Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxuknand STOP-Toxukktests

Archives of Toxicology

Volumn 91, Issue 2, 2017, Pages 839-864

  Shinde, Vaibhav ^a   Hoelting, Lisa ^b   Srinivasan, Sureshkumar Perumal ^a   Meisig, Johannes ^e,f   Meganathan, Kesavan ^a   Jagtap, Smita ^a   Grinberg, Marianna ^c   Liebing, Julia ^d   Bluethgen, Nils ^e,f   Rahnenführer, Jörg ^c   Rempel, Eugen ^c,g   Stoeber, Regina ^d   Schildknecht, Stefan ^b   Förster, Sunniva ^b   Godoy, Patricio ^d   van Thriel, Christoph ^d   Gaspar, John Antonydas ^a   Hescheler, Jürgen ^a   Waldmann, Tanja ^b   Hengstler, Jan G ^d   Leist, Marcel ^b   Sachinidis, Agapios ^a   more..

^a UNIVERSITY OF COLOGNE   (Germany)

^b UNIVERSITY OF KONSTANZ   (Germany)

^c TU DORTMUND UNIVERSITY   (Germany)

^d LEIBNIZ RESEARCH CENTRE FOR WORKING ENVIRONMENT AND HUMAN FACTORS   (Germany)

^e CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

^f HUMBOLDT UNIVERSITY   (Germany)

^g UNIVERSITY OF HEIDELBERG   (Germany)

Author keywords

Developmental toxicity; Genomics biomarkers; Human stem cells; In vitro test systems; Transcriptome

Indexed keywords

GLUTATHIONE REDUCTASE; HISTONE DEACETYLASE INHIBITOR; ISOCITRATE DEHYDROGENASE; MERCURY; THALIDOMIDE; TRANSCRIPTION FACTOR; TRANSCRIPTOME; VALPROIC ACID; TERATOGENIC AGENT;

ARTICLE; BIOEQUIVALENCE; CELL DIFFERENTIATION; CELL GROWTH; CELL MATURATION; CONTROLLED STUDY; DOWN REGULATION; ENZYME ACTIVITY; ENZYME INHIBITION; GENE EXPRESSION; GENE EXPRESSION PROFILING; GERM LAYER; HUMAN; HUMAN CELL; HUMAN EMBRYONIC STEM CELL; IN VITRO STUDY; NEURAL CREST CELL; PRIORITY JOURNAL; QUANTITATIVE ANALYSIS; STEM CELL; UPREGULATION; ANIMAL; CELL LINE; DRUG EFFECTS; EMBRYONIC STEM CELL; GENE EXPRESSION REGULATION; GENETICS; MOUSE; PHYSIOLOGY; PLURIPOTENT STEM CELL; PROCEDURES; TOXICITY TESTING;

ANIMALS; CELL DIFFERENTIATION; CELL LINE; EMBRYONIC STEM CELLS; GENE EXPRESSION REGULATION, DEVELOPMENTAL; HUMANS; MICE; PLURIPOTENT STEM CELLS; STEM CELLS; TERATOGENS; TOXICITY TESTS; TRANSCRIPTOME;

EID: 84969242925     PISSN: 03405761     EISSN: 14320738     Source Type: Journal    
DOI: 10.1007/s00204-016-1741-8     Document Type: Article

References (90)

1. Adler S, Basketter D, Creton S, Pelkonen O, van Benthem J, Zuang V, Andersen KE, Angers-Loustau A, Aptula A, Bal-Price A, Benfenati E, Bernauer U, Bessems J, Bois FY, Boobis A, Brandon E, Bremer S, Broschard T, Casati S, Coecke S, Corvi R, Cronin M, Daston G, Dekant W, Felter S, Grignard E, Gundert-Remy U, Heinonen T, Kimber I, Kleinjans J, Komulainen H, Kreiling R, Kreysa J, Leite SB, Loizou G, Maxwell G, Mazzatorta P, Munn S, Pfuhler S, Phrakonkham P, Piersma A, Poth A, Prieto P, Repetto G, Rogiers V, Schoeters G, Schwarz M, Serafimova R, Tahti H, Testai E, van Delft J, van Loveren H, Vinken M, Worth A, Zaldivar JM (2011) Alternative (non-animal) methods for cosmetics testing: current status and future prospects-2010. Arch Toxicol 85:367–485
2. Ahmad K, Khan S, Adil M, Saeed M, Srivastava AK (2014) Structure based molecular inhibition of Caspase-8 for treatment of multi-neurodegenerative diseases using known natural compounds. Bioinformation 10:191–195
3. Al-ayadhi LY, Mostafa GA (2011) Increased serum osteopontin levels in autistic children: relation to the disease severity. Brain Behav Immun 25:1393–1398
4. Anderson BM, Schnetz-Boutaud NC, Bartlett J, Wotawa AM, Wright HH, Abramson RK, Cuccaro ML, Gilbert JR, Pericak-Vance MA, Haines JL (2009) Examination of association of genes in the serotonin system to autism. Neurogenetics 10:209–216
5. Annunen S, Körkkö J, Czarny M, Warman ML, Brunner HG, Kääriäinen H, Mulliken JB, Tranebjaerg L, Brooks DG, Cox GF, Cruysberg JR, Curtis MA, Davenport SLH, Friedrich CA, Kaitila I, Krawczynski MR, Latos-Bielenska A, Mukai S, BrR Olsen, Shinno N, Somer M, Vikkula M, Zlotogora J, Prockop DJ, Ala-Kokko L (1999) Splicing mutations of 54-bp exons in the COL11A1 gene cause marshall syndrome, but other mutations cause overlapping marshall/stickler phenotypes. Am J Hum Genet 65:974–983
6. Ardinger HH, Atkin JF, Blackston RD, Elsas LJ, Clarren SK, Livingstone S, Flannery DB, Pellock JM, Harrod MJ, Lammer EJ (1988) Verification of the fetal valproate syndrome phenotype. Am J Med Genet 29:171–185
7. Badeeb OM, Micheal S, Koenekoop RK, den Hollander AI, Hedrawi MT (2014) CYP1B1 mutations in patients with primary congenital glaucoma from Saudi Arabia. BMC Med Genet 15(1):1–5
8. Balmer NV, Klima S, Rempel E, Ivanova VN, Kolde R, Weng MK, Meganathan K, Henry M, Sachinidis A, Berthold MR, Hengstler JG, Rahnenfuhrer J, Waldmann T, Leist M (2014) From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol 88:1451–1468
9. Batista-Brito R, Rossignol E, Hjerling-Leffler J, Denaxa M, Wegner M, Lefebvre V, Pachnis V, Fishell G (2009) The cell-intrinsic requirement of Sox6 for cortical interneuron development. Neuron 63:466–481
10. Blake SM, Strasser V, Andrade N, Duit S, Hofbauer R, Schneider WJ, Nimpf J (2008) Thrombospondin-1 binds to ApoER2 and VLDL receptor and functions in postnatal neuronal migration. EMBO J 27:3069–3080
11. Burbacher TM, Rodier PM, Weiss B (1990) Methylmercury developmental neurotoxicity: a comparison of effects in humans and animals. Neurotoxicol Teratol 12:191–202
12. Cahan P, Li H, Morris SA, Lummertz da Rocha E, Daley GQ, Collins JJ (2014) Cell Net: network biology applied to stem cell engineering. Cell 158:903–915
13. Chabas D, Baranzini SE, Mitchell D, Bernard CCA, Rittling SR, Denhardt DT, Sobel RA, Lock C, Karpuj M, Pedotti R, Heller R, Oksenberg JR, Steinman L (2001) The Influence of the Proinflammatory Cytokine, Osteopontin, on Autoimmune Demyelinating Disease. Science 294:1731–1735
14. Chambers D, Wilson L, Maden M, Lumsden A (2007) RALDH-independent generation of retinoic acid during vertebrate embryogenesis by CYP1B1. Development 134:1369–1383
15. 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 27:275–280
16. Chandane PG, Shah I (2014) Indian J Hum Genet 20(2):187–188
17. Chen IH, Wang HH, Hsieh YS, Huang WC, Yeh HI, Chuang YJ (2013) PRSS23 is essential for the Snail-dependent endothelial-to-mesenchymal transition during valvulogenesis in zebrafish. Cardiovasc Res 97:443–453
18. Chomiak T, Turner N, Hu B (2013) What We Have Learned about Autism Spectrum Disorder from Valproic Acid. Patholog Res Int 2013:8. doi:10.1155/2013/712758
19. Chung YW, Jeong D, Noh OJ, Park YH, Kang SI, Lee MG, Lee TH, Yim MB, Kim IY (2009) Antioxidative role of selenoprotein W in oxidant-induced mouse embryonic neuronal cell death. Mol Cells 27:609–613
20. Crosby AH, Patel H, Chioza BA, Proukakis C, Gurtz K, Patton MA, Sharifi R, Harlalka G, Simpson MA, Dick K, Reed JA, Al-Memar A, Chrzanowska-Lightowlers ZMA, Cross HE, Lightowlers RN (2010) Defective mitochondrial mRNA maturation is associated with spastic ataxia. Am J Hum Genet 87:655–660
21. Decressac M, Pain S, Chabeauti PY, Frangeul L, Thiriet N, Herzog H, Vergote J, Chalon S, Jaber M, Gaillard A (2012) Neuroprotection by neuropeptide Y in cell and animal models of Parkinson’s disease. Neurobiol Aging 33:2125–2137
22. Forsby A, Blaauboer B (2007) Integration of in vitro neurotoxicity data with biokinetic modelling for the estimation of in vivo neurotoxicity. Hum Exp Toxicol 26:333–338
23. Godoy P, Schmidt-Heck W, Natarajan K, Lucendo-Villarin B, Szkolnicka D, Asplund A, Bjorquist P, Widera A, Stober R, Campos G, Hammad S, Sachinidis A, Chaudhari U, Damm G, Weiss TS, Nussler A, Synnergren J, Edlund K, Kuppers-Munther B, Hay DC, Hengstler JG (2015) Gene networks and transcription factor motifs defining the differentiation of stem cells into hepatocyte-like cells. J Hepatol 63:934–942
24. Goodrich JM, Wang Y, Gillespie B, Werner R, Franzblau A, Basu N (2011) Glutathione enzyme and selenoprotein polymorphisms associate with mercury biomarker levels in Michigan dental professionals. Toxicol Appl Pharmacol 257:301–308
25. Goodrich JM, Basu N, Franzblau A, Dolinoy DC (2013) Mercury biomarkers and DNA methylation among michigan dental professionals. Environ Mol Mutagen 54:195–203
26. Harbron C, Chang KM, South MC (2007) RefPlus: an R package extending the RMA algorithm. Bioinformatics 23:2493–2494
27. Hengstler JG, Foth H, Kahl R, Kramer PJ, Lilienblum W, Schulz T, Schweinfurth H (2006) The REACH concept and its impact on toxicological sciences. Toxicology 220:232–239
28. Hornby SJ, Welham RA (2003) Congenital nasolacrimal duct obstruction requiring external dacryocystorhinostomies in a child with foetal valproate syndrome. Eye (Lond) 17:546–547
29. Hsieh FY, Ma TL, Shih HY, Lin SJ, Huang CW, Wang HY, Cheng YC (2013) Dner inhibits neural progenitor proliferation and induces neuronal and glial differentiation in zebrafish. Dev Biol 375:1–12
30. Ingram JL, Peckham SM, Tisdale B, Rodier PM (2000) Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism. Neurotoxicol Teratol 22:319–324
31. Ishii N, Ozaki K, Sato H, Mizuno H, Saito S, Takahashi A, Miyamoto Y, Ikegawa S, Kamatani N, Hori M, Nakamura Y, Tanaka T (2006) Identification of a novel non-coding RNA, MIAT, that confers risk of myocardial infarction. J Hum Genet 51:1087–1099
32. Jagtap S, Meganathan K, Gaspar J, Wagh V, Winkler J, Hescheler J, Sachinidis A (2011) Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol 162:1743–1756
33. Jentink J, Loane MA, Dolk H, Barisic I, Garne E, Morris JK, de Jong-van den Berg LT (2010) Valproic acid monotherapy in pregnancy and major congenital malformations. N Engl J Med 362:2185–2193
34. Johnson WE, Li C, Rabinovic A (2007) Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 8:118–127
35. Kim YJ, Chai YG, Ryu JC (2005) Selenoprotein W as molecular target of methylmercury in human neuronal cells is down-regulated by GSH depletion. Biochem Biophys Res Commun 330:1095–1102
36. Kloss BAV, Reis LM, Brémond-Gignac D, Glaser T, Semina EV (2012) Analysis of FOXD3 sequence variation in human ocular disease. Mol Vis 18:1740–1749
37. Krug AK, Kolde R, Gaspar JA, Rempel E, Balmer NV, Meganathan K, Vojnits K, Baquie M, Waldmann T, Ensenat-Waser R, Jagtap S, Evans RM, Julien S, Peterson H, Zagoura D, Kadereit S, Gerhard D, Sotiriadou I, Heke M, Natarajan K, Henry M, Winkler J, Marchan R, Stoppini L, Bosgra S, Westerhout J, Verwei M, Vilo J, Kortenkamp A, Hescheler J, Hothorn L, Bremer S, van Thriel C, Krause KH, Hengstler JG, Rahnenfuhrer J, Leist M, Sachinidis A (2013) Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol 87:123–143
38. Kubota A, Hida A, Ichikawa Y, Momose Y, Goto J, Igeta Y, Hashida H, Yoshida K, Ikeda S, Kanazawa I, Tsuji S (2009) A novel ferritin light chain gene mutation in a Japanese family with neuroferritinopathy: description of clinical features and implications for genotype-phenotype correlations. Mov Disord 24:441–445
39. Kuegler PB, Zimmer B, Waldmann T, Baudis B, Ilmjarv S, Hescheler J, Gaughwin P, Brundin P, Mundy W, Bal-Price AK, Schrattenholz A, Krause KH, van Thriel C, Rao MS, Kadereit S, Leist M (2010) Markers of murine embryonic and neural stem cells, neurons and astrocytes: reference points for developmental neurotoxicity testing. ALTEX 27:17–42
40. Leist M, Bremer S, Brundin P, Hescheler J, Kirkeby A, Krause KH, Poerzgen P, Puceat M, Schmidt M, Schrattenholz A, Zak NB, Hentze H (2008) The biological and ethical basis of the use of human embryonic stem cells for in vitro test systems or cell therapy. ALTEX 25:163–190
41. Leist M, Ringwald A, Kolde R, Bremer S, van Thriel C, Krause KH, Rahnenfuhrer J, Sachinidis A, Hescheler J, Hengstler JG (2013) Test systems of developmental toxicity: state-of-the art and future perspectives. Arch Toxicol 87:2037–2042
42. Liu Y, Chen YY, Liu H, Yao CJ, Zhu XX, Chen DJ, Yang J, Lu YJ, Cao JY (2015) Association between ubiquitin carboxy-terminal hydrolase-L1 S18Y variant and risk of Parkinson’s disease: the impact of ethnicity and onset age. Neurol Sci 36:179–188
43. Lu Z, Kipnis J (2010) Thrombospondin 1–a key astrocyte-derived neurogenic factor. FASEB J 24:1925–1934
44. Luo J, Li S, Qin X, Peng Q, Liu Y, Yang S, Xiong Y, Zeng Z (2016) Association of the NQO1 C609T polymorphism with Alzheimer's disease in Chinese populations: a meta-analysis. Int J Neurosci 126:199–204
45. Ma L, Golden S, Wu L, Maxson R (1996) The molecular basis of Boston-type craniosynostosis: the Pro148-->His mutation in the N-terminal arm of the MSX2 homeodomain stabilizes DNA binding without altering nucleotide sequence preferences. Hum Mol Genet 5:1915–1920
46. Mannan AU, Boehm J, Sauter SM, Rauber A, Byrne PC, Neesen J, Engel W (2006) Spastin, the most commonly mutated protein in hereditary spastic paraplegia interacts with Reticulon 1 an endoplasmic reticulum protein. Neurogenetics 7:93–103
47. McCallion AS, Chakravarti A (2001) EDNRB/EDN3 and Hirschsprung disease type II. Pigment Cell Res 14:161–169
48. Meganathan K, Jagtap S, Wagh V, Winkler J, Gaspar JA, Hildebrand D, Trusch M, Lehmann K, Hescheler J, Schluter H, Sachinidis A (2012) Identification of thalidomide-specific transcriptomics and proteomics signatures during differentiation of human embryonic stem cells. PLoS ONE 7:e44228
49. Meganathan K, Jagtap S, Srinivasan SP, Wagh V, Hescheler J, Hengstler J, Leist M, Sachinidis A (2015) Neuronal developmental gene and miRNA signatures induced by histone deacetylase inhibitors in human embryonic stem cells. Cell Death Dis 6:e1756
50. Menegola E, Di Renzo F, Broccia ML, Prudenziati M, Minucci S, Massa V, Giavini E (2005) Inhibition of histone deacetylase activity on specific embryonic tissues as a new mechanism for teratogenicity. Birth Defects Res B Dev Reprod Toxicol 74:392–398
51. Mol PG, Arnardottir AH, Motola D, Vrijlandt PJ, Duijnhoven RG, Haaijer-Ruskamp FM, de Graeff PA, Denig P, Straus SM (2013) Post-approval safety issues with innovative drugs: a European cohort study. Drug Saf 36:1105–1115
52. Mutter J, Curth A, Naumann J, Deth R, Walach H (2010) Does inorganic mercury play a role in Alzheimer's disease? A systematic review and an integrated molecular mechanism. J Alzheimers Dis 22:357–374
53. Ni M, Li X, Yin Z, Jiang H, Sidoryk-WÄgrzynowicz M, Milatovic D, Cai J, Aschner M (2010) Methylmercury Induces Acute Oxidative Stress, Altering Nrf2 Protein Level in Primary Microglial Cells. Toxicol Sci 116:590–603
54. Pendergrass JC, Haley BE, Vimy MJ, Winfield SA, Lorscheider FL (1997) Mercury vapor inhalation inhibits binding of GTP to tubulin in rat brain: similarity to a molecular lesion in Alzheimer diseased brain. Neurotoxicology 18:315–324
55. Pitts MW, Byrns CN, Ogawa-Wong AN, Kremer P, Berry MJ (2014) Selenoproteins in nervous system development and function. Biol Trace Elem Res 161:231–245
56. Pollitt R, McMahon R, Nunn J, Bamford R, Afifi A, Bishop N, Dalton A (2006) Mutation analysis of COL1A1 and COL1A2 in patients diagnosed with osteogenesis imperfecta type I-IV. Hum Mutat 27:716
57. Raina AK, Templeton DJ, Deak JC, Perry G, Smith MA (1999) Quinone reductase (NQO1), a sensitive redox indicator, is increased in Alzheimer's disease. Redox Rep 4:23–27
58. Rao S-Q, Hu H-L, Ye N, Shen Y, Xu Q (2015) Genetic variants in long non-coding RNA MIAT contribute to risk of paranoid schizophrenia in a Chinese Han population. Schizophr Res 166:125–130
59. Reif R (2014a) The body-on-a-chip concept: possibilities and limitations. Excli j 13:1283–1285
60. Reif R (2014b) Concepts of predictive toxicology. EXCLI J 13:1292–1294
61. Rempel E, Hoelting L, Waldmann T, Balmer NV, Schildknecht S, Grinberg M, Das Gaspar JA, Shinde V, Stober R, Marchan R, van Thriel C, Liebing J, Meisig J, Bluthgen N, Sachinidis A, Rahnenfuhrer J, Hengstler JG, Leist M (2015) A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol 89:1599–1618
62. Richards AJ, Yates JR, Williams R, Payne SJ, Pope FM, Scott JD, Snead MP (1996) A family with Stickler syndrome type 2 has a mutation in the COL11A1 gene resulting in the substitution of glycine 97 by valine in alpha 1 (XI) collagen. Hum Mol Genet 5:1339–1343
63. Ruzzo EK, Capo-Chichi JM, Ben-Zeev B, Chitayat D, Mao H, Pappas AL, Hitomi Y, Lu YF, Yao X, Hamdan FF, Pelak K, Reznik-Wolf H, Bar-Joseph I, Oz-Levi D, Lev D, Lerman-Sagie T, Leshinsky-Silver E, Anikster Y, Ben-Asher E, Olender T, Colleaux L, Décarie JC, Blaser S, Banwell B, Joshi RB, He XP, Patry L, Silver RJ, Dobrzeniecka S, Islam MS, Hasnat A, Samuels ME, Aryal DK, Rodriguiz RM, Jiang Y, Wetsel WC, McNamara JO, Rouleau GA, Silver DL, Lancet D, Pras E, Mitchell GA, Michaud JL, Goldstein DB (2013) Deficiency of asparagine synthetase causes congenital microcephaly and a progressive form of encephalopathy. Neuron 80:429–441
64. Sampaolo S, Esposito T, Gianfrancesco F, Napolitano F, Lombardi L, Luca R, Roperto F, Di Iorio G (2015) A novel GBE1 mutation and features of polyglucosan bodies autophagy in adult polyglucosan body disease. Neuromuscul Disord 25:247–252
65. Shin MK, Levorse JM, Ingram RS, Tilghman SM (1999) The temporal requirement for endothelin receptor-B signalling during neural crest development. Nature 402:496–501
66. Shinde V, Klima S, Sureshkumar PS, Meganathan K, Jagtap S, Rempel E, Rahnenfuhrer J, Hengstler JG, Waldmann T, Hescheler J, Leist M, Sachinidis A (2015) Human pluripotent stem cell based developmental toxicity assays for chemical safety screening and systems biology data generation. J Vis Exp 110:e52333
67. Sisnaiske J, Hausherr V, Krug AK, Zimmer B, Hengstler JG, Leist M, van Thriel C (2014) Acrylamide alters neurotransmitter induced calcium responses in murine ESC-derived and primary neurons. Neurotoxicology 43:117–126
68. Srivastava S, Cohen J, Pevsner J, Aradhya S, McKnight D, Butler E, Johnston M, Fatemi A (2014) A novel variant in GABRB2 associated with intellectual disability and epilepsy. Am J Med Genet A 164A:2914–2921
69. 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 121:73–87
70. Stober R (2014) Transcriptome based differentiation of harmless, teratogenetic and cytotoxic concentration ranges of valproic acid. EXCLI J 13:1281–1282
71. Stoilov I, Rezaie T, Jansson I, Schenkman JB, Sarfarazi M (2004) Expression of cytochrome P4501b1 (Cyp1b1) during early murine development. Mol Vis 10:629–636
72. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147
73. Tohgo A, Eiraku M, Miyazaki T, Miura E, Kawaguchi SY, Nishi M, Watanabe M, Hirano T, Kengaku M, Takeshima H (2006) Impaired cerebellar functions in mutant mice lacking DNER. Mol Cell Neurosci 31:326–333
74. Toyama T, Sumi D, Shinkai Y, Yasutake A, Taguchi K, Tong KI, Yamamoto M, Kumagai Y (2007) Cytoprotective role of Nrf2/Keap1 system in methylmercury toxicity. Biochem Biophys Res Commun 363:645–650
75. Vidal R, Ghetti B, Takao M, Brefel-Courbon C, Uro-Coste E, Glazier BS, Siani V, Benson MD, Calvas P, Miravalle L, Rascol O, Delisle MB (2004) Intracellular ferritin accumulation in neural and extraneural tissue characterizes a neurodegenerative disease associated with a mutation in the ferritin light polypeptide gene. J Neuropathol Exp Neurol 63:363–380
76. Waldmann T, Rempel E, Balmer NV, Konig A, Kolde R, Gaspar JA, Henry M, Hescheler J, Sachinidis A, Rahnenfuhrer J, Hengstler JG, Leist M (2014) Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol 27:408–420
77. Wang JT, Kunzevitzky NJ, Dugas JC, Cameron M, Barres BA, Goldberg JL (2007) Disease gene candidates revealed by expression profiling of retinal ganglion cell development. J Neurosci 27:8593–8603
78. Ward LM, Lalic L, Roughley PJ, Glorieux FH (2001) Thirty-three novel COL1A1 and COL1A2 mutations in patients with osteogenesis imperfecta types I-IV. Hum Mutat 17:434
79. Ward TL, Valberg SJ, Adelson DL, Abbey CA, Binns MM, Mickelson JR (2004) Glycogen branching enzyme (GBE1) mutation causing equine glycogen storage disease IV. Mamm Genome 15:570–577
80. Warrier V, Baron-Cohen S, Chakrabarti B (2013) Genetic variation in GABRB3 is associated with Asperger syndrome and multiple endophenotypes relevant to autism. Mol Autism 4:1–11
81. Webb EA, AlMutair A, Kelberman D, Bacchelli C, Chanudet E, Lescai F, Andoniadou CL, Banyan A, Alsawaid A, Alrifai MT, Alahmesh MA, Balwi M, Mousavy-Gharavy SN, Lukovic B, Burke D, McCabe MJ, Kasia T, Kleta R, Stupka E, Beales PL, Thompson DA, Chong WK, Alkuraya FS, Martinez-Barbera JP, Sowden JC, Dattani MT (2013) ARNT2 mutation causes hypopituitarism, post-natal microcephaly, visual and renal anomalies. Brain 136:3096–3105
82. Webber DM, MacLeod SL, Bamshad MJ, Shaw GM, Finnell RH, Shete SS, Witte JS, Erickson SW, Murphy LD, Hobbs C (2015) Developments in our understanding of the genetic basis of birth defects. Birth Defects Res A Clin Mol Teratol 103:680–691
83. Weng MK, Natarajan K, Scholz D, Ivanova VN, Sachinidis A, Hengstler JG, Waldmann T, Leist M (2014) Lineage-specific regulation of epigenetic modifier genes in human liver and brain. PLoS ONE 9:e102035
84. Wobst H, Forster S, Laurini C, Sekulla A, Dreiseidler M, Hohfeld J, Schmitz B, Diestel S (2012) UCHL1 regulates ubiquitination and recycling of the neural cell adhesion molecule NCAM. FEBS J 279:4398–4409
85. Wuyts W, Reardon W, Preis S, Homfray T, Rasore-Quartino A, Christians H, Willems PJ, Van Hul W (2000) Identification of mutations in the MSX2 homeobox gene in families affected with foramina parietalia permagna. Hum Mol Genet 9:1251–1255
86. Yang P, Li X, Xu C, Eckert RL, Reece EA, Zielke HR, Wang F (2013) Maternal hyperglycemia activates an ASK1-FoxO3a-caspase 8 pathway that leads to embryonic neural tube defects. Sci Signal 6:ra74
87. Yasuda T, Nihira T, Ren Y-R, Cao X-Q, Wada K, Setsuie R, Kabuta T, Wada K, Hattori N, Mizuno Y, Mochizuki H (2009) Effects of UCH-L1 on α-synuclein over-expression mouse model of Parkinson’s disease. J Neurochem 108:932–944
88. Yin Z, Jiang H, Syversen T, Rocha JB, Farina M, Aschner M (2008) The methylmercury-L-cysteine conjugate is a substrate for the L-type large neutral amino acid transporter. J Neurochem 107:1083–1090
89. Zimmer B, Kuegler PB, Baudis B, Genewsky A, Tanavde V, Koh W, Tan B, Waldmann T, Kadereit S, Leist M (2011) Coordinated waves of gene expression during neuronal differentiation of embryonic stem cells as basis for novel approaches to developmental neurotoxicity testing. Cell Death Differ 18:383–395
90. Zimmer B, Pallocca G, Dreser N, Foerster S, Waldmann T, Westerhout J, Julien S, Krause KH, van Thriel C, Hengstler JG, Sachinidis A, Bosgra S, Leist M (2014) Profiling of drugs and environmental chemicals for functional impairment of neural crest migration in a novel stem cell-based test battery. Arch Toxicol 88:1109–1126