 2018;15(1):41–52. https://doi.org/10.1080/1547691X.2018.1445145.

    Article  CAS  PubMed  Google Scholar 

  113. Li K, Sun J, Yang J, Roberts SM, Zhang X, Cui X, et al. Molecular mechanisms of perfluorooctanoate-induced hepatocyte apoptosis in mice using proteomic techniques. Environ Sci Technol. 2017;51(19):11380–9. https://doi.org/10.1021/acs.est.7b02690.

    Article  CAS  PubMed  Google Scholar 

  114. Zhou YH, Cichocki JA, Soldatow VY, Scholl EH, Gallins PJ, Jima D, et al. Editor’s highlight: comparative dose-response analysis of liver and kidney transcriptomic effects of trichloroethylene and tetrachloroethylene in B6C3F1 mouse. Toxicol Sci. 2017;160(1):95–110. https://doi.org/10.1093/toxsci/kfx165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Julien B, Pinteur C, Vega N, Labaronne E, Vidal H, Naville D, et al. Evidence for estrogeno-mimetic effects of a mixture of low-dose pollutants in a model of ovariectomized mice. Environ Toxicol Pharmacol. 2018;57:34–40. https://doi.org/10.1016/j.etap.2017.11.008.

    Article  CAS  PubMed  Google Scholar 

  116. Lin Y, Min L, Huang Q, Chen Y, Fang C, Sun X, et al. The combined effects of DEHP and PCBs on phospholipase in the livers of mice. Environ Toxicol. 2015;30(2):197–204. https://doi.org/10.1002/tox.21885.

    Article  CAS  PubMed  Google Scholar 

  117. Liu D, Perkins JT, Petriello MC, Hennig B. Exposure to coplanar PCBs induces endothelial cell inflammation through epigenetic regulation of NF-kappaB subunit p65. Toxicol Appl Pharmacol. 2015;289(3):457–65. https://doi.org/10.1016/j.taap.2015.10.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Bucher S, Le Guillou D, Allard J, Pinon G, Begriche K, Tete A, et al. Possible involvement of mitochondrial dysfunction and oxidative stress in a cellular model of NAFLD progression induced by benzo[a]pyrene/ethanol coexposure. Oxidative Med Cell Longev. 2018;2018:4396403. https://doi.org/10.1155/2018/4396403.

    Article  CAS  Google Scholar 

  119. • Petriello MC, Hoffman JB, Vsevolozhskaya O, Morris AJ, Hennig B. Dioxin-like PCB 126 increases intestinal inflammation and disrupts gut microbiota and metabolic homeostasis. Environ Pollut. 2018;242(Pt A):1022–32. https://doi.org/10.1016/j.envpol.2018.07.039 This study demonstrated how PCBs can alter the gut microbiome and promote metabolic toxicity through the gut:liver axis.

    Article  CAS  PubMed  Google Scholar 

  120. Gadupudi GS, Elser BA, Sandgruber FA, Li X, Gibson-Corley KN, Robertson LW. PCB126 inhibits the activation of AMPK-CREB signal transduction required for energy sensing in liver. Toxicol Sci. 2018;163(2):440–53. https://doi.org/10.1093/toxsci/kfy041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Gadupudi GS, Klingelhutz AJ, Robertson LW. Diminished phosphorylation of CREB is a key event in the dysregulation of gluconeogenesis and glycogenolysis in PCB126 hepatotoxicity. Chem Res Toxicol. 2016;29(9):1504–9. https://doi.org/10.1021/acs.chemrestox.6b00172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Vladykovskaya E, Sithu SD, Haberzettl P, Wickramasinghe NS, Merchant ML, Hill BG, et al. Lipid peroxidation product 4-hydroxy-trans-2-nonenal causes endothelial activation by inducing endoplasmic reticulum stress. J Biol Chem. 2012;287(14):11398–409. https://doi.org/10.1074/jbc.M111.320416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Chen WY, Wang M, Zhang J, Barve SS, McClain CJ, Joshi-Barve S. Acrolein disrupts tight junction proteins and causes ER stress-mediated epithelial cell death leading to intestinal barrier dysfunction and permeability. Am J Pathol. 2017.

  124. Arumugam S, Girish Subbiah K, Kemparaju K, Thirunavukkarasu C. Neutrophil extracellular traps in acrolein promoted hepatic ischemia reperfusion injury: therapeutic potential of NOX2 and p38MAPK inhibitors. J Cell Physiol. 2018;233(4):3244–61. https://doi.org/10.1002/jcp.26167.

    Article  CAS  PubMed  Google Scholar 

  125. Registry AfTSD. ATSDR’s substance priority list 2017.

    Google Scholar 

  126. Agency USEP. Volatile organic compounds’ impact on indoor air quality 2017.

    Google Scholar 

  127. Cleary E, Asher M, Olawoyin R, Zhang K. Assessment of indoor air quality exposures and impacts on respiratory outcomes in River Rouge and Dearborn, Michigan. Chemosphere. 2017;187:320–9. https://doi.org/10.1016/j.chemosphere.2017.08.091.

    Article  CAS  PubMed  Google Scholar 

  128. Philip BK, Mumtaz MM, Latendresse JR, Mehendale HM. Impact of repeated exposure on toxicity of perchloroethylene in Swiss Webster mice. Toxicology. 2007;232(1–2):1–14. https://doi.org/10.1016/j.tox.2006.12.018.

    Article  CAS  PubMed  Google Scholar 

  129. Cichocki JA, Furuya S, Luo YS, Iwata Y, Konganti K, Chiu WA, et al. Nonalcoholic fatty liver disease is a susceptibility factor for perchloroethylene-induced liver effects in mice. Toxicol Sci. 2017;159(1):102–13.

    Article  CAS  Google Scholar 

  130. Cichocki JA, Furuya S, Konganti K, Luo YS, McDonald TJ, Iwata Y, et al. Impact of nonalcoholic fatty liver disease on toxicokinetics of tetrachloroethylene in mice. J Pharmacol Exp Ther. 2017;361(1):17–28. https://doi.org/10.1124/jpet.116.238790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Pawlak M, Lefebvre P, Staels B. Molecular mechanism of PPARalpha action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J Hepatol. 2015;62(3):720–33. https://doi.org/10.1016/j.jhep.2014.10.039.

    Article  CAS  PubMed  Google Scholar 

  132. Savini I, Catani MV, Evangelista D, Gasperi V, Avigliano L. Obesity-associated oxidative stress: strategies finalized to improve redox state. Int J Mol Sci. 2013;14(5):10497–538. https://doi.org/10.3390/ijms140510497.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Kozlov AV, Lancaster JR Jr, Meszaros AT, Weidinger A. Mitochondria-meditated pathways of organ failure upon inflammation. RedoxBiol. 2017;13:170–81.

    CAS  Google Scholar 

  134. Hassoun E, Mettling C. Dichloroacetate and trichloroacetate toxicity in AML12 cells: role of oxidative stress. J Biochem Mol Toxicol. 2015;29(11):508–12. https://doi.org/10.1002/jbt.21720.

    Article  CAS  PubMed  Google Scholar 

  135. Hassoun E, Cearfoss J, Mamada S, Al-Hassan N, Brown M, Heimberger K, et al. The effects of mixtures of dichloroacetate and trichloroacetate on induction of oxidative stress in livers of mice after subchronic exposure. J Toxicol Environ Health A. 2014;77(6):313–23. https://doi.org/10.1080/15287394.2013.864576.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Mohammad MK, Avila D, Zhang J, Barve S, Arteel G, McClain C, et al. Acrolein cytotoxicity in hepatocytes involves endoplasmic reticulum stress, mitochondrial dysfunction and oxidative stress. Toxicol Appl Pharmacol. 2012;265(1):73–82. https://doi.org/10.1016/j.taap.2012.09.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Moghe A, Ghare S, Lamoreau B, Mohammad M, Barve S, McClain C, et al. Molecular mechanisms of acrolein toxicity: relevance to human disease. Toxicol Sci. 2015;143(2):242–55. https://doi.org/10.1093/toxsci/kfu233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Fagone P, Jackowski S. Membrane phospholipid synthesis and endoplasmic reticulum function. J Lipid Res. 2009;50(Suppl):S311–6. https://doi.org/10.1194/jlr.R800049-JLR200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Pagliassotti MJ, Kim PY, Estrada AL, Stewart CM, Gentile CL. Endoplasmic reticulum stress in obesity and obesity-related disorders: an expanded view. Metabolism. 2016;65(9):1238–46. https://doi.org/10.1016/j.metabol.2016.05.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56(7):1761–72. https://doi.org/10.2337/db06-1491.

    Article  CAS  PubMed  Google Scholar 

  141. Mehal WZ. The Gordian Knot of dysbiosis, obesity and NAFLD. Nat Rev Gastroenterol Hepatol. 2013;10(11):637–44. https://doi.org/10.1038/nrgastro.2013.146.

    Article  PubMed  Google Scholar 

  142. Irene P, Chiara R, Laura A, Maria GD, Melania G, Cristina F, et al. Lack of NLRP3-inflammasome leads to gut-liver axis derangement, gut dysbiosis and a worsened phenotype in a mouse model of NAFLD. Sci Rep. 2017;7(1):12200.

    Article  Google Scholar 

  143. Rahman K, Desai C, Iyer SS, Thorn NE, Kumar P, Liu Y, et al. Loss of junctional adhesion molecule a promotes severe steatohepatitis in mice on a diet high in saturated fat, fructose, and cholesterol. Gastroenterology. 2016;151(4):733–46 e12. https://doi.org/10.1053/j.gastro.2016.06.022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Schuster S, Johnson CD, Hennebelle M, Holtmann T, Taha AY, Kirpich IA, et al. Oxidized linoleic acid metabolites induce liver mitochondrial dysfunction, apoptosis, and NLRP3 activation in mice. J Lipid Res. 2018;59(9):1597–609. https://doi.org/10.1194/jlr.M083741.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Zhang K, Kaufman RJ. From endoplasmic-reticulum stress to the inflammatory response. Nature. 2008;454(7203):455–62. https://doi.org/10.1038/nature07203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Karlmark KR, Weiskirchen R, Zimmermann HW, Gassler N, Ginhoux F, Weber C, et al. Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology (Baltimore, Md). 2009;50(1):261–74.

    Article  CAS  Google Scholar 

  147. Blossom SJ, Fernandes L, Bai S, Khare S, Gokulan K, Yuan Y, et al. Opposing actions of developmental trichloroethylene and high-fat diet coexposure on markers of lipogenesis and inflammation in autoimmune-prone mice. Toxicol Sci. 2018;164(1):313–27. https://doi.org/10.1093/toxsci/kfy091.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Yang H, Biermann MH, Brauner JM, Liu Y, Zhao Y, Herrmann M. New insights into neutrophil extracellular traps: mechanisms of formation and role in inflammation. Front Immunol. 2016;7:302.

    PubMed  PubMed Central  Google Scholar 

  149. Kania-Korwel I, Wu X, Wang K, Lehmler HJ. Identification of lipidomic markers of chronic 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) exposure in the male rat liver. Toxicology. 2017;390:124–34. https://doi.org/10.1016/j.tox.2017.09.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Deng P, Barney J, Petriello MC, Morris AJ, Wahlang B, Hennig B. Hepatic metabolomics reveals that liver injury increases PCB 126-induced oxidative stress and metabolic dysfunction. Chemosphere. 2019;217:140–9. https://doi.org/10.1016/j.chemosphere.2018.10.196.

    Article  CAS  PubMed  Google Scholar 

  151. Fader KA, Zacharewski TR. Beyond the aryl hydrocarbon receptor: pathway interactions in the hepatotoxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds. Curr Opin Toxicol. 2017;2:36–41. https://doi.org/10.1016/j.cotox.2017.01.010.

    Article  PubMed  PubMed Central  Google Scholar 

  152. Baskin-Bey ES, Anan A, Isomoto H, Bronk SF, Gores GJ. Constitutive androstane receptor agonist, TCPOBOP, attenuates steatohepatitis in the methionine choline-deficient diet-fed mouse. World J Gastroenterol. 2007;13(42):5635–41.

    Article  CAS  Google Scholar 

  153. Wahlang B, Falkner KC, Clair HB, Al-Eryani L, Prough RA, States JC, et al. Human receptor activation by aroclor 1260, a polychlorinated biphenyl mixture. Toxicol Sci. 2014;140(2):283–97. https://doi.org/10.1093/toxsci/kfu083.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Natarajan A, Wagner B, Sibilia M. The EGF receptor is required for efficient liver regeneration. Proc Natl Acad Sci U S A. 2007;104(43):17081–6. https://doi.org/10.1073/pnas.0704126104.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Robles MS, Humphrey SJ, Mann M. Phosphorylation is a central mechanism for circadian control of metabolism and physiology. Cell Metab. 2017;25(1):118–27. https://doi.org/10.1016/j.cmet.2016.10.004.

    Article  CAS  PubMed  Google Scholar 

  156. Gunewardena S, Walesky C, Apte U. Global gene expression changes in liver following hepatocyte nuclear factor 4 alpha deletion in adult mice. Genomics data. 2015;5:126–8. https://doi.org/10.1016/j.gdata.2015.05.037.

    Article  PubMed  PubMed Central  Google Scholar 

  157. Tatum-Gibbs K, Wambaugh JF, Das KP, Zehr RD, Strynar MJ, Lindstrom AB, et al. Comparative pharmacokinetics of perfluorononanoic acid in rat and mouse. Toxicology. 2011;281(1–3):48–55. https://doi.org/10.1016/j.tox.2011.01.003.

    Article  CAS  PubMed  Google Scholar 

  158. Olsen GW, Hansen KJ, Stevenson LA, Burris JM, Mandel JH. Human donor liver and serum concentrations of perfluorooctanesulfonate and other perfluorochemicals. Environ Sci Technol. 2003;37(5):888–91.

    Article  CAS  Google Scholar 

  159. Bijland S, Rensen PC, Pieterman EJ, Maas AC, van der Hoorn JW, van Erk MJ, et al. Perfluoroalkyl sulfonates cause alkyl chain length-dependent hepatic steatosis and hypolipidemia mainly by impairing lipoprotein production in APOE*3-Leiden CETP mice. Toxicol Sci. 2011;123(1):290–303. https://doi.org/10.1093/toxsci/kfr142.

    Article  CAS  PubMed  Google Scholar 

  160. Wang L, Wang Y, Liang Y, Li J, Liu Y, Zhang J, et al. Specific accumulation of lipid droplets in hepatocyte nuclei of PFOA-exposed BALB/c mice. Sci Rep. 2013;3:2174. https://doi.org/10.1038/srep02174.

    Article  PubMed  PubMed Central  Google Scholar 

  161. Rebholz SL, Jones T, Herrick RL, **e C, Calafat AM, Pinney SM, et al. Hypercholesterolemia with consumption of PFOA-laced Western diets is dependent on strain and sex of mice. Toxicol Rep. 2016;3:46–54. https://doi.org/10.1016/j.toxrep.2015.11.004.

    Article  CAS  PubMed  Google Scholar 

  162. DeWitt JC, Peden-Adams MM, Keller JM, Germolec DR. Immunotoxicity of perfluorinated compounds: recent developments. Toxicol Pathol. 2012;40(2):300–11. https://doi.org/10.1177/0192623311428473.

    Article  CAS  PubMed  Google Scholar 

  163. Jain RB, Ducatman A. Selective associations of recent low concentrations of perfluoroalkyl substances with liver function biomarkers: NHANES 2011-2014 data on US adults aged >/= 20 years. J Occup Environ Med. 2018. https://doi.org/10.1097/JOM.0000000000001532.

  164. Mann J, Reeves HL, Feldstein AE. Liquid biopsy for liver diseases. Gut. 2018;67(12):2204–12. https://doi.org/10.1136/gutjnl-2017-315846.

    Article  CAS  PubMed  Google Scholar 

  165. Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149(2):389–97 e10. https://doi.org/10.1053/j.gastro.2015.04.043.

    Article  PubMed  PubMed Central  Google Scholar 

  166. Mailloux RJ, Florian M, Chen Q, Yan J, Petrov I, Coughlan MC, et al. Exposure to a northern contaminant mixture (NCM) alters hepatic energy and lipid metabolism exacerbating hepatic steatosis in obese JCR rats. PLoS One. 2014;9(9):e106832. https://doi.org/10.1371/journal.pone.0106832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Pencikova K, Svrzkova L, Strapacova S, Neca J, Bartonkova I, Dvorak Z, et al. In vitro profiling of toxic effects of prominent environmental lower-chlorinated PCB congeners linked with endocrine disruption and tumor promotion. Environ Pollut. 2018;237:473–86. https://doi.org/10.1016/j.envpol.2018.02.067.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Zhang Q, Lu M, Wang C, Du J, Zhou P, Zhao M. Characterization of estrogen receptor alpha activities in polychlorinated biphenyls by in vitro dual-luciferase reporter gene assay. Environ Pollut. 2014;189:169–75. https://doi.org/10.1016/j.envpol.2014.03.001.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported in part by the National Institute of Environmental Health Sciences (R35ES028373, P42ES023716, T32ES011564, F31ES028982), the National Institute of General Medical Sciences (P20GM113226), the National Institute of Diabetes and Digestive and Kidney Diseases (K01DK096042, R03DK107912), and the National Institute on Alcohol Abuse and Alcoholism (P50AA024337, R01AA024102).

Author information

Authors and Affiliations

  1. Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY, 40202, USA

    Banrida Wahlang, Josiah E. Hardesty, K. Cameron Falkner, Irina A Kirpich & Matthew C. Cave

  2. University of Louisville Superfund Research Center, University of Louisville, Louisville, KY, 40202, USA

    Banrida Wahlang & Matthew C. Cave

  3. Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, 40202, USA

    Jian **, Erica F. Daly & Matthew C. Cave

  4. Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Juliane I. Beier

  5. Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Juliane I. Beier

  6. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Regina D. Schnegelberger

  7. Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40202, USA

    Russell A. Prough & Matthew C. Cave

  8. Hepatobiology & Toxicology COBRE Center, University of Louisville School of Medicine, Louisville, KY, 40202, USA

    Irina A Kirpich & Matthew C. Cave

  9. University of Louisville Alcohol Research Center, University of Louisville, Louisville, KY, 40202, USA

    Irina A Kirpich & Matthew C. Cave

  10. The Robley Rex Veterans Affairs Medical Center, Louisville, KY, 40206, USA

    Matthew C. Cave

  11. The Jewish Hospital Liver Transplant Program, Louisville, KY, 40202, USA

    Matthew C. Cave

  12. Kosair Charities Clinical & Translational Research Building, 505 South Hancock Street, Louisville, KY, 40202, USA

    Matthew C. Cave

Authors
  1. Banrida Wahlang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jian **
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Juliane I. Beier
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Josiah E. Hardesty
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Erica F. Daly
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Regina D. Schnegelberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K. Cameron Falkner
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Russell A. Prough
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Irina A Kirpich
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Matthew C. Cave
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Matthew C. Cave.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Banrida Wahlang and Jian ** denote joint first authorship

This article is part of the Topical Collection on Mechanisms of Toxicity

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wahlang, B., **, J., Beier, J.I. et al. Mechanisms of Environmental Contributions to Fatty Liver Disease. Curr Envir Health Rpt 6, 80–94 (2019). https://doi.org/10.1007/s40572-019-00232-w

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40572-019-00232-w

Keywords

Search

Navigation