Al-Eryani L, Wahlang B, Falkner KC et al (2015) Identification of environmental chemicals associated with the development of toxicant-associated fatty liver disease in rodents. Toxicol Pathol 43(4):482–497. https://doi.org/10.1177/0192623314549960

Article  CAS  PubMed  Google Scholar 

Angrish MM, Kaiser JP, McQueen CA, Chorley BN (2016) Tipping the balance: hepatotoxicity and the 4 apical key events of hepatic steatosis. Toxicol Sci 150(2):261–268. https://doi.org/10.1093/toxsci/kfw018

Article  CAS  PubMed  Google Scholar 

Ankley GT, Edwards SW (2018) The Adverse outcome pathway: a multifaceted framework supporting 21(st) century toxicology. Curr Opin Toxicol 9:1–7. https://doi.org/10.1016/j.cotox.2018.03.004

Article  PubMed  PubMed Central  Google Scholar 

Bitter A, Rummele P, Klein K et al (2015) Pregnane X receptor activation and silencing promote steatosis of human hepatic cells by distinct lipogenic mechanisms. Arch Toxicol 89(11):2089–2103. https://doi.org/10.1007/s00204-014-1348-x

Article  CAS  PubMed  Google Scholar 

Braeuning A, Sanna R, Huelsken J, Schwarz M (2009) Inducibility of drug-metabolizing enzymes by xenobiotics in mice with liver-specific knockout of Ctnnb1. Drug Metab Dispos 37(5):1138–1145. https://doi.org/10.1124/dmd.108.026179

Article  CAS  PubMed  Google Scholar 

Braeuning A, Vetter S, Orsetti S, Schwarz M (2012) Paradoxical cytotoxicity of tert-butylhydroquinone in vitro: what kills the untreated cells? Arch Toxicol 86(9):1481–1487. https://doi.org/10.1007/s00204-012-0841-3

Article  CAS  PubMed  Google Scholar 

Dentin R, Girard J, Postic C (2005) Carbohydrate responsive element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c): two key regulators of glucose metabolism and lipid synthesis in liver. Biochimie 87(1):81–86. https://doi.org/10.1016/j.biochi.2004.11.008

Article  CAS  PubMed  Google Scholar 

Donato MT, Tolosa L, Jimenez N, Castell JV, Gomez-Lechon MJ (2012) High-content imaging technology for the evaluation of drug-induced steatosis using a multiparametric cell-based assay. J Biomol Screen 17(3):394–400. https://doi.org/10.1177/1087057111427586

Article  CAS  PubMed  Google Scholar 

EFSA (2015) The 2013 European Union report on pesticide residues in food. EFSA J 13(3):4038

Article  CAS  Google Scholar 

EFSA (2012) Identification of cumulative assessment groups of pesticides, vol 9. EFSA Supporting Publications, Parma, Italy, pp 1-303

Georgopapadakou NH (1998) Antifungals: mechanism of action and resistance, established and novel drugs. Curr Opin Microbiol 1(5):547–557

Article  CAS  PubMed  Google Scholar 

Goetz AK, Dix DJ (2009) Mode of action for reproductive and hepatic toxicity inferred from a genomic study of triazole antifungals. Toxicol Sci 110(2):449–462. https://doi.org/10.1093/toxsci/kfp098

Article  CAS  PubMed  Google Scholar 

Gripon P, Rumin S, Urban S et al (2002) Infection of a human hepatoma cell line by hepatitis B virus. Proc Natl Acad Sci USA 99(24):15655–15660. https://doi.org/10.1073/pnas.232137699

Article  CAS  PubMed  Google Scholar 

Hampf M, Gossen M (2006) A protocol for combined Photinus and Renilla luciferase quantification compatible with protein assays. Anal Biochem 356(1):94–99. https://doi.org/10.1016/j.ab.2006.04.046

Article  CAS  PubMed  Google Scholar 

Heise T, Schmidt F, Knebel C et al (2015) Hepatotoxic effects of (tri)azole fungicides in a broad dose range. Arch Toxicol 89(11):2105–2117. https://doi.org/10.1007/s00204-014-1336-1

Article  CAS  PubMed  Google Scholar 

Heise T, Schmidt F, Knebel C et al (2018) Hepatotoxic combination effects of three azole fungicides in a broad dose range. Arch Toxicol 92(2):859–872. https://doi.org/10.1007/s00204-017-2087-6

Article  CAS  PubMed  Google Scholar 

Hester SD, Nesnow S (2008) Transcriptional responses in thyroid tissues from rats treated with a tumorigenic and a non-tumorigenic triazole conazole fungicide. Toxicol Appl Pharmacol 227(3):357–369. https://doi.org/10.1016/j.taap.2007.10.030

Article  CAS  PubMed  Google Scholar 

Joshi-Barve S, Kirpich I, Cave MC, Marsano LS, McClain CJ (2015) Alcoholic, nonalcoholic, and toxicant-associated steatohepatitis: mechanistic similarities and differences. Cell Mol Gastroenterol Hepatol 1(4):356–367. https://doi.org/10.1016/j.jcmgh.2015.05.006

Article  PubMed  PubMed Central  Google Scholar 

Kienhuis AS, Slob W, Gremmer ER, Vermeulen JP, Ezendam J (2015) A Dose-response modeling approach shows that effects from mixture exposure to the skin sensitizers isoeugenol and cinnamal are in line with dose addition and not with synergism. Toxicol Sci 147(1):68–74. https://doi.org/10.1093/toxsci/kfv109

Article  CAS  PubMed  Google Scholar 

Kleiner DE, Brunt EM, Van Natta M et al (2005) Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41(6):1313–1321. https://doi.org/10.1002/hep.20701

Article  PubMed  Google Scholar 

Knebel C, Kebben J, Eberini I et al (2018a) Propiconazole is an activator of AHR and causes concentration additive effects with an established AHR ligand. Arch Toxicol 92:3471–3486. https://doi.org/10.1007/s00204-018-2321-x

Article  CAS  PubMed  Google Scholar 

Knebel C, Neeb J, Zahn E et al (2018b) Unexpected effects of propiconazole, tebuconazole, and their mixture on the receptors CAR and PXR in human liver cells. Toxicol Sci 163(1):170–181. https://doi.org/10.1093/toxsci/kfy026

Article  CAS  PubMed  Google Scholar 

Knebel C, Heise T, Zanger UM, Lampen A, Marx-Stoelting P, Braeuning A (2019) The azole fungicide tebuconazole affects human CYP1A1 and CYP1A2 expression by an aryl hydrocarbon receptor-dependent pathway. Food Chem Toxicol 123:481–491. https://doi.org/10.1016/j.fct.2018.11.039

Article  CAS  PubMed  Google Scholar 

Kortenkamp A, Backhaus T, Faust M (2009) State of the art report on mixture toxicity. EU Report. European Commission, Brussels, Belgium

Luckert C, Braeuning A, de Sousa G et al (2018) Adverse outcome pathway-driven analysis of liver steatosis in vitro: a case study with cyproconazole. Chem Res Toxicol 31(8):784–798. https://doi.org/10.1021/acs.chemrestox.8b00112

Article  CAS  PubMed  Google Scholar 

Marx-Stoelting P, Ganzenberg K, Knebel C et al (2017) Hepatotoxic effects of cyproconazole and prochloraz in wild-type and hCAR/hPXR mice. Arch Toxicol 91:2895–2907. https://doi.org/10.1007/s00204-016-1925-2

Article  CAS  PubMed  Google Scholar 

Mellor CL, Steinmetz FP, Cronin MT (2015) The identification of nuclear receptors associated with hepatic steatosis to develop and extend adverse outcome pathways. Crit Rev Toxicol 46:1–15. https://doi.org/10.3109/10408444.2015.1089471

Article  CAS  Google Scholar 

Noureddin M, Rinella ME (2015) Nonalcoholic fatty liver disease, diabetes, obesity, and hepatocellular carcinoma. Clin Liver Dis 19(2):361–379. https://doi.org/10.1016/j.cld.2015.01.012

Article  PubMed  PubMed Central  Google Scholar 

Prutner W, Nicken P, Haunhorst E, Hamscher G, Steinberg P (2013) Effects of single pesticides and binary pesticide mixtures on estrone production in H295R cells. Arch Toxicol 87(12):2201–2214. https://doi.org/10.1007/s00204-013-1081-x

Article  CAS  PubMed  Google Scholar 

Rieke S, Heise T, Schmidt F et al (2017) Mixture effects of azole fungicides on the adrenal gland in a broad dose range. Toxicology 385:28–37. https://doi.org/10.1016/j.tox.2017.04.012

Article  CAS  PubMed  Google Scholar 

Roth A, Looser R, Kaufmann M et al (2008) Regulatory cross-talk between drug metabolism and lipid homeostasis: constitutive androstane receptor and pregnane X receptor increase Insig-1 expression. Mol Pharmacol 73(4):1282–1289. https://doi.org/10.1124/mol.107.041012

Article  CAS  PubMed  Google Scholar 

Sae-Lee C, Moolsuwan K, Chan L, Poungvarin N (2016) ChREBP regulates itself and metabolic genes implicated in lipid accumulation in beta-cell line. PLoS One 11(1):e0147411. https://doi.org/10.1371/journal.pone.0147411

Article  CAS  PubMed  PubMed Central  Google Scholar 

Schmidt F, Marx-Stoelting P, Haider W et al (2016) Combination effects of azole fungicides in male rats in a broad dose range. Toxicology 355–356:54–63. https://doi.org/10.1016/j.tox.2016.05.018

Article  CAS  PubMed  Google Scholar 

Shimano H (2001) Sterol regulatory element-binding proteins (SREBPs): transcriptional regulators of lipid synthetic genes. Prog Lipid Res 40(6):439–452

Article  CAS  PubMed  Google Scholar 

Spruiell K, Jones DZ, Cullen JM, Awumey EM, Gonzalez FJ, Gyamfi MA (2014) Role of human pregnane X receptor in high fat diet-induced obesity in pre-menopausal female mice. Biochem Pharmacol 89(3):399–412. https://doi.org/10.1016/j.bcp.2014.03.019

Article  CAS  PubMed  PubMed Central  Google Scholar 

Spruiell K, Richardson RM, Cullen JM, Awumey EM, Gonzalez FJ, Gyamfi MA (2014) Role of pregnane X receptor in obesity and glucose homeostasis in male mice. J Biol Chem 289(6):3244–3261. https://doi.org/10.1074/jbc.M113.494575

Article  CAS  PubMed  Google Scholar 

Stepankova M, Pastorkova B, Bachleda P, Dvorak Z (2017) Itraconazole cis-diastereoisomers activate aryl hydrocarbon receptor AhR and pregnane X receptor PXR and induce CYP1A1 in human cell lines and human hepatocytes. Toxicology 383:40–49. https://doi.org/10.1016/j.tox.2017.04.002

Article  CAS  PubMed  Google Scholar 

Tanner N, Kubik L, Luckert C et al (2018) Regulation of drug metabolism by the interplay of inflammatory signaling, steatosis, and xeno-sensing receptors in HepaRG cells. Drug Metab Dispos 46(4):326–335. https://doi.org/10.1124/dmd.117.078675

Article  CAS  PubMed  Google Scholar 

Tolosa L, Gomez-Lechon MJ, Jimenez N, Hervas D, Jover R, Donato MT (2016) Advantageous use of HepaRG cells for the screening and mechanistic study of drug-induced steatosis. Toxicol Appl Pharmacol 302:1–9. https://doi.org/10.1016/j.taap.2016.04.007

Article  CAS  PubMed  Google Scholar 

Tonazzi A, Eberini I, Indiveri C (2013) Molecular mechanism of inhibition of the mitochondrial carnitine/acylcarnitine transporter by omeprazole revealed by proteoliposome assay, mutagenesis and bioinformatics. PLoS One 8(12):e82286. https://doi.org/10.1371/journal.pone.0082286

Article  CAS  PubMed  PubMed Central  Google Scholar 

Tully DB, Bao W, Goetz AK et al (2006) Gene expression profiling in liver and testis of rats to characterize the toxicity of triazole fungicides. Toxicol Appl Pharmacol 215(3):260–273. https://doi.org/10.1016/j.taap.2006.02.015

Article  CAS  PubMed  Google Scholar 

Vinken M (2013) The adverse outcome pathway concept: a pragmatic tool in toxicology. Toxicology 312:158–165. https://doi.org/10.1016/j.tox.2013.08.011

Article  CAS  PubMed  Google Scholar 

Vinken M (2015) Adverse outcome pathways and drug-induced liver injury testing. Chem Res Toxicol 28(7):1391–1397. https://doi.org/10.1021/acs.chemrestox.5b00208

Article  CAS  PubMed  PubMed Central  Google Scholar 

Vinken M (2016) Adverse outcome pathways as tools to assess drug-induced toxicity. Methods Mol Biol 1425:325–337. https://doi.org/10.1007/978-1-4939-3609-0_14 (Clifton, NJ)

Article  CAS  PubMed  PubMed Central  Google Scholar 

White DL, Kanwal F, El-Serag HB (2012) Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 10(12):1342–1359.e2. https://doi.org/10.1016/j.cgh.2012.10.001

Article  PubMed  PubMed Central  Google Scholar 

Zahn E, Wolfrum J, Knebel C et al (2018) Mixture effects of two plant protection products in liver cell lines. Food Chem Toxicol 112:299–309. https://doi.org/10.1016/j.fct.2017.12.067

Article  CAS  PubMed  Google Scholar