{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T19:45:04Z","timestamp":1790106304305,"version":"4.0.1"},"reference-count":58,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2022,12,28]],"date-time":"2022-12-28T00:00:00Z","timestamp":1672185600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,12,28]],"date-time":"2022-12-28T00:00:00Z","timestamp":1672185600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["681002 (Eu-ToxRisk)"],"award-info":[{"award-number":["681002 (Eu-ToxRisk)"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["No. 964537 (RISKHUNT3R)"],"award-info":[{"award-number":["No. 964537 (RISKHUNT3R)"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arch Toxicol"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Environmental or occupational exposure of humans to trichloroethylene (TCE) has been associated with different extrahepatic toxic effects, including nephrotoxicity and neurotoxicity. Bioactivation of TCE via the glutathione (GSH) conjugation pathway has been proposed as underlying mechanism, although only few mechanistic studies have used cell models of human origin. In this study, six human derived cell models were evaluated as in vitro models representing potential target tissues of TCE-conjugates: RPTEC\/TERT1 (kidney), HepaRG (liver), HUVEC\/TERT2 (vascular endothelial), LUHMES (neuronal, dopaminergic), human induced pluripotent stem cells (hiPSC) derived peripheral neurons (UKN5) and hiPSC-derived differentiated brain cortical cultures containing all subtypes of neurons and astrocytes (BCC42). A high throughput transcriptomic screening, utilizing mRNA templated oligo-sequencing (TempO-Seq), was used to study transcriptomic effects after exposure to TCE-conjugates. Cells were exposed to a wide range of concentrations of S-(1,2-<jats:italic>trans<\/jats:italic>-dichlorovinyl)glutathione (1,2-DCVG), S-(1,2-<jats:italic>trans<\/jats:italic>-dichlorovinyl)-L-cysteine (1,2-DCVC), S-(2,2-dichlorovinyl)glutathione (2,2-DCVG), and S-(2,2-dichlorovinyl)-L-cysteine (2,2-DCVC). 1,2-DCVC caused stress responses belonging to the <jats:italic>Nrf2 pathway<\/jats:italic> and <jats:italic>Unfolded protein response<\/jats:italic> in all the tested models but to different extents. The renal model was the most sensitive model to both 1,2-DCVC and 1,2-DCVG, with an early <jats:italic>Nrf2<\/jats:italic>-response at 3\u00a0\u00b5M and hundreds of differentially expressed genes at higher concentrations. Exposure to 2,2-DCVG and 2,2-DCVC also resulted in the upregulation of <jats:italic>Nrf2 pathway<\/jats:italic> genes in RPTEC\/TERT1 although at higher concentrations. Of the three neuronal models, both the LUHMES and BCC42 showed significant <jats:italic>Nrf2<\/jats:italic>-responses and at higher concentration UPR-responses, supporting recent hypotheses that 1,2-DCVC may be involved in neurotoxic effects of TCE. The cell models with the highest expression of \u03b3-glutamyltransferase (GGT) enzymes, showed cellular responses to both 1,2-DCVG and 1,2-DCVC. Little to no effects were found in the neuronal models from 1,2-DCVG exposure due to their low GGT-expression. This study expands our knowledge on tissue specificity of TCE S-conjugates and emphasizes the value of human cell models together with transcriptomics for such mechanistic studies.<\/jats:p>","DOI":"10.1007\/s00204-022-03436-6","type":"journal-article","created":{"date-parts":[[2022,12,28]],"date-time":"2022-12-28T11:05:50Z","timestamp":1672225550000},"page":"523-545","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Transcriptomic-based evaluation of trichloroethylene glutathione and cysteine conjugates demonstrate phenotype-dependent stress responses in a panel of human in vitro models"],"prefix":"10.1007","volume":"97","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7301-2473","authenticated-orcid":false,"given":"Liliana","family":"Capinha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaran","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Katharina","family":"Holzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Katharina","family":"\u00dcckert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melinda","family":"Zana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giada","family":"Carta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cormac","family":"Murphy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna","family":"Baldovini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra","family":"Mazidi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Grillari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andras","family":"Dinnyes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bob","family":"van de Water","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Leist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan N. M.","family":"Commandeur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Jennings","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,12,28]]},"reference":[{"issue":"1","key":"3436_CR1","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.tiv.2014.10.005","volume":"30","author":"L Aschauer","year":"2015","unstructured":"Aschauer L, Limonciel A, Wilmes A, Stanzel S, Kopp-Schneider A, Hewitt P, Lukas A, Leonard MO, Pfaller W, Jennings P (2015) Application of RPTEC\/TERT1 cells for investigation of repeat dose nephrotoxicity: a transcriptomic study. Toxicology 30(1):106\u2013116. https:\/\/doi.org\/10.1016\/j.tiv.2014.10.005","journal-title":"Toxicology"},{"key":"3436_CR2","unstructured":"Biopredic, International (2017) Differentiated HepaRG \u00ae cells cryopreserved: description and user guide for thawing, culture and use. Fr HepaRG, hepatic stem cell line. https:\/\/www.heparg.com\/vars\/fichiers\/Products\/HepaRG_differentiated_User_Guide.pdf."},{"issue":"1","key":"3436_CR3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s002040050461","volume":"72","author":"G Birner","year":"1997","unstructured":"Birner G, Bernauer U, Werner M, Dekant W (1997) Biotransformation, excretion and nephrotoxicity of haloalkene-derived cysteine S-conjugates. Arch Toxicol 72(1):1\u20138. https:\/\/doi.org\/10.1007\/s002040050461","journal-title":"Arch Toxicol"},{"issue":"3","key":"3436_CR4","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1021\/tx9902082","volume":"13","author":"JL Bolton","year":"2000","unstructured":"Bolton JL, Trush MA, Penning TM, Dryhurst G, Monks TJ (2000) Role of quinones in toxicology. Chem Res Toxicol 13(3):135\u2013160. https:\/\/doi.org\/10.1021\/tx9902082","journal-title":"Chem Res Toxicol"},{"key":"3436_CR5","doi-asserted-by":"publisher","unstructured":"Bruning T, Bolt HM (2000) Renal toxicity and carcinogenicity of trichloroethylene: key results, mechanisms, and controversies. Crit Rev Toxicol 30(3):253\u2013285. https:\/\/doi.org\/10.1080\/10408440091159202.","DOI":"10.1080\/10408440091159202"},{"key":"3436_CR6","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.toxlet.2021.01.021","volume":"341","author":"L Capinha","year":"2021","unstructured":"Capinha L, Jennings P, Commandeur JNM (2021) Bioactivation of trichloroethylene to three regioisomeric glutathione conjugates by liver fractions and recombinant human glutathione transferases: species differences and implications for human risk assessment. Toxicol Lett 341:94\u2013106. https:\/\/doi.org\/10.1016\/j.toxlet.2021.01.021","journal-title":"Toxicol Lett"},{"issue":"3","key":"3436_CR7","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1038\/nbt.1529","volume":"27","author":"SM Chambers","year":"2009","unstructured":"Chambers SM, Fasano CA, Papapetrou EP, Tomishima M, Sadelain M, Studer L (2009) Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol 27(3):275\u2013280. https:\/\/doi.org\/10.1038\/nbt.1529","journal-title":"Nat Biotechnol"},{"key":"3436_CR8","doi-asserted-by":"publisher","unstructured":"Cichocki JA, Guyton KZ, Guha N, Chiu WA, Rusyn I, Lash LH (2016) Target organ metabolism, toxicity, and mechanisms of trichloroethylene and perchloroethylene: key similarities, differences, and data gaps. J Pharmacol Exp Ther 359(1):110\u2013123. https:\/\/doi.org\/10.1124\/jpet.116.232629.","DOI":"10.1124\/jpet.116.232629"},{"issue":"5","key":"3436_CR9","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1007\/bf02284259","volume":"65","author":"JNM Commandeur","year":"1991","unstructured":"Commandeur JNM, Boogaard PJ, Mulder GJ, Vermeulen NPE (1991) Mutagenicity and cytotoxicity of two regioisomeric mercapturic acids and cysteine S-conjugates of trichloroethylene. Arch Toxicol 65(5):373\u2013380. https:\/\/doi.org\/10.1007\/bf02284259","journal-title":"Arch Toxicol"},{"issue":"1","key":"3436_CR10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00726-005-0243-4","volume":"30","author":"AJL Cooper","year":"2006","unstructured":"Cooper AJL, Pinto JT (2006) Cysteine S-conjugate \u03b2-lyases. Amino Acids 30(1):1\u201315. https:\/\/doi.org\/10.1007\/s00726-005-0243-4","journal-title":"Amino Acids"},{"issue":"1","key":"3436_CR11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s10565-015-9293-x","volume":"31","author":"P Cristofori","year":"2015","unstructured":"Cristofori P, Sauer AV, Trevisan A (2015) Three common pathways of nephrotoxicity induced by halogenated alkenes. Cell Biol Toxicol 31(1):1\u201313. https:\/\/doi.org\/10.1007\/s10565-015-9293-x","journal-title":"Cell Biol Toxicol"},{"issue":"1","key":"3436_CR12","doi-asserted-by":"publisher","first-page":"43","DOI":"10.3109\/03602538908994144","volume":"20","author":"W Dekant","year":"1989","unstructured":"Dekant W, Vamvakas S, Anders MW (1989) Bioactivation of nephrototoxic haloalkenes by glutathione conjugation: formation of toxic and mutagenic intermediates by cysteine conjugate beta-lyase. Drug Metab Rev 20(1):43\u201383. https:\/\/doi.org\/10.3109\/03602538908994144","journal-title":"Drug Metab Rev"},{"key":"3436_CR13","doi-asserted-by":"publisher","unstructured":"De Miranda BR, Greenamyre JT (2020) Trichloroethylene, a ubiquitous environmental contaminant in the risk for Parkinson's disease. Environ Sci Process Impacts 22(3):543\u2013554. https:\/\/doi.org\/10.1039\/c9em00578a.","DOI":"10.1039\/c9em00578a"},{"key":"3436_CR14","doi-asserted-by":"publisher","unstructured":"Elkin ER, Harris SM, Loch-Caruso R (2018) Trichloroethylene metabolite S-(1,2-dichlorovinyl)-l-cysteine induces lipid peroxidation-associated apoptosis via the intrinsic and extrinsic apoptosis pathways in a first-trimester placental cell line. Toxicol Appl Pharmacol 338:30\u201342. https:\/\/doi.org\/10.1016\/j.taap.2017.11.006.","DOI":"10.1016\/j.taap.2017.11.006"},{"key":"3436_CR15","doi-asserted-by":"publisher","unstructured":"Elkin ER, Bridges D, Loch-Caruso R (2019) The trichloroethylene metabolite S-(1,2-dichlorovinyl)-L-cysteine induces progressive mitochondrial dysfunction in HTR-8\/SVneo trophoblasts. Toxicology 427:152283. https:\/\/doi.org\/10.1016\/j.tox.2019.152283.","DOI":"10.1016\/j.tox.2019.152283"},{"key":"3436_CR16","doi-asserted-by":"publisher","unstructured":"Elkin ER, Bakulski KM, Colacino JA, Bridges D, Kilburn BA, Armant DR, Loch-Caruso R (2021) Transcriptional profiling of the response to the trichloroethylene metabolite S-(1,2-dichlorovinyl)-L-cysteine revealed activation of the eIF2alpha\/ATF4 integrated stress response in two in vitro placental models. Arch Toxicol 95(5):1595\u20131619. https:\/\/doi.org\/10.1007\/s00204-021-03011-5.","DOI":"10.1007\/s00204-021-03011-5"},{"key":"3436_CR17","doi-asserted-by":"publisher","first-page":"3643","DOI":"10.1007\/s00204-019-02591-7","volume":"93","author":"SE Escher","year":"2019","unstructured":"Escher SE, Kamp H, Bennekou SH, Bitsch A, Fisher C, Graepel R, Hengstler JG, Herzler M, Knight D, Leist M, Norinder U, Ou\u00e9draogo G, Pastor M, Stuard S, White A, Zdrazil B, van de Water B, Kroese D (2019) Towards grouping concepts based on new approach methodologies in chemical hazard assessment: the read-across approach of the EU-ToxRisk project. Arch Toxicol 93:3643\u20133667. https:\/\/doi.org\/10.1007\/s00204-019-02591-7","journal-title":"Arch Toxicol"},{"issue":"2","key":"3436_CR18","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1002\/ana.21288","volume":"63","author":"DM Gash","year":"2008","unstructured":"Gash DM, Rutland K, Hudson NL, Sullivan PG, Bing G, Cass WA, Jignesh D et al (2008) Trichloroethylene: Parkinsonism and complex 1 mitochondrial neurotoxicity. Annals Neurol 63(2):184\u2013192. https:\/\/doi.org\/10.1002\/ana.21288","journal-title":"Annals Neurol"},{"issue":"1","key":"3436_CR19","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1093\/toxsci\/kfab009","volume":"181","author":"JA Harrill","year":"2021","unstructured":"Harrill JA, Everett LJ, Haggard DE, Sheffield T, Bundy JL, Willis CM, Thomas RS, Shah I, Judson RS (2021) High-throughput transcriptomics platform for screening environmental chemicals. Toxicol Sci 181(1):68\u201389. https:\/\/doi.org\/10.1093\/toxsci\/kfab009","journal-title":"Toxicol Sci"},{"issue":"4","key":"3436_CR20","doi-asserted-by":"publisher","first-page":"476","DOI":"10.5966\/sctm.2015-0108","volume":"5","author":"L Hoelting","year":"2016","unstructured":"Hoelting L, Klima S, Karreman C, Grinberg M, Meisig J, Henry M, Rotshteyn T, Rahnenf\u00fchrer J, Bl\u00fcthgen N, Sachinidis A, Waldmann T, Leist M (2016) Stem cell-derived immature human dorsal root ganglia neurons to identify peripheral neurotoxicants. Stem Cells Transl Med 5(4):476\u2013487. https:\/\/doi.org\/10.5966\/sctm.2015-0108","journal-title":"Stem Cells Transl Med"},{"issue":"7","key":"3436_CR21","doi-asserted-by":"publisher","first-page":"3734","DOI":"10.3390\/ijms23073734","volume":"23","author":"A-K Holzer","year":"2022","unstructured":"Holzer A-K, Suciu I, Karreman C, Goj T, Leist M (2022) Specific attenuation of purinergic signaling during bortezomib-induced peripheral neuropathy in. Int J Mol Sci 23(7):3734\u20133734. https:\/\/doi.org\/10.3390\/ijms23073734","journal-title":"Int J Mol Sci"},{"key":"3436_CR22","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1007\/s002040050264","volume":"70","author":"O Ilinskaja","year":"1996","unstructured":"Ilinskaja O, Vamvakas S (1996) Alterations of the renal function in the isolated perfused rat kidney system after in vivo and in vitro application of S-(1,2-dichlorovinyl)-L-cysteine and S-(2,2-dichlorovinyl)-L-cysteine. Arch Toxicol 70:224\u2013229","journal-title":"Arch Toxicol"},{"issue":"3","key":"3436_CR23","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1152\/ajprenal.00005.2007","volume":"293","author":"P Jennings","year":"2007","unstructured":"Jennings P, Koppelstaetter C, Aydin S, Abberger T, Wolf AM, Mayer G, Walter Pfaller G, Mayer PW (2007) Cyclosporine A induces senescence in renal tubular epithelial cells. Am J Physiol Renal Physiol 293(3):831\u2013838. https:\/\/doi.org\/10.1152\/ajprenal.00005.2007","journal-title":"Am J Physiol Renal Physiol"},{"issue":"3","key":"3436_CR24","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1016\/j.tiv.2008.12.023","volume":"23","author":"P Jennings","year":"2009","unstructured":"Jennings P, Aydin S, Bennett J, McBride R, Weiland C, Tuite N, Gruber LN, Perco P, Gaora P\u00d3, Ellinger-Ziegelbauer H, Ahr HJ, Van Kooten C, Daha MR, Prieto P, Ryan MP, Pfaller W, McMorrow T (2009) Inter-laboratory comparison of human renal proximal tubule (HK-2) transcriptome alterations due to Cyclosporine A exposure and medium exhaustion. Toxicology 23(3):486\u2013499. https:\/\/doi.org\/10.1016\/j.tiv.2008.12.023","journal-title":"Toxicology"},{"key":"3436_CR25","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq1156","author":"A Kamburov","year":"2011","unstructured":"Kamburov A, Pentchev K, Galicka H, Wierling C, Lehrach H, Herwig R (2011) ConsensusPathDB: toward a more complete picture of cell biology. Nucleic Acids Res. https:\/\/doi.org\/10.1093\/nar\/gkq1156","journal-title":"Nucleic Acids Res"},{"issue":"7","key":"3436_CR26","doi-asserted-by":"publisher","first-page":"1444","DOI":"10.1124\/dmd.107.020016","volume":"36","author":"KP Kanebratt","year":"2008","unstructured":"Kanebratt KP, Andersson TB (2008) Evaluation of HepaRG cells as an in vitro model for human drug metabolism studies. Drug Metab Dispos 36(7):1444\u20131452. https:\/\/doi.org\/10.1124\/dmd.107.020016","journal-title":"Drug Metab Dispos"},{"issue":"5","key":"3436_CR27","doi-asserted-by":"publisher","first-page":"1703","DOI":"10.1007\/s00204-021-03024-0","volume":"95","author":"S Klima","year":"2021","unstructured":"Klima S, Br\u00fcll M, Spreng AS, Suciu I, Falt T, Schwamborn JC, Waldmann T, Karreman C, Leist M (2021) A human stem cell-derived test system for agents modifying neuronal N-methyl-d-aspartate-type glutamate receptor Ca2+-signalling. Arch Toxicol 95(5):1703\u20131722. https:\/\/doi.org\/10.1007\/s00204-021-03024-0","journal-title":"Arch Toxicol"},{"key":"3436_CR28","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2020.104837","author":"DJ Knight","year":"2021","unstructured":"Knight DJ, Deluyker H, Chaudhry Q, Vidal JM, de Boer A (2021) A call for action on the development and implementation of new methodologies for safety assessment of chemical-based products in the EU \u2013 A short communication. Regul Toxicol Pharmacol. https:\/\/doi.org\/10.1016\/j.yrtph.2020.104837","journal-title":"Regul Toxicol Pharmacol"},{"issue":"5","key":"3436_CR29","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.3390\/cells9051122","volume":"9","author":"J Kobolak","year":"2020","unstructured":"Kobolak J, Teglasi A, Bellak T, Janstova Z, Molnar K, Zana M, Bock I, Laszlo L, Dinnyes A (2020) Human induced pluripotent stem cell-derived 3D-neurospheres are suitable for neurotoxicity screening. Cells 9(5):1122. https:\/\/doi.org\/10.3390\/cells9051122","journal-title":"Cells"},{"issue":"7","key":"3436_CR30","doi-asserted-by":"publisher","first-page":"2435","DOI":"10.1007\/s00204-020-02802-6","volume":"94","author":"A Krebs","year":"2020","unstructured":"Krebs A, van Vugt-Lussenburg BMA, Waldmann T, Albrecht W, Boei J, ter Braak B, Brajnik M, Braunbeck T, Brecklinghaus T, Busquet F, Dinnyes A, Dokler J, Dolde X, Exner TE, Fisher C, Fluri D, Forsby A, Hengstler JG, Holzer AK, Janstova Z, Jennings P, Kisitu J, Kobolak J, Kumar M, Limonciel A, Lundqvist J, Mihalik B, Moritz W, Pallocca G, Ulloa APC, Pastor M, Rovida C, Sarkans U, Schimming JP, Schmidt BZ, St\u00f6ber R, Strassfeld T, van de Water B, Wilmes A, van der Burg B, Verfaillie CM, von Hellfeld R, Vrieling H, Vrijenhoek NG, Leist M (2020) The EU-ToxRisk method documentation, data processing and chemical testing pipeline for the regulatory use of new approach methods. Arch Toxicol 94(7):2435\u20132461. https:\/\/doi.org\/10.1007\/s00204-020-02802-6","journal-title":"Arch Toxicol"},{"key":"3436_CR31","doi-asserted-by":"crossref","unstructured":"Kroll J, Waltenberger J (1997) The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells. J Biol Chem 272 (51): 32521\u201332827. http:\/\/www.jbc.org.","DOI":"10.1074\/jbc.272.51.32521"},{"issue":"12","key":"3436_CR32","doi-asserted-by":"publisher","first-page":"2215","DOI":"10.1007\/s00204-013-1072-y","volume":"87","author":"AK Krug","year":"2013","unstructured":"Krug AK, Balmer NV, Matt F, Sch\u00f6nenberger F, Merhof D, Leist M (2013) Evaluation of a human neurite growth assay as specific screen for developmental neurotoxicants. Arch Toxicol 87(12):2215\u20132231. https:\/\/doi.org\/10.1007\/s00204-013-1072-y","journal-title":"Arch Toxicol"},{"key":"3436_CR33","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2014.166","author":"AK Krug","year":"2014","unstructured":"Krug AK, Gutbier S, Zhao L, P\u00f6ltl D, Kullmann C, Ivanova V, F\u00f6rster S, Jagtap S, Meiser J, Leparc G, Schildknecht S, Adam M, Hiller K, Farhan H, Brunner T, Hartung T, Sachinidis A, Leist M (2014) Transcriptional and metabolic adaptation of human neurons to the mitochondrial toxicant MPP +. Cell Death Dis. https:\/\/doi.org\/10.1038\/cddis.2014.166","journal-title":"Cell Death Dis"},{"key":"3436_CR34","doi-asserted-by":"publisher","unstructured":"Lash LH, Parker JC (2001) Hepatic and renal toxicities associated with perchloroethylene. Pharmacol Rev 53 (2): 177\u2013208. https:\/\/doi.org\/10.1124\/pharmrev2. http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/11356983.","DOI":"10.1124\/pharmrev2"},{"key":"3436_CR35","unstructured":"Lash LH, Xu Y, Elfarra AA, Duescher RJ, Parker JC (1995) Glutathione-dependent metabolism of trichloroethylene in isolated liver and kidney cells of rats and its role in mitochondrial and cellular toxicity. Drug Metabol Dispos 23 (8): 846\u2013853. https:\/\/dmd.aspetjournals.org\/content\/dmd\/23\/8\/846.full.pdf."},{"issue":"2","key":"3436_CR36","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/j.taap.2004.09.023","volume":"206","author":"LH Lash","year":"2005","unstructured":"Lash LH, Putt DA, Hueni SE, Horwitz BP (2005) Molecular markers of trichloroethylene-induced toxicity in human kidney cells. Toxicol Appl Pharmacol 206(2):157\u2013168. https:\/\/doi.org\/10.1016\/j.taap.2004.09.023","journal-title":"Toxicol Appl Pharmacol"},{"key":"3436_CR37","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.mrrev.2014.04.003","volume":"762","author":"LH Lash","year":"2014","unstructured":"Lash LH, Chiu WA, Guyton KZ, Rusyn I (2014) Trichloroethylene biotransformation and its role in mutagenicity, carcinogenicity and target organ toxicity. Mutation Res Rev Mutation Res 762:22\u201336. https:\/\/doi.org\/10.1016\/j.mrrev.2014.04.003","journal-title":"Mutation Res Rev Mutation Res"},{"key":"3436_CR38","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1016\/j.crtox.2021.07.003","volume":"2","author":"F Lee","year":"2021","unstructured":"Lee F, Shah I, Soong YT, Xing J, Ng IC, Tasnim F, Hanry Yu (2021) Reproducibility and robustness of high-throughput S1500+ transcriptomics on primary rat hepatocytes for chemical-induced hepatotoxicity assessment. Curr Res Toxicol 2:282\u2013295. https:\/\/doi.org\/10.1016\/j.crtox.2021.07.003","journal-title":"Curr Res Toxicol"},{"issue":"8","key":"3436_CR39","doi-asserted-by":"publisher","first-page":"2517","DOI":"10.1007\/s00204-018-2256-2","volume":"92","author":"A Limonciel","year":"2018","unstructured":"Limonciel A, Ates G, Carta G, Wilmes A, Watzele M, Shepard PJ, VanSteenhouse HC, Seligmann B, Yeakley JM, van de Water B, Vinken M, Jennings P (2018) Comparison of base-line and chemical-induced transcriptomic responses in HepaRG and RPTEC\/TERT1 cells using TempO-Seq. Arch Toxicol 92(8):2517\u20132531. https:\/\/doi.org\/10.1007\/s00204-018-2256-2","journal-title":"Arch Toxicol"},{"issue":"2","key":"3436_CR40","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1093\/toxsci\/kfj107","volume":"91","author":"EA Lock","year":"2006","unstructured":"Lock EA, Reed CJ (2006) Trichloroethylene: Mechanisms of renal toxicity and renal cancer and relevance to risk assessment. Toxicol Sci 91(2):313\u2013331. https:\/\/doi.org\/10.1093\/toxsci\/kfj107","journal-title":"Toxicol Sci"},{"issue":"2","key":"3436_CR41","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/j.taap.2006.06.002","volume":"216","author":"EA Lock","year":"2006","unstructured":"Lock EA, Barth JL, Argraves SW, Schnellmann RG (2006) Changes in gene expression in human renal proximal tubule cells exposed to low concentrations of S-(1,2-dichlorovinyl)-l-cysteine, a metabolite of trichloroethylene. Toxicol Appl Pharmacol 216(2):319\u2013330. https:\/\/doi.org\/10.1016\/j.taap.2006.06.002","journal-title":"Toxicol Appl Pharmacol"},{"key":"3436_CR42","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","author":"MI Love","year":"2014","unstructured":"Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. https:\/\/doi.org\/10.1186\/s13059-014-0550-8","journal-title":"Genome Biol"},{"issue":"5","key":"3436_CR43","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1007\/s12015-015-9599-3","volume":"11","author":"M Morrison","year":"2015","unstructured":"Morrison M, Klein C, Clemann N, Collier DA, Hardy J, Barbara Hei\u03b2erer M, Cader Z, Graf M, Kaye J (2015) StemBANCC: governing access to material and data in a large stem cell research consortium. Stem Cell Rev Reports 11(5):681\u2013687. https:\/\/doi.org\/10.1007\/s12015-015-9599-3","journal-title":"Stem Cell Rev Reports"},{"issue":"3","key":"3436_CR44","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1006\/exmp.2002.2424","volume":"72","author":"AM M\u00fcller","year":"2002","unstructured":"M\u00fcller AM, Iris Hermanns M, Skrzynski C, Nesslinger M, M\u00fcller KM, James Kirkpatrick C (2002) Expression of the endothelial markers PECAM-1, vWF, and CD34 in Vivo and in. Exp Mol Pathol 72(3):221\u2013229. https:\/\/doi.org\/10.1006\/exmp.2002.2424","journal-title":"Exp Mol Pathol"},{"key":"3436_CR45","doi-asserted-by":"publisher","unstructured":"Newman D, Abuladze N, Scholz K, Dekant W, Tsuprun V, Ryazantsev S, Bondar G, Sassani P, Kurtz I, Pushkin A (2007) Specificity of aminoacylase III-mediated deacetylation of mercapturic acids. Drug Metabol Dispos 35 (1): 43\u201350. https:\/\/doi.org\/10.1124\/dmd.106.012062. https:\/\/dmd.aspetjournals.org\/content\/dmd\/35\/1\/43.full.pdf.","DOI":"10.1124\/dmd.106.012062"},{"issue":"W1","key":"3436_CR46","doi-asserted-by":"publisher","first-page":"W114","DOI":"10.1093\/nar\/gkab421","volume":"49","author":"H Nguyen","year":"2021","unstructured":"Nguyen H, Tran D, Galazka JM, Costes SV, Beheshti A, Petereit J, Draghici S, Nguyen T (2021) CPA: A web-based platform for consensus pathway analysis and interactive visualization. Nucleic Acids Res 49(W1):W114\u2013W124. https:\/\/doi.org\/10.1093\/nar\/gkab421","journal-title":"Nucleic Acids Res"},{"key":"3436_CR47","doi-asserted-by":"publisher","unstructured":"Nunes C, Singh P, Mazidi Z, Murphy C, Bourguignon A, Wellens S, Chandrasekaran V, Ghosh S, Zana M, Pamies D, Thomas A (2022) An in vitro strategy using multiple human induced pluripotent stem cell-derived models to assess the toxicity of chemicals: A case study on paraquat. Toxicol In Vitro 81:105333\u2013105333. https:\/\/doi.org\/10.1016\/j.tiv.2022.105333.","DOI":"10.1016\/j.tiv.2022.105333"},{"issue":"1\u20132","key":"3436_CR48","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/0169-328x(93)90072-w","volume":"17","author":"NJ Patel","year":"1993","unstructured":"Patel NJ, Fullone JS, Anders MW (1993) Brain uptake of S-(1,2-dichlorovinyl)glutathione and S-(1,2-dichlorovinyl)-l-cysteine, the glutathione and cysteine S-conjugates of the neurotoxin dichloroacetylene. Mol Brain Res 17(1\u20132):53\u201358. https:\/\/doi.org\/10.1016\/0169-328x(93)90072-w","journal-title":"Mol Brain Res"},{"issue":"1","key":"3436_CR49","first-page":"143","volume":"22","author":"N Patel","year":"1994","unstructured":"Patel N, Birner G, Dekant W, Anders MW (1994) Glutathione-dependent biosynthesis and bioactivation of S-(1,2-dichlorovinyl)glutathione and S-(1,2-dichlorovinyl)-L-cysteine, the glutathione and cysteine S-conjugates of dichloroacetylene, in rat tissues and subcellular fractions. Drug Metabol Dispos 22(1):143\u2013147","journal-title":"Drug Metabol Dispos"},{"key":"3436_CR50","doi-asserted-by":"publisher","unstructured":"Pinto JT, Krasnikov BF, Alcutt S, Jones ME, Dorai T, Villar MT, Artigues A, Li J, Cooper AJ (2014) Kynurenine aminotransferase III and glutamine transaminase L are identical enzymes that have cysteine S-conjugate beta-lyase activity and can transaminate L-selenomethionine. J Biol Chem 289(45):30950\u201330961. https:\/\/doi.org\/10.1074\/jbc.M114.591461.","DOI":"10.1074\/jbc.M114.591461"},{"key":"3436_CR51","doi-asserted-by":"publisher","unstructured":"Schildknecht S, Karreman C, P\u00f6ltl D, Efr\u00e9mova L, Kullmann C, Gutbier S, Krug AK, Scholz D, Gerding HR, Leist M (2013) Generation of genetically-modified human differentiated cells for toxicological tests and the study of neurodegenerative diseases. ALTEX 30(4):427\u2013444. https:\/\/doi.org\/10.14573\/altex.2013.4.427.","DOI":"10.14573\/altex.2013.4.427"},{"issue":"5","key":"3436_CR52","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1111\/j.1471-4159.2011.07255.x","volume":"119","author":"D Scholz","year":"2011","unstructured":"Scholz D, P\u00f6ltl D, Genewsky A, Weng M, Waldmann T, Schildknecht S, Leist M (2011) Rapid, complete and large-scale generation of post-mitotic neurons from the human LUHMES cell line. J Neurochem 119(5):957\u2013971. https:\/\/doi.org\/10.1111\/j.1471-4159.2011.07255.x","journal-title":"J Neurochem"},{"issue":"10","key":"3436_CR53","doi-asserted-by":"publisher","first-page":"3285","DOI":"10.1007\/s00204-021-03127-8","volume":"95","author":"KE Snijders","year":"2021","unstructured":"Snijders KE, Feh\u00e9r A, T\u00e1ncos Z, Bock I, T\u00e9gl\u00e1si A, van den Berk L, Niemeijer M, Bouwman P, Le D\u00e9v\u00e9dec SE, Mon\u00e9 MJ, Van Rossom R, Kumar M, Wilmes A, Jennings P, Verfaillie CM, Kobol\u00e1k J, ter Braak B, Dinny\u00e9s A, van de Water B (2021) Fluorescent tagging of endogenous Heme oxygenase-1 in human induced pluripotent stem cells for high content imaging of oxidative stress in various differentiated lineages. Arch Toxicol 95(10):3285\u20133302. https:\/\/doi.org\/10.1007\/s00204-021-03127-8","journal-title":"Arch Toxicol"},{"issue":"1","key":"3436_CR54","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1093\/toxsci\/kfr034","volume":"121","author":"NV Stiegler","year":"2011","unstructured":"Stiegler NV, Krug AK, Matt F, Leist M (2011) Assessment of chemical-induced impairment of human neurite outgrowth by multiparametric live cell imaging in high-density cultures. Toxicol Sci 121(1):73\u201387. https:\/\/doi.org\/10.1093\/toxsci\/kfr034","journal-title":"Toxicol Sci"},{"key":"3436_CR55","doi-asserted-by":"publisher","unstructured":"Tong ZB, Kim H, El Touny L, Simeonov A, Gerhold D (2022) LUHMES dopaminergic neurons are uniquely susceptible to ferroptosis. Neurotox Res. https:\/\/doi.org\/10.1007\/s12640-022-00538-y.","DOI":"10.1007\/s12640-022-00538-y"},{"issue":"8","key":"3436_CR56","doi-asserted-by":"publisher","first-page":"2707","DOI":"10.1007\/s00204-020-02792-5","volume":"94","author":"W van der Stel","year":"2020","unstructured":"van der Stel W, Carta G, Eakins J, Darici S, Delp J, Forsby A, Bennekou SH, Gardner I, Leist M, Danen EHJ, Walker P, van de Water B, Jennings P (2020) Multiparametric assessment of mitochondrial respiratory inhibition in HepG2 and RPTEC\/TERT1 cells using a panel of mitochondrial targeting agrochemicals. Arch Toxicol 94(8):2707\u20132729. https:\/\/doi.org\/10.1007\/s00204-020-02792-5","journal-title":"Arch Toxicol"},{"key":"3436_CR57","doi-asserted-by":"publisher","unstructured":"Wieser M, Stadler G, Jennings P, Streubel B, Pfaller W, Ambros P, Riedl C, Katinger H, Grillari J, Grillari-Voglauer R (2008) hTERT alone immortalizes epithelial cells of renal proximal tubules without changing their functional characteristics. Am J Physiol Renal Physiol 295 (5): F1365\u201375. https:\/\/doi.org\/10.1152\/ajprenal.90405.2008. https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/18715936.","DOI":"10.1152\/ajprenal.90405.2008"},{"key":"3436_CR58","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/4937689","author":"S Zhou","year":"2016","unstructured":"Zhou S, Szczesna K, Ochalek A, Kobol\u00e1k J, Varga E, Nemes C, Chandrasekaran A, Rasmussen M, Cirera S, Hyttel P, Dinny\u00e9s A, Freude KK, Avci HX (2016) Neurosphere based differentiation of human IPSC improves astrocyte differentiation. Stem Cells Int. https:\/\/doi.org\/10.1155\/2016\/4937689","journal-title":"Stem Cells Int"}],"container-title":["Archives of Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-022-03436-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00204-022-03436-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-022-03436-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,20]],"date-time":"2023-01-20T15:13:26Z","timestamp":1674227606000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00204-022-03436-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,28]]},"references-count":58,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2023,2]]}},"alternative-id":["3436"],"URL":"https:\/\/doi.org\/10.1007\/s00204-022-03436-6","relation":{},"ISSN":["0340-5761","1432-0738"],"issn-type":[{"value":"0340-5761","type":"print"},{"value":"1432-0738","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,28]]},"assertion":[{"value":"14 September 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 December 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 December 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}