A review of toxicogenomic approaches in developmental toxicology

Methods in Molecular Biology

Volumn 889, Issue , 2012, Pages 347-371

  Robinson, Joshua F ^a,b,c   Pennings, Jeroen L A ^a,c   Piersma, Aldert H ^a,c,d  

^a NATIONAL INSTITUTE FOR PUBLIC HEALTH AND THE ENVIRONMENT   (Netherlands)

^b MAASTRICHT UNIVERSITY   (Netherlands)

^c Netherlands Toxicogenomic Centre (NTC)   (Netherlands)

^d UTRECHT UNIVERSITY   (Netherlands)

Author keywords

Alternatives; Classification; Development; Embryonic stem cell test; Gene expression; Method; Microarray; Toxicogenomics; Toxicology

Indexed keywords

ACETIC ACID DERIVATIVE; ALCOHOL; CADMIUM; CAFFEINE; METHYLMERCURY; METHYOXYACETIC ACID; PHTHALIC ACID; RNA; UNCLASSIFIED DRUG; ZINC; TERATOGENIC AGENT;

DEVELOPMENTAL TOXICITY; EAR; EMBRYO DEVELOPMENT; EYE; GENE EXPRESSION; GENETIC TOXICOLOGY; NEURAL TUBE; NONHUMAN; PRIORITY JOURNAL; REVIEW; RNA ISOLATION; TERATOGENICITY; TRANSCRIPTOMICS; ANIMAL; CHEMISTRY; CLASSIFICATION; CLUSTER ANALYSIS; DEVELOPMENTAL BIOLOGY; DNA MICROARRAY; GENE EXPRESSION PROFILING; GENETIC DATABASE; GENETICS; HUMAN; ISOLATION AND PURIFICATION; METHODOLOGY; PRESERVATION; PRINCIPAL COMPONENT ANALYSIS; TOXICOGENETICS;

ANIMALS; CLUSTER ANALYSIS; DATABASES, GENETIC; DEVELOPMENTAL BIOLOGY; GENE EXPRESSION PROFILING; HUMANS; OLIGONUCLEOTIDE ARRAY SEQUENCE ANALYSIS; PRESERVATION, BIOLOGICAL; PRINCIPAL COMPONENT ANALYSIS; RESEARCH DESIGN; RNA; TERATOGENS; TOXICOGENETICS;

EID: 84866522765     PISSN: 10643745     EISSN: None     Source Type: Book Series    
DOI: 10.1007/978-1-61779-867-2_22     Document Type: Review

References (101)

1. Daston GP, Naciff JM (2010) Predicting developmental toxicity through toxicog-enomics. Birth Defects Res C Embryo Today 90:110-117
2. Metzker ML (2010) Sequencing technologies-the next generation. Nat Rev Genet 11: 31-46
3. Kultima K, Fernandez EL, Scholz B, Gustafson AL, Dencker L, Stigson M (2006) Cadmium-induced gene expression changes in the mouse embryo, and the in fluence of pretreatment with zinc. Reprod Toxicol 22:636-646
4. Green ML, Singh AV, Zhang Y, Nemeth KA, Sulik KK, Knudsen TB (2007) Reprogramming of genetic networks during initiation of the Fetal Alcohol Syndrome. Dev Dyn 236:613-631
5. Naciff JM, Hess KA, Overmann GJ, Torontali SM, Carr GJ, Tiesman JP, Foertsch LM, Richardson BD, Martinez JE, Daston GP (2005) Gene expression changes induced in the testis by transplacental exposure to high and low doses of 17{alpha}-ethynyl estradiol, genistein, or bisphenol A. Toxicol Sci 86:396-416
6. Moreira EG, Yu X, Robinson JF, Griffith W, Hong SW, Beyer RP, Bammler TK, Faustman EM (2010) Toxicogenomic pro filing in maternal and fetal rodent brains following gestational exposure to chlorpyrifos. Toxicol Appl Pharmacol 245:310-325
7. Robinson JF, Yu X, Moreira EG, Hong S, Faustman EM (2011) Arsenic-and cadmium-induced toxicogenomic response in mouse embryos undergoing neurulation. Toxicol Appl Pharmacol 15:117-129
8. Robinson JF, Guerrette Z, Yu X, Hong S, Faustman EM (2010) A systems-based approach to investigate dose-and time-dependent methylmercury-induced gene expression response in C57BL/6 mouse embryos undergoing neurulation. Birth Defects Res B Dev Reprod Toxicol 89:188-200
9. Robinson JF, Yu X, Hong S, Griffith WC, Beyer R, Kim E, Faustman EM (2009) Cadmium-induced differential toxicogenomic response in resistant and sensitive mouse strains undergoing neurulation. Toxicol Sci 107:206-219
10. Webster WS, Messerle K (1980) Changes in the mouse neuroepithelium associated with cadmium-induced neural tube defects. Teratology 21:79-88
11. van Dartel DA, Pennings JL, de la Fonteyne LJ, Brauers KJ, Claessen S, van Delft JH, Kleinjans JC, Piersma AH (2011) Concentration-dependent gene expression responses to flusilazole in embryonic stem cell differentiation cultures. Toxicol Appl Pharmacol 251:110-118
12. Wlodarczyk BJ, Cabrera RM, Hill DS, Bozinov D, Zhu H, Finnell RH (2006) Arsenic-induced gene expression changes in the neural tube of folate transport defective mouse embryos. Neurotoxicology 27:547-557
13. van Dartel DA, Pennings JL, Hendriksen PJ, van Schooten FJ, Piersma AH (2009) Early gene expression changes during embryonic stem cell differentiation into cardiomyocytes and their modulation by monobutyl phtha-late. Reprod Toxicol 27:93-102
14. Theunissen PT, Pennings JL, Robinson JF, Claessen SM, Kleinjans JC, Piersma AH (2011) Time-response evaluation by tran-scriptomics of methylmercury effects on neural differentiation of murine embryonic stem cells. Toxicol Sci 122:437-447
15. Knudsen KB, Daston GP (2010) Comprehensive toxicology. Elsevier Ltd. Amsterdam, The Netherlands
16. van Dartel DA, Pennings JL, de la Fonteyne LJ, van Herwijnen MH, van Delft JH, van Schooten FJ, Piersma AH (2010) Monitoring developmental toxicity in the embryonic stem cell test using differential gene expression of differentiation-related genes. Toxicol Sci 116:130-139
17. van Dartel DA, Pennings JL, Robinson JF, Kleinjans JC, Piersma AH (2011) Discriminating classes of developmental toxicants using gene expression pro filing in the embryonic stem cell test. Toxicol Lett 201:143-151
18. Robinson JF, van Beelen VA, Verhoef A, Renkens MF, Luijten M, van Herwijnen MH, Westerman A, Pennings JL, Piersma AH (2010) Embryotoxicant-speci fic transcrip-tomic responses in rat postimplantation whole-embryo culture. Toxicol Sci 118:675-685
19. Yang L, Kemadjou JR, Zinsmeister C, Bauer M, Legradi J, Muller F, Pankratz M, Jakel J, Strahle U (2007) Transcriptional pro filing reveals barcode-like toxicogenomic responses in the zebra fish embryo. Genome Biol 8:R227
20. Glover CN, Zheng D, Jayashankar S, Sales GD, Hogstrand C, Lundebye AK (2009) Methylmercury speciation in fluences brain gene expression and behavior in gestationally-exposed mice pups. Toxicol Sci 110:389-400
21. Okada A, Kushima K, Aoki Y, Bialer M, Fujiwara M (2005) Identi fication of early-responsive genes correlated to valproic acid-induced neural tube defects in mice. Birth Defects Res A Clin Mol Teratol 73:229-238
22. Machado A (2009) Additivity and synergism in the production of neural tube defects birth defects. Res A Clin Mol Teratol 85:341-508
23. Boverhof DR, Burgoon LD, Tashiro C, Sharratt B, Chittim B, Harkema JR, Mendrick DL, Zacharewski TR (2006) Comparative toxicogenomic analysis of the hepatotoxic effects of TCDD in Sprague Dawley rats and C57BL/6 mice. Toxicol Sci 94:398-416
24. Robinson JF, Griffith WC, Yu X, Hong S, Kim E, Faustman EM (2010) Methylmercury induced toxicogenomic response in C57 and SWV mouse embryos undergoing neural tube closure. Reprod Toxicol 30:284-291
25. Robinson JF, Yu X, Hong S, Zhou C, Kim N, DeMasi D, Faustman EM (2010) Embryonic toxicokinetic and dynamic differences underlying strain sensitivity to cadmium during neurulation. Reprod Toxicol 29:279-285
26. Brent RL, Holmes LB (1988) Clinical and basic science lessons from the thalidomide tragedy: what have we learned about the causes of limb defects? Teratology 38:241-251
27. Theunissen PT, Schulpen SH, van Dartel DA, Hermsen SA, van Schooten FJ, Piersma AH (2010) An abbreviated protocol for multilin-eage neural differentiation of murine embryonic stem cells and its perturbation by methyl mercury. Reprod Toxicol 29:383-392
28. van Dartel DA, Zeijen NJ, de la Fonteyne LJ, van Schooten FJ, Piersma AH (2009) Disentangling cellular proliferation and differentiation in the embryonic stem cell test, and its impact on the experimental protocol. Reprod Toxicol 28:254-261
29. Fang H, Yang Y, Li C, Fu S, Yang Z, Jin G, Wang K, Zhang J, Jin Y (2010) Transcriptome analysis of early organogenesis in human embryos. Dev Cell 19:174-184
30. Mitiku N, Baker JC (2007) Genomic analysis of gastrulation and organogenesis in the mouse. Dev Cell 13:897-907
31. van Dartel DA, Pennings JL, van Schooten FJ, Piersma AH (2010) Transcriptomics-based identi fication of developmental toxicants through their interference with cardiomyo-cyte differentiation of embryonic stem cells. Toxicol Appl Pharmacol 243:420-428
32. Naciff JM, Torontali SM, Overmann GI, Carr GJ, Tiesman JP, Daston GP (2005) Evaluation of the gene expression changes induced by 17-alpha-ethynyl estradiol in the immature uterus/ovaries of the rat using high density oligonucleotide arrays. Birth Defects Res B Dev Reprod Toxicol 74:164-184
33. Naciff JM, Jump ML, Torontali SM, Carr GJ, Tiesman JP, Overmann GJ, Daston GP (2002) Gene expression pro file induced by 17alpha-ethynyl estradiol, bisphenol A, and genistein in the developing female reproductive system of the rat. Toxicol Sci 68:184-199
34. Naciff JM, Overmann GJ, Torontali SM, Carr GJ, Tiesman JP, Richardson BD, Daston GP (2003) Gene expression pro file induced by 17 alpha-ethynyl estradiol in the prepubertal female reproductive system of the rat. Toxicol Sci 72:314-330
35. Luijten M, van Beelen VA, Verhoef A, Renkens MF, van Herwijnen MH, Westerman A, van Schooten FJ, Pennings JL, Piersma AH (2010) Transcriptomics analysis of retinoic acid embryotoxicity in rat postimplantation whole embryo culture. Reprod Toxicol 30:333-340
36. Jergil M, Kultima K, Gustafson AL, Dencker L, Stigson M (2009) Valproic acid-induced deregulation in vitro of genes associated in vivo with neural tube defects. Toxicol Sci 108:132-148
37. Kultima K, Jergil M, Salter H, Gustafson AL, Dencker L, Stigson M (2010) Early transcrip-tional responses in mouse embryos as a basis for selection of molecular markers predictive of valproic acid teratogenicity. Reprod Toxicol 30:457-468
38. White CA, Salamonsen LA (2005) A guide to issues in microarray analysis: application to endometrial biology. Reproduction 130: 1-13
39. Liu P, Hwang JT (2007) Quick calculation for sample size while controlling false discovery rate with application to microarray analysis. Bioinformatics 23:739-746
40. Shao Y, Tseng CH (2007) Sample size calculation with dependence adjustment for FDR-control in microarray studies. Stat Med 26:4219-4237
41. Liu CG, Spizzo R, Calin GA, Croce CM (2008) Expression pro filing of microRNA using oligo DNA arrays. Methods 44:22-30
42. Kiewe P, Gueller S, Komor M, Stroux A, Thiel E, Hofmann WK (2009) Prediction of qualitative outcome of oligonucleotide microarray hybridization by measurement of RNA integrity using the 2100 Bioanalyzer capillary electrophoresis system. Ann Hematol 88: 1177-1183
43. Ma W, Wang M, Wang ZQ, Sun L, Graber D, Matthews J, Champlin R, Yi Q, Orlowski RZ, Kwak LW, Weber DM, Thomas SK, Shah J, Kornblau S, Davis RE (2010) Effect of long-term storage in TRIzol on microarray-based gene expression pro filing. Cancer Epidemiol Biomarkers Prev 19:2445-2452
44. Opitz L, Salinas-Riester G, Grade M, Jung K, Jo P, Emons G, Ghadimi BM, Beissbarth T, Gaedcke J (2010) Impact of RNA degradation on gene expression pro filing. BMC Med Genomics 3:36
45. Mutter GL, Zahrieh D, Liu C, Neuberg D, Finkelstein D, Baker HE, Warrington JA (2004) Comparison of frozen and RNALater solid tissue storage methods for use in RNA expression microarrays. BMC Genomics 5:88
46. Sawada A, Mizufune S, Kaji N, Tokeshi M, Baba Y (2007) Evaluation of ampli fied cRNA targets for oligonucleotide microarrays. Anal Bioanal Chem 387:2645-2654
47. Wang E (2005) RNA ampli fication for successful gene pro filing analysis. J Transl Med 3:28
48. Ji W, Zhou W, Gregg K, Lindpaintner K, Davis S (2004) A method for gene expression analysis by oligonucleotide arrays from minute biological materials. Anal Biochem 331:329-339
49. Scantland S, Grenon JP, Desrochers MH, Sirard MA, Khandjian EW, Robert C (2011) Method to isolate polyribosomal mRNA from scarce samples such as mammalian oocytes and early embryos. BMC Dev Biol 11:8
50. Robert C (2010) Microarray analysis of gene expression during early development: a cautionary overview. Reproduction 140:787-801
51. Gilbert I, Scantland S, Sylvestre EL, Dufort I, Sirard MA, Robert C (2010) Providing a stable methodological basis for comparing transcript abundance of developing embryos using microarrays. Mol Hum Reprod 16:601-616
52. Duncan FE, Schultz RM (2010) Methods in enzymology-Ch. 23 gene expression pro filing of mouse oocytes and preimplanta-tion embryos. Elsevier Inc. Amsterdam, The Netherlands
53. Hardiman G (2004) Microarray platforms-comparisons and contrasts. Pharmacogenomics 5:487-502
54. Arteaga-Salas JM, Zuzan H, Langdon WB, Upton GJ, Harrison AP (2008) An overview of image-processing methods for Affymetrix GeneChips. Brief Bioinform 9:25-33
55. Guo L, Lobenhofer EK, Wang C, Shippy R, Harris SC, Zhang L, Mei N, Chen T, Herman D, Goodsaid FM, Hurban P, Phillips KL, Xu J, Deng X, Sun YA, Tong W, Dragan YP, Shi L (2006) Rat toxicogenomic study reveals analytical consistency across microarray platforms. Nat Biotechnol 24:1162-1169
56. Bosotti R, Locatelli G, Healy S, Scacheri E, Sartori L, Mercurio C, Calogero R, Isacchi A (2007) Cross platform microarray analysis for robust identi fication of differentially expressed genes. BMC Bioinformatics 8(Suppl 1):S5
57. Pedotti P, Hoen PA, Vreugdenhil E, Schenk GJ, Vossen RH, Ariyurek Y, de Hollander M, Kuiper R, van Ommen GJ, den Dunnen JT, Boer JM, de Menezes RX (2008) Can subtle changes in gene expression be consistently detected with different microarray platforms? BMC Genomics 9:124
58. Shi L, Perkins RG, Fang H, Tong W (2008) Reproducible and reliable microarray results through quality control: good laboratory pro-ficiency and appropriate data analysis practices are essential. Curr Opin Biotechnol 19:10-18
59. Yang YH, Buckley MJ, Speed TP (2001) Analysis of cDNA microarray images. Brief Bioinform 2:341-349
60. Bolstad BM, Irizarry RA, Astrand M, Speed TP (2003) A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19:185-193
61. Smyth GK, Speed T (2003) Normalization of cDNA microarray data. Methods 31:265-273
62. Vardhanabhuti S, Blakemore SJ, Clark SM, Ghosh S, Stephens RJ, Rajagopalan D (2006) A comparison of statistical tests for detecting differential expression using Affymetrix oligo-nucleotide microarrays. OMICS 10:555-566
63. Qin LX, Beyer RP, Hudson FN, Linford NJ, Morris DE, Kerr KF (2006) Evaluation of methods for oligonucleotide array data via quantitative real-time PCR. BMC Bioinformatics 7:23
64. Chen YJ, Kodell R, Sistare F, Thompson KL, Morris S, Chen JJ (2003) Normalization methods for analysis of microarray gene-expression data. J Biopharm Stat 13:57-74
65. Yang YH, Dudoit S, Luu P, Lin DM, Peng V, Ngai J, Speed TP (2002) Normalization for cDNA microarray data: a robust composite method addressing single and multiple slide systematic variation. Nucleic Acids Res 30:e15
66. Qian HR, Huang S (2005) Comparison of false discovery rate methods in identifying genes with differential expression. Genomics 86:495-503
67. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Statist Soc B 57:289-300
68. Pavlidis P (2003) Using ANOVA for gene selection from microarray studies of the nervous system. Methods 31:282-289
69. Stegle O, Denby KJ, Cooke EJ, Wild DL, Ghahramani Z, Borgwardt KM (2010) A robust Bayesian two-sample test for detecting intervals of differential gene expression in microarray time series. J Comput Biol 17:355-367
70. Jeanmougin M, de Reynies A, Marisa L, Paccard C, Nuel G, Guedj M (2010) Should we abandon the t-test in the analysis of gene expression microarray data: a comparison of variance modeling strategies. PLoS One 5:e12336
71. Saeed AI, Sharov V, White J, Li J, Liang W, Bhagabati N, Braisted J, Klapa M, Currier T, Thiagarajan M, Sturn A, Snuffin M, Rezantsev A, Popov D, Ryltsov A, Kostukovich E, Borisovsky I, Liu Z, Vinsavich A, Trush V, Quackenbush J (2003) TM4: a free, open-source system for microarray data management and analysis. Biotechniques 34:374-378
72. Hastie T, Tibshirani R, Friedman J (2009) The elements of statistical learning: data mining, inference and prediction, 2nd edn. Springer-Verlag, New York, USA
73. van Dartel DA, Pennings JL, de la Fonteyne LJ, Brauers KJ, Claessen S, van Delft JH, Kleinjans JC, Piersma AH (2011) Evaluation of developmental toxicant identi fication using gene expression pro filing in embryonic stem cell differentiation cultures. Toxicol Sci 119:126-134
74. da Huang W, Sherman BT, Tan Q, Kir J, Liu D, Bryant D, Guo Y, Stephens R, Baseler MW, Lane HC, Lempicki RA (2007) DAVID Bioinformatics Resources: expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Res 35:W169-W175
75. Sherman BT, da Huang W, Tan Q, Guo Y, Bour S, Liu D, Stephens R, Baseler MW, Lane HC, Lempicki RA (2007) DAVID Knowledgebase: a gene-centered database integrating heterogeneous gene annotation resources to facilitate high-throughput gene functional analysis. BMC Bioinformatics 8:426
76. Carbon S, Ireland A, Mungall CJ, Shu S, Marshall B, Lewis S (2009) AmiGO: online access to ontology and annotation data. Bioinformatics 25:288-289
77. da Huang W, Sherman BT, Stephens R, Baseler MW, Lane HC, Lempicki RA (2008) DAVID gene ID conversion tool. Bioinformation 2:428-430
78. Salomonis N, Hanspers K, Zambon AC, Vranizan K, Lawlor SC, Dahlquist KD, Doniger SW, Stuart J, Conklin BR, Pico AR (2007) GenMAPP 2: new features and resources for pathway analysis. BMC Bioinformatics 8:217
79. Zeeberg BR, Feng W, Wang G, Wang MD, Fojo AT, Sunshine M, Narasimhan S, Kane DW, Reinhold WC, Lababidi S, Bussey KJ, Riss J, Barrett JC, Weinstein JN (2003) GoMiner: a resource for biological interpretation of genomic and proteomic data. Genome Biol 4:R28
80. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression pro files. Proc Natl Acad Sci USA 102:15545-15550
81. Boorsma A, Foat BC, Vis D, Klis F, Bussemaker HJ (2005) T-pro filer: scoring the activity of prede fined groups of genes using gene expression data. Nucleic Acids Res 33:W592-W595
82. Ho Sui SJ, Mortimer JR, Arenillas DJ, Brumm J, Walsh CJ, Kennedy BP, Wasserman WW (2005) oPOSSUM: identi fication of over-represented transcription factor binding sites in co-expressed genes. Nucleic Acids Res 33:3154-3164
83. Lenhard B, Wasserman WW (2002) TFBS: computational framework for transcription factor binding site analysis. Bioinformatics 18:1135-1136
84. Yu X, Griffith WC, Hanspers K, Dillman JF III, Ong H, Vredevoogd MA, Faustman EM (2006) A system-based approach to interpret dose-and time-dependent microarray data: quantitative integration of gene ontology analysis for risk assessment. Toxicol Sci 92: 560-577
85. Yang L, Allen BC, Thomas RS (2007) BMDExpress: a software tool for the benchmark dose analyses of genomic data. BMC Genomics 8:387
86. Burgoon LD, Zacharewski TR (2008) Automated quantitative dose-response modeling and point of departure determination for large toxicogenomic and high-throughput screening data sets. Toxicol Sci 104:412-418
87. Parkinson H, Kapushesky M, Kolesnikov N, Rustici G, Shojatalab M, Abeygunawardena N, Berube H, Dylag M, Emam I, Farne A, Holloway E, Lukk M, Malone J, Mani R, Pilicheva E, Rayner TF, Rezwan F, Sharma A, Williams E, Bradley XZ, Adamusiak T, Brandizi M, Burdett T, Coulson R, Krestyaninova M, Kurnosov P, Maguire E, Neogi SG, Rocca-Serra P, Sansone SA, Sklyar N, Zhao M, Sarkans U, Brazma A (2009) ArrayExpress update-from an archive of functional genomics experiments to the atlas of gene expression. Nucleic Acids Res 37:D868-D872
88. Barrett T, Troup DB, Wilhite SE, Ledoux P, Rudnev D, Evangelista C, Kim IF, Soboleva A, Tomashevsky M, Marshall KA, Phillippy KH, Sherman PM, Muertter RN, Edgar R (2009) NCBI GEO: archive for high-throughput functional genomic data. Nucleic Acids Res 37:D885-D890
89. Ikeo K, Ishi-i J, Tamura T, Gojobori T, Tateno Y (2003) CIBEX: center for information biology gene expression database. C R Biol 326:1079-1082
90. Knudsen KB, Singh AV, Knudsen TB (2005) Data input module for Birth Defects Systems Manager. Reprod Toxicol 20:369-375
91. Ball CA, Brazma A (2006) MGED standards: work in progress. OMICS 10:138-144
92. Kapushesky M, Emam I, Holloway E, Kurnosov P, Zorin A, Malone J, Rustici G, Williams E, Parkinson H, Brazma A (2010) Gene expression atlas at the European bioinformatics institute. Nucleic Acids Res 38:D690-D698
93. Brooksbank C, Cameron G, Thornton J (2010) The European Bioinformatics Institute's data resources. Nucleic Acids Res 38:D17-D25
94. Lukk M, Kapushesky M, Nikkila J, Parkinson H, Goncalves A, Huber W, Ukkonen E, Brazma A (2010) A global map of human gene expression. Nat Biotechnol 28:322-324
95. Robinson JF, Theunissen PT, van Dartel DA, Pennings JL, Faustman EM, Piersma AH (2011) Comparison of MeHg-induced toxi-cogenomic responses across in vivo and in vitro models used in developmental toxicology. Reprod Toxicol 32:180-188
96. Singh AV, Knudsen KB, Knudsen TB (2007) Integrative analysis of the mouse embryonic transcriptome. Bioinformation 1:406-413
97. Harrill AH, Rusyn I (2008) Systems biology and functional genomics approaches for the identi fication of cellular responses to drug toxicity. Expert Opin Drug Metab Toxicol 4:1379-1389
98. Nigsch F, Macaluso NJ, Mitchell JB, Zmuidinavicius D (2009) Computational toxicology: an overview of the sources of data and of modelling methods. Expert Opin Drug Metab Toxicol 5:1-14
99. Waters MD, Fostel JM (2004) Toxicogenomics and systems toxicology: aims and prospects. Nat Rev Genet 5:936-948
100. Osman AM, van Dartel DA, Zwart E, Blokland M, Pennings JL, Piersma AH (2010) Proteome pro filing of mouse embryonic stem cells to de fine markers for cell differentiation and embryotoxicity. Reprod Toxicol 30:322-332
101. Robinson JF, Port JA, Yu X, Faustman EM (2010) Integrating genetic and toxicog-enomic information for determining underlying susceptibility to developmental disorders. Birth Defects Res A Clin Mol Teratol 88:920-930