Rotenone exerts developmental neurotoxicity in a human brain spheroid model

Toxicology and Applied Pharmacology

Volumn 354, Issue , 2018, Pages 101-114

  Pamies, David ^a   Block, Katharina ^a   Lau, Pierre ^b   Gribaldo, Laura ^b   Pardo, Carlos A ^c   Barreras, Paula ^c   Smirnova, Lena ^a   Wiersma, Daphne ^a   Zhao, Liang ^a,d   Harris, Georgina ^a   Hartung, Thomas ^a,e   Hogberg, Helena T ^a  

^a JOHNS HOPKINS UNIVERSITY   (United States)

^b JOINT RESEARCH CENTRE   (Italy)

^c JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^d JOHNS HOPKINS UNIVERSITY   (United States)

^e UNIVERSITY OF KONSTANZ   (Germany)

Author keywords

Developmental neurotoxicity; DNT; In Vitro; Organoids; Rotenone; Spheroids

Indexed keywords

CALCIUM ION; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; REACTIVE OXYGEN METABOLITE; ROTENONE; INSECTICIDE;

ARTICLE; ASTROCYTE; BRAIN CELL; BRAIN DEVELOPMENT; CALCIUM ABSORPTION; CONTROLLED STUDY; CYTOTOXIC CONCENTRATION; DEVELOPMENTAL TOXICITY; DOPAMINERGIC NERVE CELL; HUMAN; HUMAN CELL; IMMUNOFLUORESCENCE TEST; INDUCED PLURIPOTENT STEM CELL; NERVE CELL; NEURITE OUTGROWTH; NEUROTOXICITY; OMICS; OXIDATIVE STRESS; SPHEROID CELL; SYNAPTOGENESIS; TISSUE CULTURE; AGE; BRAIN; COMPARATIVE STUDY; DOSE RESPONSE; DRUG EFFECT; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION; GLIA; GROWTH, DEVELOPMENT AND AGING; METABOLISM; METABOLOMICS; MITOCHONDRION; MULTICELLULAR SPHEROID; NERVOUS SYSTEM DEVELOPMENT; NEURAL STEM CELL; PATHOLOGY; PATHOPHYSIOLOGY; PROCEDURES; RISK ASSESSMENT; TIME FACTOR; TOXICITY AND INTOXICATION; TOXICITY TESTING;

AGE FACTORS; BRAIN; DOSE-RESPONSE RELATIONSHIP, DRUG; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION, DEVELOPMENTAL; HUMANS; INDUCED PLURIPOTENT STEM CELLS; INSECTICIDES; METABOLOMICS; MITOCHONDRIA; NEURAL STEM CELLS; NEUROGENESIS; NEUROGLIA; NEUROTOXICITY SYNDROMES; OXIDATIVE STRESS; REACTIVE OXYGEN SPECIES; RISK ASSESSMENT; ROTENONE; SPHEROIDS, CELLULAR; TIME FACTORS; TOXICITY TESTS;

EID: 85042655982     PISSN: 0041008X     EISSN: 10960333     Source Type: Journal    
DOI: 10.1016/j.taap.2018.02.003     Document Type: Article

References (92)

1. Alhamdoosh, M., Ng, M., Wilson, N.J., Sheridan, J.M., Huynh, H., Wilson, M.J., Ritchie, M.E., Combining multiple tools outperforms individual methods in gene set enrichment analyses. Bioinformatics 33 (2017), 414–424.
2. Balmer, N.V., Klima, S., Rempel, E., Ivanova, V.N., Kolde, R., Weng, M.K., Meganathan, K., Henry, M., Sachinidis, A., Berthold, M.R., Hengstler, J.G., Rahnenfuhrer, J., Waldmann, T., Leist, M., From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch. Toxicol. 88 (2014), 1451–1468.
3. Bal-Price, A.K., Coecke, S., Costa, L., Crofton, K.M., Fritsche, E., Goldberg, A., Grandjean, P., Lein, P.J., Li, A., Lucchini, R., Mundy, W.R., Padilla, S., Persico, A.M., Seiler, A.E., Kreysa, J., Advancing the science of developmental neurotoxicity (DNT): testing for better safety evaluation. ALTEX 29 (2012), 202–215.
4. Bal-Price, A., Crofton, K.M., Leist, M., Allen, S., Arand, M., Buetler, T., Delrue, N., FitzGerald, R.E., Hartung, T., Heinonen, T., Hogberg, H., Bennekou, S.H., Lichtensteiger, W., Oggier, D., Paparella, M., Axelstad, M., Piersma, A., Rached, E., Schilter, B., Schmuck, G., Stoppini, L., Tongiorgi, E., Tiramani, M., Monnet-Tschudi, F., Wilks, M.F., Ylikomi, T., Fritsche, E., International STakeholder NETwork (ISTNET): creating a developmental neurotoxicity (DNT) testing road map for regulatory purposes. Arch. Toxicol. 89 (2015), 269–287.
5. Bal-Price, A., Crofton, K.M., Sachana, M., Shafer, T.J., Behl, M., Forsby, A., Hargreaves, A., Landesmann, B., Lein, P.J., Louisse, J., Monnet-Tschudi, F., Paini, A., Rolaki, A., Schrattenholz, A., Sunol, C., van Thriel, C., Whelan, M., Fritsche, E., Putative adverse outcome pathways relevant to neurotoxicity. Crit. Rev. Toxicol. 45 (2015), 83–91.
6. Berridge, M.J., Neuronal calcium signaling. Neuron 21:1 (1998), 13–26.
7. Betarbet, R., Sherer, T.B., MacKenzie, G., Garcia-Osuna, M., Panov, A.V., Greenamyre, J.T., Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat. Neurosci. 3 (2000), 1301–1306.
8. Boldyrev, A.A., Carpenter, D.O., Huentelman, M.J., Peters, C.M., Johnson, P., Sources of reactive oxygen species production in excitotoxin- stimulated cerebellar granule cells. Biochem. Biophys. Res. Commun. 256 (1999), 320–324.
9. Borland, M.K., Trimmer, P.A., Rubinstein, J.D., Keeney, P.M., Mohanakumar, K., Liu, L., Bennett, J.P. Jr., Chronic, low-dose rotenone reproduces Lewy neurites found in early stages of Parkinson's disease, reduces mitochondrial movement and slowly kills differentiated SH-SY5Y neural cells. Mol. Neurodegener., 3, 2008, 21.
10. Brookes, P.S., Yoon, Y., Robotham, J.L., Anders, M.W., Sheu, S.S., Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am. J. Phys. Cell Physiol. 287 (2004), C817–833.
11. Brumback, A.C., Ellwood, I.T., Kjaerby, C., Iafrati, J., Robinson, S., Lee, A.T., Patel, T., Nagaraj, S., Davatolhagh, F., Sohal, V.S., Identifying specific prefrontal neurons that contribute to autism-associated abnormalities in physiology and social behavior. Mol. Psychiatry 00 (2017), 1–12.
12. Cabezas, R., El-Bachá, R.S., González, J., Barreto, G.E., Mitochondrial functions in astrocytes: neuroprotective implications from oxidative damage by rotenone. Neurosci. Res. 74:2 (2012), 80–90, 10.1016/j.neures.2012.07.008.
13. Caiazzo, M., Dell'Anno, M.T., Dvoretskova, E., Lazarevic, D., Taverna, S., Leo, D., Sotnikova, T.D., Menegon, A., Roncaglia, P., Colciago, G., Russo, G., Carninci, P., Pezzoli, G., Gainetdinov, R.R., Gustincich, S., Dityatev, A., Broccoli, V., Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 476 (2011), 224–227.
14. Chiang, M.C., Cheng, Y.C., Chen, H.M., Liang, Y.J., Yen, C.H., Rosiglitazone promotes neurite outgrowth and mitochondrial function in N2A cells via PPARgamma pathway. Mitochondrion 14 (2014), 7–17.
15. Chomczynski, P., Sacchi, N., Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162 (1987), 156–159.
16. Chomczynski, P., Sacchi, N., The single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction: twenty-something years on. Nat. Protoc. 1 (2006), 581–585.
17. Clapham, D.E., Calcium signaling. Cell 131 (2007), 1047–1058.
18. Coecke, S., Goldberg, A.M., Allen, S., Buzanska, L., Calamandrei, G., Crofton, K., Hareng, L., Hartung, T., Knaut, H., Honegger, P., Jacobs, M., Lein, P., Li, A., Mundy, W., Owen, D., Schneider, S., Silbergeld, E., Reum, T., Trnovec, T., Monnet-Tschudi, F., Bal-Price, A., Workgroup report: incorporating in vitro alternative methods for developmental neurotoxicity into international hazard and risk assessment strategies. Environ. Health Perspect. 115 (2007), 924–931.
19. Crofton, K.M., Mundy, W.R., Lein, P.J., Bal-Price, A., Coecke, S., Seiler, A.E., Knaut, H., Buzanska, L., Goldberg, A., Developmental neurotoxicity testing: recommendations for developing alternative methods for the screening and prioritization of chemicals. ALTEX 28 (2011), 9–15.
20. Crofton, K., Fritsche, E., Ylikomi, T., Bal-Price, A., International STakeholder NETwork (ISTNET) for creating a developmental neurotoxicity testing (DNT) roadmap for regulatory purposes. ALTEX 31 (2014), 223–224.
21. Darmanis, S., Sloan, S.A., Zhang, Y., Enge, M., Caneda, C., Shuer, L.M., Hayden Gephart, M.G., Barres, B.A., Quake, S.R., A survey of human brain transcriptome diversity at the single cell level. Proc. Natl. Acad. Sci. U. S. A. 112 (2015), 7285–7290.
22. Dubovicky, M., Neurobehavioral manifestations of developmental impairment of the brain. Interdiscip. Toxicol. 3 (2010), 59–67.
23. Dugan, L.L., Kim-Han, J.S., Astrocyte mitochondria in in vitro models of ischemia. J. Bioenerg. Biomembr. 36:4 (2004), 317–321.
24. EPA, Memorandum: Rotenone: final HED chapter of the registration eligibility decision (RED). PC Code: 071003. DP Barcode: D328478. Washington, D.C., 2006.
25. EPA, Reregistration eligibility decision for rotenone. EPA 738-R-07-005. Case No. 0255, 2006.
26. Fang, Du, Qing, Yu, Yan, Shijun, Chen, Doris, Yan, Shirley ShiDu, Development and dynamic regulation of mitochondrial network in human midbrain dopaminergic neurons differentiated from iPSCs. Stem Cell Rep. 7:4 (2016), 678–692.
27. Fleming, S.M., Zhu, C., Fernagut, P.O., Mehta, A., DiCarlo, C.D., Seaman, R.L., Chesselet, M.F., Behavioral and immunohistochemical effects of chronic intravenous and subcutaneous infusions of varying doses of rotenone. Exp. Neurol. 187 (2004), 418–429.
28. Fritsche, E., Crofton, K.M., Hernandez, A.F., Hougaard Bennekou, S., Leist, M., Bal-Price, A., Reaves, E., Wilks, M.F., Terron, A., Solecki, R., Sachana, M., Gourmelon, A., OECD/EFSA workshop on developmental neurotoxicity (DNT): the use of non-animal test methods for regulatory purposes. ALTEX 34 (2017), 311–315.
29. Giorgi, C., Romagnoli, A., Pinton, P., Rizzuto, R., Ca2+ signaling, mitochondria and cell death. Curr. Mol. Med. 8 (2008), 119–130.
30. Giorgi, C., Agnoletto, C., Bononi, A., Bonora, M., De Marchi, E., Marchi, S., Missiroli, S., Patergnani, S., Poletti, F., Rimessi, A., Suski, J.M., Wieckowski, M.R., Pinton, P., Mitochondrial calcium homeostasis as potential target for mitochondrial medicine. Mitochondrion 12 (2012), 77–85.
31. Grandjean, P., Landrigan, P.J., Developmental neurotoxicity of industrial chemicals. Lancet 368 (2006), 2167–2178.
32. Greenamyre, J.T., Betarbet, R., Sherer, T.B., The rotenone model of Parkinson's disease: genes, environment and mitochondria. Parkinsonism Relat. Disord. 9 (2003), S59–64.
33. Hartley, R.S., Margulis, M., Fishman, P.S., Lee, V.M., Tang, C.M., Functional synapses are formed between human NTera2 (NT2N, hNT) neurons grown on astrocytes. J. Comp. Neurol. 407 (1999), 1–10.
34. Hatcher, J.M., Pennell, K.D., Miller, G.W., Parkinson's disease and pesticides: a toxicological perspective. Trends Pharmacol. Sci. 29 (2008), 322–329.
35. Hoelting, L., Klima, S., Karreman, C., Grinberg, M., Meisig, J., Henry, M., Rotshteyn, T., Rahnenfuhrer, J., Bluthgen, N., Sachinidis, A., Waldmann, T., Leist, M., Stem cell-derived immature human dorsal root ganglia neurons to identify peripheral neurotoxicants. Stem Cells Transl. Med. 5 (2016), 476–487.
36. Hogberg, H.T., Kinsner-Ovaskainen, A., Coecke, S., Hartung, T., Bal-Price, A.K., mRNA expression is a relevant tool to identify developmental neurotoxicants using an in vitro approach. Toxicol. Sci. 113 (2010), 95–115.
37. Hogberg, H.T., Sobanski, T., Novellino, A., Whelan, M., Weiss, D.G., Bal-Price, A.K., Application of micro-electrode arrays (MEAs) as an emerging technology for developmental neurotoxicity: evaluation of domoic acid-induced effects in primary cultures of rat cortical neurons. Neurotoxicology 32 (2011), 158–168.
38. Hogberg, H.T., Bressler, J., Christian, K.M., Harris, G., Makri, G., O'Driscoll, C., Pamies, D., Smirnova, L., Wen, Z., Hartung, T., Toward a 3D model of human brain development for studying gene/environment interactions. Stem Cell Res Ther, 4(Suppl. 1), 2013, S4.
39. Ishido, M., Suzuki, J., Masuo, Y., Neonatal rotenone lesions cause onset of hyperactivity during juvenile and adulthood in the rat. Toxicol. Lett. 266 (2017), 42–48, 10.1016/j.toxlet.2016.12.008.
40. Kansanen, E., Kuosmanen, S.M., Leinonen, H., Levonen, A.L., The Keap1-Nrf2 pathway: mechanisms of activation and dysregulation in cancer. Redox Biol. 1 (2013), 45–49.
41. Khera, K.S., Whalen, C., Angers, G., Teratogenicity study on pyrethrum and rotenone (natural origin) and ronnel in pregnant rats. J. Toxicol. Environ. Health 10 (1982), 111–119.
42. Krug, A.K., Balmer, N.V., Matt, F., Schonenberger, F., Merhof, D., Leist, M., Evaluation of a human neurite growth assay as specific screen for developmental neurotoxicants. Arch. Toxicol. 87 (2013), 2215–2231.
43. Krug, A.K., Gutbier, S., Zhao, L., Poltl, D., Kullmann, C., Ivanova, V., Forster, S., Jagtap, S., Meiser, J., Leparc, G., Schildknecht, S., Adam, M., Hiller, K., Farhan, H., Brunner, T., Hartung, T., Sachinidis, A., Leist, M., Transcriptional and metabolic adaptation of human neurons to the mitochondrial toxicant MPP. Cell Death Dis., 5, 2014, e1222.
44. La Manno, G., Gyllborg, D., Codeluppi, S., Nishimura, K., Salto, C., Zeisel, A., Borm, L.E., Stott, S.R.W., Toledo, E.M., Villaescusa, J.C., Lonnerberg, P., Ryge, J., Barker, R.A., Arenas, E., Linnarsson, S., Molecular diversity of midbrain development in mouse, human, and stem cells. Cell, 167(566–580), 2016, e519.
45. Lancaster, M.A., Renner, M., Martin, C.A., Wenzel, D., Bicknell, L.S., Hurles, M.E., Homfray, T., Penninger, J.M., Jackson, A.P., Knoblich, J.A., Cerebral organoids model human brain development and microcephaly. Nature, 501, 2013, 373.
46. Laurenza, I., Pallocca, G., Mennecozzi, M., Scelfo, B., Pamies, D., Bal-Price, A., A human pluripotent carcinoma stem cell-based model for in vitro developmental neurotoxicity testing: effects of methylmercury, lead and aluminum evaluated by gene expression studies. Int. J. Dev. Neurosci. 31 (2013), 679–691.
47. Lein, P., Locke, P., Goldberg, A., Meeting report: alternatives for developmental neurotoxicity testing. Environ. Health Perspect. 115 (2007), 764–768.
48. Levine, J.H., Simonds, E.F., Bendall, S.C., Davis, K.L., Amir el, A.D., Tadmor, M.D., Litvin, O., Fienberg, H.G., Jager, A., Zunder, E.R., Finck, R., Gedman, A.L., Radtke, I., Downing, J.R., Pe'er, D., Nolan, G.P., Data-driven phenotypic dissection of AML reveals progenitor-like cells that correlate with prognosis. Cell 162 (2015), 184–197.
49. Li, A.A., Mink, P.J., McIntosh, L.J., Teta, M.J., Finley, B., Evaluation of epidemiologic and animal data associating pesticides with Parkinson's disease. J. Occup. Environ. Med. 47 (2005), 1059–1087.
50. Li, A.A., Sheets, L.P., Raffaele, K., Moser, V., Hofstra, A., Hoberman, A., Makris, S.L., Garman, R., Bolon, B., Kaufmann, W., Auer, R., Lau, E., Vidmar, T., Bowers, W.J., Recommendations for harmonization of data collection and analysis of developmental neurotoxicity endpoints in regulatory guideline studies: Proceedings of workshops presented at Society of Toxicology and joint Teratology Society and Neurobehavioral Teratology Society meetings. Neurotoxicol. Teratol. 63 (2017), 24–45.
51. Liu, Q., Spusta, S.C., Mi, R., Lassiter, R.N., Stark, M.R., Hoke, A., Rao, M.S., Zeng, X., Human neural crest stem cells derived from human ESCs and induced pluripotent stem cells: induction, maintenance, and differentiation into functional schwann cells. Stem Cells Transl. Med. 1 (2012), 266–278.
52. Livak, K.J., Schmittgen, T.D., Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25 (2001), 402–408, 10.1006/meth.2001.1262.
53. Melo, K.M., Oliveira, R., Grisolia, C.K., Domingues, I., Pieczarka, J.C., de Souza Filho, J., Nagamachi, C.Y., Short-term exposure to low doses of rotenone induces developmental, biochemical, behavioral, and histological changes in fish. Environ. Sci. Pollut. Res. Int. 22 (2015), 13926–13938.
54. Nandipati, S., Litvan, I., Environmental exposures and Parkinson's disease. Int. J. Environ. Res. Public Health, 13, 2016.
55. Nieto, M., Monuki, E.S., Tang, H., Imitola, J., Haubst, N., Khoury, S.J., Cunningham, J., Gotz, M., Walsh, C.A., Expression of Cux-1 and Cux-2 in the subventricular zone and upper layers II-IV of the cerebral cortex. J. Comp. Neurol. 479 (2004), 168–180.
56. OECD, Test No. 426: Developmental Neurotoxicity Study. 2007, OECD Publishing, 10.1787/9789264067394-en.
57. O'Rahilly, R., Muller, F., Significant features in the early prenatal development of the human brain. Ann. Anat. 190 (2008), 105–118.
58. Pallocca, G., Fabbri, M., Sacco, M.G., Gribaldo, L., Pamies, D., Laurenza, I., Bal-Price, A., miRNA expression profiling in a human stem cell-based model as a tool for developmental neurotoxicity testing. Cell Biol. Toxicol. 29 (2013), 239–257.
59. Pamies, D., Barreras, P., Block, K., Makri, G., Kumar, A., Wiersma, D., Smirnova, L., Zang, C., Bressler, J., Christian, K.M., Harris, G., Ming, G.L., Berlinicke, C.J., Kyro, K., Song, H., Pardo, C.A., Hartung, T., Hogberg, H.T., A human brain microphysiological system derived from induced pluripotent stem cells to study neurological diseases and toxicity. ALTEX 34 (2017), 362–376.
60. Pasca, A.M., Sloan, S.A., Clarke, L.E., Tian, Y., Makinson, C.D., Huber, N., Kim, C.H., Park, J.Y., O'Rourke, N.A., Nguyen, K.D., Smith, S.J., Huguenard, J.R., Geschwind, D.H., Barres, B.A., Pasca, S.P., Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat. Methods 12 (2015), 671–678.
61. Perier, C., Bove, J., Vila, M., Przedborski, S., The rotenone model of Parkinson's disease. Trends Neurosci. 26 (2003), 345–346.
62. Persson, A.K., Kim, I., Zhao, P., Estacion, M., Black, J.A., Waxman, S.G., Sodium channels contribute to degeneration of dorsal root ganglion neurites induced by mitochondrial dysfunction in an in vitro model of axonal injury. J. Neurosci. 33 (2013), 19250–19261.
63. Pistollato, F., Canovas-Jorda, D., Zagoura, D., Bal-Price, A., Nrf2 pathway activation upon rotenone treatment in human iPSC-derived neural stem cells undergoing differentiation towards neurons and astrocytes. Neurochem. Int. 108 (2017), 457–471.
64. Quadrato, G., Nguyen, T., Macosko, E.Z., Sherwood, J.L., Min Yang, S., Berger, D.R., Maria, N., Scholvin, J., Goldman, M., Kinney, J.P., Boyden, E.S., Lichtman, J.W., Williams, Z.M., McCarroll, S.A., Arlotta, P., Cell diversity and network dynamics in photosensitive human brain organoids. Nature 545 (2017), 48–53.
65. Rao, V.K., Chauhan, S.P.S., Teratogenic effects of rotenone on the early development of chick embryos in vitro. Teratology 4:2 (2004), 191–197.
66. Rice, D., Barone, S. Jr., Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ. Health Perspect. 108:Suppl. 3 (2000), 511–533.
67. Richter, F., Hamann, M., Richter, A., Chronic rotenone treatment induces behavioral effects but no pathological signs of parkinsonism in mice. J. Neurosci. Res. 85 (2007), 681–691.
68. Rizzuto, R., Bernardi, P., Pozzan, T., Mitochondria as all-round players of the calcium game. J. Physiol. 529:Pt 1 (2000), 37–47.
69. Sanchez, M., Gastaldi, L., Remedi, M., Caceres, A., Landa, C., Rotenone-induced toxicity is mediated by Rho-GTPases in hippocampal neurons. Toxicol. Sci. 104 (2008), 352–361.
70. Saravanan, K.S., Sindhu, K.M., Mohanakumar, K.P., Acute intranigral infusion of rotenone in rats causes progressive biochemical lesions in the striatum similar to Parkinson's disease. Brain Res. 1049 (2005), 147–155.
71. Schettler, T., Toxic threats to neurologic development of children. Environ. Health Perspect. 109:Suppl. 6 (2001), 813–816.
72. Shi, Y.L., Feng, S., Chen, W., Hua, Z.C., Bian, J.J., Yin, W., Mitochondrial inhibitor sensitizes non-small-cell lung carcinoma cells to TRAIL-induced apoptosis by reactive oxygen species and Bcl-X(L)/p53-mediated amplification mechanisms. Cell Death Dis., 5, 2014, e1579.
73. Sindhu, K.M., Saravanan, K.S., Mohanakumar, K.P., Behavioral differences in a rotenone-induced hemiparkinsonian rat model developed following intranigral or median forebrain bundle infusion. Brain Res. 1051 (2005), 25–34.
74. Sloan, S.A., Darmanis, S., Huber, N., Khan, T.A., Birey, F., Caneda, C., Reimer, R., Quake, S.R., Barres, B.A., Pasca, S.P., Human astrocyte maturation captured in 3D cerebral cortical spheroids derived from pluripotent stem cells. Neuron, 95, 2017 (779-790 e776).
75. Smirnova, L., Hogberg, H.T., Leist, M., Hartung, T., Developmental neurotoxicity - challenges in the 21st century and in vitro opportunities. ALTEX 31 (2014), 129–156.
76. Spencer, F., Sing, L.T., Reproductive responses to rotenone during decidualized pseudogestation and gestation in rats. Bull. Environ. Contam. Toxicol. 28 (1982), 360–368.
77. Spivey, A., Rotenone and paraquat linked to Parkinson's disease: human exposure study supports years of animal studies. Environ. Health Perspect., 119, 2011, A259.
78. Stern, M., Gierse, A., Tan, S., Bicker, G., Human Ntera2 cells as a predictive in vitro test system for developmental neurotoxicity. Arch. Toxicol. 88 (2014), 127–136.
79. Subramaniam, S.R., Chesselet, M.F., Mitochondrial dysfunction and oxidative stress in Parkinson's disease. Prog. Neurobiol. 106–107 (2013), 17–32.
80. Swarnkar, S., Goswami, P., Kamat, P.K., Gupta, S., Patro, I.K., Singh, S., Nath, C., Rotenone-induced apoptosis and role of calcium: a study on neuro-2a cells. Arch. Toxicol. 86 (2012), 1387–1397.
81. Takahashi, K., Yamanaka, S., Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126 (2006), 663–676.
82. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., Yamanaka, S., Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131 (2007), 861–872.
83. Tanner, C.M., Kamel, F., Ross, G.W., Hoppin, J.A., Goldman, S.M., Korell, M., Marras, C., Bhudhikanok, G.S., Kasten, M., Chade, A.R., Comyns, K., Richards, M.B., Meng, C., Priestley, B., Fernandez, H.H., Cambi, F., Umbach, D.M., Blair, A., Sandler, D.P., Langston, J.W., Rotenone, paraquat, and Parkinson's disease. Environ. Health Perspect. 119 (2011), 866–872.
84. USEPA, Health effects guidelines OPPTS 870.6300 developmental neurotoxicity study Office of Prevention Pesticides and Toxic Substances. http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0156-0042, 1998.
85. van Vliet, E., Stoppini, L., Balestrino, M., Eskes, C., Griesinger, C., Sobanski, T., Whelan, M., Hartung, T., Coecke, S., Electrophysiological recording of re-aggregating brain cell cultures on multi-electrode arrays to detect acute neurotoxic effects. Neurotoxicology 28 (2007), 1136–1146.
86. van Vliet, E., Morath, S., Eskes, C., Linge, J., Rappsilber, J., Honegger, P., Hartung, T., Coecke, S., A novel in vitro metabolomics approach for neurotoxicity testing, proof of principle for methyl mercury chloride and caffeine. Neurotoxicology 29 (2008), 1–12.
87. Wang, X.J., Xu, J.X., Possible involvement of Ca2+ signaling in rotenone-induced apoptosis in human neuroblastoma SH-SY5Y cells. Neurosci. Lett. 376 (2005), 127–132.
88. Wen, Z., Nguyen, H.N., Guo, Z., Lalli, M.A., Wang, X., Su, Y., Kim, N.S., Yoon, K.J., Shin, J., Zhang, C., Makri, G., Nauen, D., Yu, H., Guzman, E., Chiang, C.H., Yoritomo, N., Kaibuchi, K., Zou, J., Christian, K.M., Cheng, L., Ross, C.A., Margolis, R.L., Chen, G., Kosik, K.S., Song, H., Ming, G.L., Synaptic dysregulation in a human iPS cell model of mental disorders. Nature 515 (2014), 414–418.
89. Xiang, Y., Tanaka, Y., Patterson, B., Kang, Y.J., Govindaiah, G., Roselaar, N., Cakir, B., Kim, K.Y., Lombroso, A.P., Hwang, S.M., Zhong, M., Stanley, E.G., Elefanty, A.G., Naegele, J.R., Lee, S.H., Weissman, S.M., Park, I.H., Fusion of regionally specified hPSC-derived organoids models human brain development and interneuron migration. Cell Stem Cell, 21(383–398), 2017, e387.
90. Zagoura, D., Canovas-Jorda, D., Pistollato, F., Bremer-Hoffmann, S., Bal-Price, A., Evaluation of the rotenone-induced activation of the Nrf2 pathway in a neuronal model derived from human induced pluripotent stem cells. Neurochem. Int. 106 (2017), 62–73.
91. Zander, N.E., Piehler, T., Hogberg, H., Pamies, D., Explosive blast loading on human 3D aggregate minibrains. Cell. Mol. Neurobiol. 37:7 (2017), 1331–1334.
92. Zheng, G.X., Terry, J.M., Belgrader, P., Ryvkin, P., Bent, Z.W., Wilson, R., Ziraldo, S.B., Wheeler, T.D., McDermott, G.P., Zhu, J., Gregory, M.T., Shuga, J., Montesclaros, L., Underwood, J.G., Masquelier, D.A., Nishimura, S.Y., Schnall-Levin, M., Wyatt, P.W., Hindson, C.M., Bharadwaj, R., Wong, A., Ness, K.D., Beppu, L.W., Deeg, H.J., McFarland, C., Loeb, K.R., Valente, W.J., Ericson, N.G., Stevens, E.A., Radich, J.P., Mikkelsen, T.S., Hindson, B.J., Bielas, J.H., Massively parallel digital transcriptional profiling of single cells. Nat. Commun., 8, 2017, 14049.