Lead exposure disrupts global DNA methylation in human embryonic stem cells and alters their neuronal differentiation

Toxicological Sciences

Volumn 139, Issue 1, 2014, Pages 142-161

  Senut, Marie Claude ^a,b   Sen, Arko ^a,b   Cingolani, Pablo ^a,b,c   Shaik, Asra ^a,b   Land, Susan J ^a,b   Ruden, Douglas M ^a,b  

^a WAYNE STATE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b WAYNE STATE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c MCGILL UNIVERSITY   (Canada)

Author keywords

DNA methylation; Heavy metal; Human embryonic stem cell; Lead; Neuronal differentiation

Indexed keywords

ACETIC ACID; LEAD; MSI1 PROTEIN; NESTIN; PROTEIN; TRANSCRIPTION FACTOR PAX6; UNCLASSIFIED DRUG; PRIMER DNA;

ARTICLE; CELL STRUCTURE; CELL VIABILITY; CELL VIABILITY ASSAY; CONTROLLED STUDY; CPG ISLAND; CYTOTOXICITY; DNA METHYLATION; EMBRYONIC STEM CELL; GENE EXPRESSION; GENETIC ANALYSIS; HUMAN; HUMAN CELL; IMMUNOFLUORESCENCE TEST; IMMUNOHISTOCHEMISTRY; IN VITRO STUDY; LONG TERM EXPOSURE; MTT ASSAY; NERVE CELL DIFFERENTIATION; NEURAL STEM CELL; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; ROSETTE FORMATION; CELL DIFFERENTIATION; CYTOLOGY; DRUG EFFECTS; NERVE CELL; NUCLEOTIDE SEQUENCE; TOXICITY;

BASE SEQUENCE; CELL DIFFERENTIATION; DNA METHYLATION; DNA PRIMERS; EMBRYONIC STEM CELLS; HUMANS; LEAD; NEURONS;

EID: 84899080543     PISSN: 10966080     EISSN: 10960929     Source Type: Journal    
DOI: 10.1093/toxsci/kfu028     Document Type: Article

References (95)

1. Alicea, B., Murthy, S., Keaton, S. A., Cobbett, P., Cibelli, J. B., and Suhr, S. T. (2013). Defining the diversity of phenotypic respecification using multiple cell lines and reprogramming regimens. Stem Cells Dev. 22, 2641-2654.
2. Baek, D. H., Park, S. H., Park, J. H., Choi, Y., Park, K. D., Kang, J. W., Choi, K. S., and Kim, H. S. (2011). Embryotoxicity of lead (II) acetate and aroclor 1254 using a new end point of the embryonic stem cell test. Int. J. Toxicol. 30, 498-509.
3. Basha, M. R., Wei, W., Bakheet, S. A., Benitez, N., Siddiqi, H. K., Ge, Y. W., Lahiri, D. K., and Zawia, N. H. (2005). The fetal basis of amyloidogenesis: Exposure to lead and latent overexpression of amyloid precursor protein and beta-amyloid in the aging brain. J. Neurosci. 25, 823-829.
4. Beissbarth, T., and Speed, T. P. (2004). GOstat: Find statistically overrepresented Gene Ontologies within a group of genes. Bioinformatics 20, 1464- 1465.
5. Bellinger, D. C. (2013). Prenatal exposures to environmental chemicals and children's neurodevelopment: An update. Saf. Health Work 4, 1-11.
6. Bihaqi, S.W., Bahmani, A., Subaiea, G. M., and Zawia, N. H. (2013). Infantile exposure to lead and late-age cognitive decline: Relevance to AD. Alzheimers Dement., doi: 10.1016/j.jalz.2013.02.012.
7. Bihaqi, S. W., Huang, H., Wu, J., and Zawia, N. H. (2011). Infant exposure to lead (Pb) and epigenetic modifications in the aging primate brain: Implications for Alzheimer's disease. J. Alzheimers Dis. 27, 819-833
8. Bihaqi, S. W., and Zawia, N. H. (2012). Alzheimer's disease biomarkers and epigenetic intermediates following exposure to Pb in vitro. Curr. Alzheimer Res. 9, 555-562
9. Bolin, C. M., Basha, R., Cox, D., Zawia, N. H., Maloney, B., Lahiri, D. K., and Cardozo-Pelaez, F. (2006). Exposure to lead and the developmental origin of oxidative DNA damage in the aging brain. FASEB J. 20, 788-790.
10. Brandt, S. K., Weatherly, M. E., Ware, L., Linn, D. M., and Linn, C. L. (2011). Calcium preconditioning triggers neuroprotection in retinal ganglion cells. Neuroscience 172, 387-397.
11. Brubaker, C. J., Schmithorst, V. J., Haynes, E. N., Dietrich, K. N., Egelhoff, J. C., Lindquist, D. M., Lanphear, B. P., and Cecil, K. M. (2009). Altered myelination and axonal integrity in adults with childhood lead exposure: A diffusion tensor imaging study. Neurotoxicology 30, 867-875.
12. Canfield, R. L., Henderson, C. R., Jr, Cory-Slechta, D. A., Cox, C., Jusko, T. A., and Lanphear, B. P. (2003). Intellectual impairment in children with blood lead concentrations below 10 microg per deciliter. N. Engl. J. Med. 348, 1517-1526.
13. Cecil, K. M., Brubaker, C. J., Adler, C. M., Dietrich, K. N., Altaye, M., Egelhoff, J. C., Wessel, S., Elangovan, I., Hornung, R., Jarvis, K., et al. (2008). Decreased brain volume in adults with childhood lead exposure. PLoS Med. 5, e112.
14. Chang, E. A., Beyhan, Z., Yoo, M. S., Siripattarapravat, K., Ko, T., Lookingland, K. J., Madhukar, B. V., and Cibelli, J. B. (2010). Increased cellular turnover in response to fluoxetine in neuronal precursors derived from human embryonic stem cells. Int. J. Dev. Biol. 54, 707-715.
15. Davidovics, Z., and DiCicco-Bloom, E. (2005). Moderate lead exposure elicits neurotrophic effects in cerebral cortical precursor cells in culture. J. Neurosci. Res. 80, 817-825.
16. Dedeurwaerder, S., Defrance, M., Calonne, E., Denis, H., Sotiriou, C., and Fuks, F. (2011). Evaluation of the Infinium Methylation 450K technology. Epigenomics 3, 771-784.
17. Dosunmu, R., Alashwal, H., and Zawia, N. H. (2012). Genome-wide expression and methylation profiling in the aged rodent brain due to early-life Pb exposure and its relevance to aging. Mech. Ageing Dev. 133, 435-443.
18. Elango, N., and Yi, S. V. (2011). Functional relevance of CpG island length for regulation of gene expression. Genetics 187, 1077-1083.
19. Fisher, C. L., and Fisher, A. G. (2011). Chromatin states in pluripotent, differentiated, and reprogrammed cells. Curr. Opin. Gen. Dev. 21, 140-146.
20. Franklin, J. L., Berechid, B. E., Cutting, F. B., Presente, A., Chambers, C.B., Foltz, D. R., Ferreira, A., and Nye, J. S. (1999). Autonomous and nonautonomous regulation of mammalian neurite development by Notch1 and Delta1. Curr. Biol. 9, 1448-1457.
21. Gensel, J. C., Schonberg, D. L., Alexander, J. K., McTigue, D. M., and Popovich, P. G. (2010). Semi-automated Sholl analysis for quantifying changes in growth and differentiation of neurons and glia. J. Neurosci. Methods 190, 71-79.
22. Giddabasappa, A., Hamilton, W. R., Chaney, S., Xiao, W., Johnson, J. E., Mukherjee, S., and Fox, D. A. (2011). Low-level gestational lead exposure increases retinal progenitor cell proliferation and rod photoreceptor and bipolar cell neurogenesis in mice. Environ. Health Perspect. 119, 71-77.
23. Gilbert, M. E., Kelly, M. E., Samsam, T. E., andGoodman, J.H. (2005). Chronic developmental lead exposure reduces neurogenesis in adult rat hippocampus but does not impair spatial learning. Toxicol. Sci. 86, 365-374.
24. Guilarte, T. R., Opler, M., and Pletnikov, M. (2012). Is lead exposure in early life an environmental risk factor for Schizophrenia? Neurobiological connections and testable hypotheses. Neurotoxicology 33, 560-574.
25. Gundacker, C., Scheinast, M., Damjanovic, L., Fuchs, C., Rosner, M., and Hengstschlager, M. (2012). Proliferation potential of human amniotic fluid stem cells differently responds to mercury and lead exposure. Amino Acids 43, 937-949.
26. Hanley, J. A., Negassa, A., Edwardes, M. D., and Forrester, J. E. (2003). Statistical analysis of correlated data using generalized estimating equations: An orientation. Am. J. Epidemiol. 157, 364-375.
27. Hanna, C. W., Bloom, M. S., Robinson, W. P., Kim, D., Parsons, P. J., vom Saal, F. S., Taylor, J. A., Steuerwald, A. J., and Fujimoto, V. Y. (2012). DNA methylation changes in whole blood is associated with exposure to the environmental contaminants, mercury, lead, cadmium and bisphenol A, in women undergoing ovarian stimulation for IVF. Hum. Reprod. 27, 1401-1410.
28. Holmberg, J., Armulik, A., Senti, K. A., Edoff, K., Spalding, K., Momma, S., Cassidy, R., Flanagan, J.G., and Frisen, J. (2005). Ephrin-A2 reverse signaling negatively regulates neural progenitor proliferation and neurogenesis. Genes Dev. 19, 462-471.
29. Huang, F., and Schneider, J. S. (2004). Effects of lead exposure on proliferation and differentiation of neural stem cells derived from different regions of embryonic rat brain. Neurotoxicology 25, 1001-1012.
30. Hu, B. Y., and Zhang, S. C. (2010). Directed differentiation of neural-stem cells and subtype-specific neurons from hESCs. Methods Mol. Biol. 636, 123-137.
31. Imai, T., Tokunaga, A., Yoshida, T., Hashimoto, M., Mikoshiba, K., Weinmaster, G., Nakafuku, M., and Okano, H. (2001). The neural RNA-binding protein Musashi1 translationally regulates mammalian numb gene expression by interacting with its mRNA. Mol. Cell Biol. 21, 3888-3900.
32. Jaako-Movits, K., Zharkovsky, T., Romantchik, O., Jurgenson, M., Merisalu, E., Heidmets, L. T., and Zharkovsky, A. (2005). Developmental lead exposure impairs contextual fear conditioning and reduces adult hippocampal neurogenesis in the rat brain. Int. J. Dev. Neurosci. 23, 627-635.
33. Jiao, J.-W., Feldheim, D. A., and Chen, D. F. (2008) Ephrins are negative regulators of adult neurogenesis in diverse regions of the central nervous system. Proc. Natl. Acad. Sci. U.S.A. 105, 8778-8783.
34. Jobe, E. M., McQuate, A. L., and Zhao, X. (2012). Crosstalk among epigenetic pathways regulates neurogenesis. Front. Neurosci. 6, 59.
35. Jones, N. M., Kardashyan, L., Callaway, J. K., Lee, E. M., and Beart, P. M. (2008). Long-term functional and protective actions of preconditioning with hypoxia, cobalt chloride, and desferrioxamine against hypoxic-ischemic injury in neonatal rats. Pediatr. Res. 63, 620-624.
36. Kaneko, Y., Sakakibara, S., Imai, T., Suzuki, A., Nakamura, Y., Sawamoto, K., Ogawa, Y., Toyama, Y., Miyata, T., and Okano, H. (2000). Musashi1: An evolutionally conserved marker for CNS progenitor cells including neural stem cells. Dev. Neurosci. 22, 139-153.
37. Kermani, S., Karbalaie, K., Madani, S. H., Jahangirnejad, A. A., Eslaminejad, M. B., Nasr-Esfahani, M. H., and Baharvand, H. (2008). Effect of lead on proliferation and neural differentiation of mouse bone marrow-mesenchymal stem cells. Toxicol. In Vitro 22, 995-1001.
38. Knight, H. M., Walker, R., James, R., Porteous, D. J., Muir, W. J., Blackwood, D. H. R., and Pickard, B. S. (2012).GRIK4/KA1 protein expression in human brain and correlation with bipolar disorder risk variant status. Am. J. Med. Genet. B Neuropsychiatr. Genet. 22, 21-29.
39. Kovatsi, L., Georgiou, E., Ioannou, A., Haitoglou, C., Tzimagiorgis, G., Tsoukali, H., and Kouidou, S. (2010). p16 promoter methylation in Pb2+ - exposed individuals. Clin. Toxicol. 48, 124-128.
40. Krencik, R., and Zhang, S. C. (2006). Stem cell neural differentiation: A model for chemical biology. Curr. Opin. Chem. Biol. 10, 592-597.
41. Kuehn, B. M. (2012). Panel advises tougher limits on lead exposure. JAMA 307, 445.
42. Lanphear, B. P., Hornung, R., Khoury, J., Yolton, K., Baghurst, P., Bellinger, D.C., Canfield, R. L., Dietrich, K. N., Bornschein, R., Greene, T., et al. (2005). Low-level environmental lead exposure and children's intellectual function: An international pooled analysis. Environ. Health Perspect. 113, 894-849.
43. Lee, S. K., and Pfaff, S. L. (2003). Synchronization of neurogenesis and motor neuron specification bydirect coupling of bHLH and homeodomain transcription factors. Neuron 38, 731-645.
44. Lidsky, T. I., and Schneider, J. S. (2003). Lead neurotoxicity in children: Basic mechanisms and clinical correlates. Brain 126, 5-19.
45. Livak, K. J., and Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25, 402-408.
46. Maher, P. (2001). How protein kinase C activation protects nerve cells from oxidative stress-induced cell death. J. Neurosci. 21, 2929-2938.
47. Mata, J., Marguerat, S., and Bahler, J. (2005). Post-transcriptional control of gene expression: A genome-wide perspective. Trends Biochem. Sci. 30, 506- 514.
48. Mazumdar, M., Xia, W., Hofmann, O., Gregas, M., Sui, S. H., Hide, W., Yang, T., Needleman, H. L., and Bellinger, D. C. (2012). Prenatal lead levels, plasma amyloid beta levels, and gene expression in young adulthood. Environ. Health Perspect. 120, 702-707.
49. Meissner, A., Mikkelsen, T. S., Gu, H., Wernig, M., Hanna, J., Sivachenko, A., Zhang, X., Bernstein, B. E., Nusbaum, C., Jaffe, D. B., et al. (2008). Genomescale DNA methylation maps of pluripotent and differentiated cells. Nature 454, 766-770.
50. Nava-Ruiz, C., Mendez-Armenta, M., and Rios, C. (2012). Lead neurotoxicity: Effects on brain nitric oxide synthase. J. Mol. Histol. 43, 553-563.
51. Neal, A. P., and Guilarte, T. R. (2010). Molecular neurobiology of lead (Pb(2+)): Effects on synaptic function. Mol. Neurobiol. 42, 151-160.
52. Nelson, M. M., and Espy, K. A. (2009). Low-level lead exposure and contingency-based responding in preschoolers: An exploratory study. Dev. Neuropsychol. 34, 494-506.
53. Nishimura, T., Yamaguchi, T., Tokunaga, A., Hara, A., Hamaguchi, T., Kato, K., Iwamatsu, A., Okano, H., and Kaibuchi, K. (2006). Role of numb in dendritic spine developmentwith a Cdc42 GEF intersectin and EphB2. Mol. Biol. Cell 17, 1273-1285.
54. Okano, H., Kawahara, H., Toriya, M., Nakao, K., Shibata, S., and Imai, T. (2005). Function of RNA-binding protein Musashi-1 in stem cells. Exp. Cell Res. 306, 349-356.
55. Osumi, N., Shinohara, H., Numayama-Tsuruta, K., and Maekawa, M. (2008). Concise review: Pax6 transcription factor contributes to both embryonic and adult neurogenesis as a multifunctional regulator. Stem Cells 26, 1663-1672.
56. Peng, S., Hajela, R. K., and Atchison, W. D. (2002). Characteristics of block by Pb2+ of function of human neuronal L-, N-, and R-type Ca2+ channels transiently expressed in human embryonic kidney 293 cells. Mol. Pharmacol. 62, 1418-1430.
57. Pidsley, R., Wong, C. C. Y., Volta, M., Lunnon, K., Mill, J., and Schalkwyk, L.C. (2013). A data-driven approach to preprocessing Illumina 450K methylation array data. BMC Genomics 14, 293.
58. Pilsner, J. R., Hu, H., Ettinger, A., Sanchez, B. N., Wright, R. O., Cantonwine, D., Lazarus, A., Lamadrid-Figueroa, H., Mercado-Garcia, A., Tellez-Rojo, M. M., et al. (2009). Influence of prenatal lead exposure on genomic methylation of cord blood DNA. Environ. Health Perspect. 117, 1466-1471.
59. Rahman, A., Brew, B. J., and Guillemin, G. J. (2011). Lead dysregulates serine/threonine protein phosphatases in human neurons. Neurochem. Res. 36, 195-204.
60. Ross, P. J., Suhr, S. T., Rodriguez, R. M., Chang, E. A., Wang, K., Siripattarapravat, K., Ko, T., and Cibelli, J. B. (2010). Human-induced pluripotent stem cells produced under xeno-free conditions. Stem Cells Dev. 19, 1221-1229.
61. Sakakibara, S., Imai, T., Hamaguchi, K., Okabe, M., Aruga, J., Nakajima, K., Yasutomi, D., Nagata, T., Kurihara, Y., Uesugi, S., et al. (1996). Mouse- Musashi-1, a neural RNA-binding protein highly enriched in the mammalian CNS stem cell. Dev. Biol. 176, 230-242.
62. Sanchez-Martin, F. J., Fan, X., Lindquist, D. M., Xia, X., and Puga, A. (2013). Lead induces similar gene expression changes in brains of gestationally exposed adult mice and in neurons differentiated from mouse embryonic stem cells. PLoS ONE 8, e80558.
63. Sanders, T., Liu, Y., Buchner, V., and Tchounwou, P. B. (2009). Neurotoxic effects and biomarkers of lead exposure: A review. Rev. Environ. Health 24, 15-45.
64. Sandoval, J., Heyn, H., Moran, S., Serra-Musach, J., Pujana, M. A., Bibikova, M., and Esteller, M. (2011). Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome. Epigenetics 6, 692-702.
65. Schneider, J. S., Kidd, S. K., and Anderson, D. W. (2013). Influence of developmental lead exposure on expression of DNA methyltransferases and methyl cytosine-binding proteins in hippocampus. Toxicol. Lett. 217, 75-81.
66. Sebastian-Serrano, A., Sandonis, A., Cardozo, M., Rodriguez-Tornos, F. M., Bovolenta, P., and Nieto, M. (2012). Palphax6 expression in postmitotic neurons mediates the growth of axons in response to SFRP1. PLoS ONE 7, e31590.
67. Senut, M. C., Cingolani, P., Sen, A., Kruger, A., Shaik, A., Hirsch, H., Suhr, S.T., and Ruden, D. (2012). Epigenetics of early-life lead exposure and effects on brain development. Epigenomics 4, 665-674.
68. Senut, M. C., Suhr, S. T., Kaspar, B., and Gage, F. H. (2000). Intraneuronal aggregate formation and cell death after viral expression of expanded polyglutamine tracts in the adult rat brain. J. Neurosci. 20, 219-229.
69. Shen, Q., Zhong, W., Jan, Y. N., and Temple, S. (2002). Asymmetric Numb distribution is critical for asymmetric cell division of mouse cerebral cortical stem cells and neuroblasts. Development 129, 4843-4853.
70. Sholl, D. A. (1953). Dendritic organization in the neurons of the visual and motor cortices of the cat. J. Anat. 87, 387-406.
71. Sofer, T., Schifano, E. D., Hoppin, J. A., Hou, L., and Baccarelli, A. A. (2013). A-clustering: A novel method for the detection of co-regulated methylation regions, and regions associated with exposure. Bioinformatics 29, 2884- 2891.
72. Stokes, L., Letz, R., Gerr, F., Kolczak, M., McNeill, F. E., Chettle, D. R., and Kaye, W. E. (1998). Neurotoxicity in young adults 20 years after childhood exposure to lead: The Bunker Hill experience. Occup. Environ. Med. 55, 507- 516.
73. Sultan, F. A., and Day, J. J. (2011). Epigenetic mechanisms in memory and synaptic function. Epigenomics 3, 157-181.
74. Sun, Y., Nadal-Vincens, M., Misono, S., Lin, M. Z., Zubiaga, A., Hua, X., Fan, G., and Greenberg, M. E. (2001). Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms. Neuron 104, 365- 376.
75. Tejedo, J. R., Tapia-Limonchi, R., Mora-Castilla, S., Cahuana, G.M., Hmadcha, A., Martin, F., Bedoya, F. J., and Soria, B. (2010). Low concentrations of nitric oxide delay the differentiation of embryonic stem cells and promote their survival. Cell Death Dis. 1, e80.
76. Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., Waknitz, M. A., Swiergiel, J.J., Marshall, V. S., and Jones, J. M. (1998). Embryonic stem cell lines derived from human blastocysts. Science 282, 1145-1147.
77. Toscano, C. D., and Guilarte, T. R. (2005). Lead neurotoxicity: From exposure to molecular effects. Brain Res. Brain Res. Rev. 49, 529-554.
78. Touleimat, N., and Tost, J. (2012). Complete pipeline for Infinium((R)) Human Methylation 450K BeadChip data processing using subset quantile normalization for accurate DNA methylation estimation. Epigenomics 4, 325-341.
79. Verina, T., Rohde, C. A., and Guilarte, T. R. (2007). Environmental lead exposure during early life alters granule cell neurogenesis and morphology in the hippocampus of young adult rats. Neuroscience 145, 1037-1047.
80. Visan, A., Hayess, K., Sittner, D., Pohl, E. E., Riebeling, C., Slawik, B., Gulich, K., Oelgeschlager, M., Luch, A., and Seiler, A. E. (2012). Neural differentiation of mouse embryonic stem cells as a tool to assess developmental neurotoxicity in vitro. Neurotoxicology 33, 1135-1146.
81. Waimey, K. E., Huamng, P.-H., Chen, M., and Cheng, H.-J. (2008). Plexin- A3 and plexin-A4 restrict the migration of sympathetic neurons but not their neural crest precursors. Dev. Bio. 315, 448-458.
82. Wang, D., Yan, L., Hu, Q., Sucheston, L. E., Higgins, M. J., Ambrosone, C.B., Johnson, C. S., Smiraglia, D. J., and Liu, S. (2012). IMA: An R package for high-throughput analysis of Illumina's 450K Infinium methylation data. Bioinformatics 28, 729-730.
83. White, L. D., Cory-Slechta, D. A., Gilbert, M. E., Tiffany-Castiglioni, E., Zawia, N. H., Virgolini, M., Rossi-George, A., Lasley, S.M., Qian, Y. C., and Basha, M. R. (2007). New and evolving concepts in the neurotoxicology of lead. Toxicol. Appl. Pharmacol. 225, 1-27.
84. Willems, E., Leyns, L., and Vandesompele, J. (2008). Standardization of realtime PCR gene expression data from independent biological replicates. Anal. Biochem. 379, 127-129.
85. Wobus, A. M., and Loser, P. (2011). Present state and future perspectives of using pluripotent stem cells in toxicology research. Arch. Toxicol. 85, 79- 117.
86. Wright, J. P., Dietrich, K. N., Ris, M. D., Hornung, R. W., Wessel, S. D., Lanphear, B. P., Ho, M., and Rae, M. N. (2008). Association of prenatal and childhood blood lead concentrations with criminal arrests in early adulthood. PLoS Med. 5, e101.
87. Wright, R. O., Schwartz, J., Wright, R. J., Bollati, V., Tarantini, L., Park, S.K., Hu, H., Sparrow, D., Vokonas, P., and Baccarelli, A. (2010). Biomarkers of lead exposure and DNA methylation within retrotransposons. Environ. Health Perspect. 118, 790-795.
88. Wu, J., Basha, M. R., Brock, B., Cox, D. P., Cardozo-Pelaez, F., McPherson, C.A., Harry, J., Rice, D. C., Maloney, B., Chen, D., et al. (2008a). Alzheimer's disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): Evidence for a developmental origin and environmental link for AD. J. Neurosci. 28, 3-9.
89. Wu, J., Basha, M. R., and Zawia, N. H. (2008b). The environment, epigenetics and amyloidogenesis. J. Mol. Neurosci. 34, 1-7.
90. Xie, W., Schultz, M. D., Lister, R., Hou, Z., Rajagopal, N., Ray, P., Whitaker, J.W., Tian, S., Hawkins, R. D., Leung, D., et al. (2013) Epigenomic analysis of multilineage differentiation of human embryonic stem cells. Cell 153, 1134- 1148.
91. Yamagata, Y., Szabo, P., Szuts, D., Bacquet, C., Aranyi, T., and Paldi, A. (2012). Rapid turnover of DNA methylation in human cells. Epigenetics 7, 141-145.
92. Zhang, S. C., Wernig, M., Duncan, I. D., Brustle, O., and Thomson, J. A. (2001). In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat. Biotechnol. 19, 1129-1133.
93. Zimmer, B., Kuegler, P. B., Baudis, B., Genewsky, A., Tanavde, V., Koh, W., Tan, B., Waldmann, T., Kadereit, S., and 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.
94. Zimmer, B., Lee, G., Balmer, N. V., Meganathan, K., Sachinidis, A., Studer, L., and Leist, M. (2012). Evaluation of developmental toxicants and signaling pathways in a functional test based on the migration of human neural crest cells. Environ. Health Perspect. 120, 1116-1122.
95. Zurich, M. G., Eskes, C., Honegger, P., Berode, M., and Monnet-Tschudi, F. (2002). Maturation-dependent neurotoxicity of lead acetate in vitro: Implication of glial reactions. J. Neurosci. Res. 70, 108-116.