Toxicology and Epigenetics, 2 Vols.

Description

Epigenetics is the study of both heritable and non-heritable changes in the regulation of gene activity and expression that occur without an alteration in the DNA sequence. This dynamic and rapidly developing discipline is making its impact across the biomedical sciences, in particular in toxicology where epigenetic differences can mean that different individuals respond differently to the same drug or chemical.

Toxicology and Epigenetics reflects the multidimensional character of this emerging area of toxicology, describing cutting-edge molecular technologies to unravel epigenetic changes, the use of in vivo and in vitro models, as well as the potential use of toxicological epigenetics in regulatory environments. An international team of experts consider the interplay between epigenetics and toxicology in a number of areas, including environmental, nutritional, pharmacological, and computational toxicology, nanomaterials, proteomics and metabolomics, and cancer research.

Topics covered include:

• environment, epigenetics and diseases
• DNA methylation and toxicogenomics
• chromatin at the intersection of disease and therapy
• epigenomic actions of environmental arsenicals
• environment, epigenetics and cardiovascular health
• toxicology, epigenetics and autoimmunity
• ocular epigenomics: potential sites of environmental impact in development and disease
• nuclear RNA silencing and related phenomena in animals
• epigenomics – impact for drug safety sciences
• methods of global epigenomic profiling
• transcriptomics: applications in epigenetic toxicology

Toxicology and Epigenetics is an essential insight into the current trends and future directions of research in this rapidly expanding field for investigators, toxicologists, risk assessors and regulators in academia, industry and government.

Table of Contents

• Preface xxi
• Acknowledgment xxiii
• List of Contributors xxv

1. Introduction 1
   Saura C. Sahu
• References 2
2. Environment, Epigenetics, and Diseases 5
   Robert Y.S. Cheng and Wan-yee Tang
1. Perceptions of epigenetics 5
2. Environmental epigenetics and human diseases 8
3. Implications of environmental epigenetics and future prospects 16
4. Key questions to be answered 17
• Acknowledgments 17
• References 17
3. DNA Methylation and Toxicogenomics 25
   Deepti Deobagkar and Dileep Deobagkar
1. Introduction 25
2. Toxicology 26
3. Toxicogenomics 27
4. Epigenetics 29
5. DNA methylation 30
6. DNA methyltransferases 34
7. Techniques of methylation detection 34
8. Toxicogenomics and epigenetics 40
9. Hydroxymethyl cytosine and toxicogenomics 42
10. MicroRNAs 42
11. DNA methylation in cancer 42
12. Bioinformatics approach 44
13. Summary 45
• Acknowledgements 46
• References 46
4. Chromatin at the Intersection of Disease and Therapy 51
   Delphine Qu
1. Epigenetic marks on chromatin: a complex pathway with high flexibility 51
2. Epigenetic modifications and potential therapy in other diseases 60
3. Conclusion 66
• References 66
5. Molecular Epigenetic Changes Caused by Environmental Pollutants 73
   Solange S. Lewis, Gregory J. Weber, Jennifer L. Freeman, and Maria S. Sepulveda
1. Introduction 73
2. DNA methylation 75
3. Histone modifications 75
4. Small non-coding RNAs 76
5. Epigenetic assays 76
6. Bisphenol A (BPA) 78
7. Dichlorodiphenyltrichloroethane (DDT) 83
8. Dioxin (TCDD or 2,3,7,8-tetrachlorodibenzo-p-dioxin) 84
9. 17 Hexabromocyclododecane (HBCD) 85
10. Methoxychlor 86
11. Mixture of polychlorinated biphenyls, methyl mercury, and organochlorine pesticides 87
12. Polybrominated diphenyl ethers (PBDEs) 88
13. Phthalate (di-2-ethylhexyl phthalate or DEHP) 88
14. Vinclozolin 88
15. Epigenetic changes induced by metals 90
16. Concluding remarks 101
• References 102
6. Epigenetic Mediation of Environmental Exposures to Polycyclic Aromatic Hydrocarbons 111
   Bekim Sadikovic and David I. Rodenhiser
1. Introduction 111
2. Epigenetic modifications: DNA methylation 112
3. DNA methylation and cancer 113
4. Epigenetic histone modifications 114
5. Benzo(a)pyrene–a prototype PAH and environmental carcinogen 115
6. Molecular mechanisms of benzopyrene carcinogenicity: geno- and epigeno-toxicity 115
7. Epigenetic effects of multiple/synergistic carcinogen exposures 120
8. Summary and future considerations 122
• Acknowledgements 123
• References 123
7. Epigenomic Actions of Environmental Arsenicals 129
   Paul L. Severson and Bernard W. Futscher
1. Introduction 129
2. Arsenicals in relation to human health 130
3. Arsenical mechanisms of action 131
4. Models to study arsenical action 133
5. Models used to study epigenetic action 134
6. Epigenetic effects of arsenicals 135
7. Perspectives 140
• References 141
8. Arsenic-Induced Changes to the Epigenome 149
   Kathryn A. Bailey and Rebecca C. Fry
1. Introduction 149
2. Arsenic exposure and DNA methylation 152
3. DNA methylation changes associated with arsenic exposure 168
4. Histone modifications associated with arsenic exposure 178
5. MicroRNA (miRNA) alterations associated with arsenic exposure 181
6. Conclusions and future directions 182
• Acknowledgments 183
• References 183
9. Environmental Epigenetics, Asthma, and Allergy: Our Environment’s Molecular Footprints 191
   Stephanie Lovinsky-Desir and Rachel L. Miller
1. Introduction 191
2. Asthma environmental toxicants associated with epigenetic regulation 193
3. Epigenetic changes and asthma phenotype 197
4. ‘Pharmacoepigenetics’ 200
5. Conclusion 200
• References 201
10. miRNAs in Human Prostate Cancer 205
    Ernest K. Amankwah and Jong Y. Park
1. Introduction 205
2. Biogenesis, function, and target of miRNA 206
3. miRNA and human cancer 208
4. miRNAs as oncogenes and tumor suppressors 209
5. Expression profile of miRNA in prostate cancer 210
6. miRNA as therapeutic targets for prostate cancer 213
7. Conclusion and future directions 213
• References 213
11. Environment, Epigenetics, and Cardiovascular Health 219
    Sanjukta Ghosh and Andrea Baccarelli
1. Introduction 219
2. Epidemiological evidence of environmental factors affecting cardiovascular health 220
3. Cause and effect relation between environmental exposure and cardiovascular diseases 222
4. Cardiovascular epigenetic signatures as risk factors and biomarkers for environmental exposure 232
5. Conclusion 233
• References 233
12. Toxicology, Epigenetics, and Autoimmunity 241
    Craig A. Cooney and Kathleen M. Gilbert
1. Introduction 241
2. Drugs and toxicants in epigenetics 243
3. Metabolic requirements for epigenetics 244
4. Autoimmunity and epigenetics 245
5. Conclusion 251
• References 252
13. Toxicoepigenomics in Lupus 261
    Donna Ray and Bruce Richardson
1. Introduction 261
2. Etiology of lupus 262
3. Epigenetics and lupus 264
4. Environmental contributions to lupus 267
5. Summary 270
• References 270
14. Ocular Epigenomics: Potential Sites of Environmental Impact in Development and Disease 275
    Kenneth P. Mitton
1. Introduction 275
2. Gene expression in ocular development 277
3. Epigenetic regulation in ocular development 280
4. DNA-methylation changes in ocular disease 283
5. Inherited and age-related diseases of the eye 286
1. Genetic diseases 286
2. Diabetes: metabolic memory 287
3. Spinocerebellar ataxia type 7 (SCA7): histone acetylation 287
6. Pharmacological effects on retinal function 287
7. Future research 289
• References 289
15. Nuclear RNA Silencing and Related Phenomena in Animals 297
    Radek Malik and Petr Svoboda
1. Introduction 297
2. Conclusion 310
• Acknowledgments 310
• References 310
16. Epigenetic Biomarkers in Cancer Detection and Diagnosis 317
    Ashley G. Rivenbark and William B. Coleman
1. DNA methylation 317
2. Epigenetics of cancer 319
3. Epigenetic biomarkers for cancer diagnostics: DNA methylation 320
4. Application of aberrant DNA methylation to cancer diagnostics 323
5. Epigenetic biomarkers in breast cancer 323
6. Epigenetic biomarkers in prostate cancer 324
7. Epigenetic biomarkers in lung cancer 325
8. Epigenetic biomarkers in colorectal cancer 326
9. Epigenetic biomarkers in liver cancer 328
10. Cancer detection and diagnosis 330
• References 332
17. Epigenetic Histone Changes in the Toxicologic Mode of Action of Arsenic 339
    John F. Reichard and Alvaro Puga
1. Introduction 339
2. Epigenetics and cancer 340
3. Epigenetics effects of arsenic 341
4. Conclusions 348
• References 350
18. Irreversible Effects of Diethylstilbestrol on Reproductive Organs and a Current Approach for Epigenetic Effects of Endocrine Disrupting Chemicals 357
    Shinichi Miyagawa, Ryohei Yatsu, Tamotsu Sudo, Katsuhide Igarashi, Jun Kanno, and Taisen Iguchi
1. Introduction 357
2. Adverse effects of perinatally-exposed DES on the mouse vagina 358
3. MeDIP-ChIP 359
4. Future research needs 362
• Acknowledgments 363
• References 363
19. Epigenomics–Impact for Drug Safety Sciences 365
    Harri Lempi Pierre Moulin, Philippe Couttet, Olivier Grenet, Jennifer Marlowe, Jonathan Moggs, and Rainen, Raphaelle Luisier, Arne Muller, Philippe Marc, David Heard, Federico Bolognani, emi Terranova
1. Introduction the dynamic epigenome and perturbations in disease 365
2. Relevance of epigenetics for toxicology 370
3. Toward identifying epigenetic biomarkers of drug-induced toxicity 371
4. Challenges of integrating epigenetic analysis into toxicity testing 373
5. Practical considerations 374
6. Bioinformatics and modeling of epigenomic data 376
7. Case study: identification of early mechanism and biomarkers for non-genotoxic carcinogenesis (NGC) 378
8. Conclusions 379
• Acknowledgments 380
• References 380
20. Archival Toxicoepigenetics: Molecular Analysis of Modified DNA from Preserved Tissues in Toxicology Studies 387
    B. Alex Merrick
1. Introduction 387
2. Preservation of tissue: effects on protein and nucleic acids 388
3. Extraction of nucleic acids from fixed or embedded tissues 391
4. Analysis of methylated DNA for epigenetics 394
5. Survey of epigenetic studies using formalin preserved tissues 395
6. Prospects for toxicoepigenetics in preserved tissues 401
7. Conclusion 402
• References 403
21. Nanoparticles and Toxicoepigenomics 409
    Manasi P. Jain, Angela O. Choi, and Dusica Maysinger
1. Nanoparticles 409
2. Particles and the environment 410
3. Nanoparticles in soil 412
4. Nanoparticles in water 412
5. Nanoparticles and air 413
6. Nanoparticles in medicine 414
7. Nanotoxicology 414
8. Nanotoxicology in humans and experimental animals 414
9. Complications with nanotoxicological studies 416
10. Molecular mechanisms of nanoparticle toxicity and cellular defense mechanisms 417
11. Molecular mechanisms of nanoparticle-induced cytotoxicity 418
12. Nano-epigenomcs and epigenetics 419
13. Conclusion 421
• References 422
22. Methods of Global Epigenomic Profiling 427
    Michael W.Y. Chan, Zhengang Peng, Jennifer R. Chao, Yingwei Li, Matthew T. Zuzolo, and Huey-Jen L. Lin
1. Introduction 427
2. DNA methylation 428
3. Histone modifications and chromatin remodeling 435
4. Noncoding RNA 439
5. Summary and discussion 440
• Acknowledgments 440
• References 440
23. Transcriptomics: Applications in Epigenetic Toxicology 445
    Pius Joseph
1. Introduction 445
2. Microarray analysis of gene expression profiles 446
3. Gene expression studies–challenges 453
4. Conclusions 456
• Acknowledgments 456
• Disclaimer 457
• References 457
24. Carcinogenic Metals Alter Histone Tail Modifications 459
    Yana Chervona and Max Costa
1. Introduction 459
2. Epigenetics and histone tail modifications 460
3. Arsenic 462
4. Nickel 463
5. Hexavalent chromium (Cr [VI]) 466
6. Cadmium 468
7. Summary 470
• References 470
25. Prediction of Epigenetic and Stochastic Gene Expression Profiles of Late Effects after Radiation Exposure 475
    Yoko Hirabayashi and Tohru Inoue
1. Introduction–pathological profiling (diagnostic endpoint) and toxicological profiling (probabilistic endpoint) 475
2. Radiation exposure and dosimetric quantum biology 477
3. Common gene expression profiles after subacute and prolonged effects after radiation exposure 478
4. Stochastic expression gene profiles after radiation exposure 483
5. Conclusions 492
• Appendix A 494
• Appendix B 495
• Appendix C 495
• References 509
26. Modulation of Developmentally Regulated Gene Expression Programs through Targeting of Polycomb and Trithorax Group Proteins 511
    Marjorie Brand and F.J. Dilworth
1. Introduction 511
2. Polycomb group (PcG) proteins 512
3. Trithorax group genes 516
4. Model for the transcriptional regulation of developmentally regulated genes by PcG and TrxG 526
5. PcG and TrxG proteins in disease 527
6. Targeting PcG and TrxG proteins in disease 528
• References 529
27. Chromatin Insulators and Epigenetic Inheritance in Health and Disease 539
    Jingping Yang and Victor G. Corces
1. Introduction 539
2. Structure and organization of insulators 540
3. Insulators and chromatin architecture 543
4. Regulation of insulator function 552
5. Insulators and the external/internal cellular environment 555
6. Insulators and disease 557
7. Concluding remarks 560
• Acknowledgments 561
• References 561
28. Bioinformatics for High-Throughput Toxico-Epigenomics Studies 569
    Maureen A. Sartor, Dana C. Dolinoy, Laura S. Rozek, and Gilbert S. Omenn
1. Introduction 569
2. Evaluating environmental influences on the epigenome 570
3. Establishment of the field of environmental epigenomics 570
4. An evolutionary perspective: the case of genomic imprinting 571
5. Transitioning from epigenetics to epigenomics and related bioinformatics 572
6. Observational studies in epigenomics 576
7. Integrative analyses with epigenomics data 577
8. Gene set enrichment and concept tools for pathway analyses 578
9. Databases and resources 580
10. Illustrative applications from environmental exposures/perturbations 581
11. University of Michigan NIEHS P30 center approach 583
12. Future directions 584
• Acknowledgments 584
• References 584
29. Computational Methods in Toxicoepigenomics 589
    Joo Chuan Tong
1. Introduction 589
2. Data sources 589
3. Computational tools 591
4. Conclusion 592
• References 592
30. Databases and Tools for Computational Epigenomics 595
    V. Umashankar and S. Gurunathan
1. Introduction 595
2. Epigenetics and Computational Epigenetics 596
3. Epigenomics and Computational Epigenomics 596
4. Human Epigenome Project (HEP) 596
5. Epigenome Prediction Mechanism 597
6. Epigenomics Databases 599
7. Tools Employed in Computational Epigenomics 606
8. Sophisticated Algorithms 611
9. Conclusion 612
• References 613
• Website References 613
31. Interface of Epigenetics and Carcinogenic Risk Assessment 615
    Paul Nioi
1. Introduction 615
2. Key epigenetic changes implicated in carcinogenesis 616
3. DNA methylation changes in chemical carcinogenesis 617
4. Methods of detecting alterations in the genomic methylome 623
5. Conclusions 624
• References 627
32. Epigenetic Modifications in Chemical Carcinogenesis 631
    Igor P. Pogribny, Igor Koturbash, and Frederick A. Beland
1. Introduction 631
2. Epigenetic alterations in cancer cells 632
3. Role of epigenetic alterations in chemical carcinogenesis 634
4. Future perspectives: epigenetic alterations and cancer risk assessment 638
• References 638
33. Application of Cancer Toxicoepigenomics in Identifying High-Risk Populations 645
    Mukesh Verma and Krishna K. Banaudha
1. Introduction: epigenetic mechanisms and cancer 645
2. Toxicity and cancer epigenetics 646
3. Advantages of using a cohort consortia approach to studying toxicoepigenomics in cancer 649
4. Data integration 650
5. Challenges and future directions 650
• References 651

• Index 653