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
Acknowledgments 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
2.1 Perceptions of epigenetics 5
2.2 Environmental epigenetics and human diseases 8
2.3 Implications of environmental epigenetics and future prospects 16
2.4 Key questions to be answered 17
Acknowledgments 17
References 17
3 DNA Methylation and Toxicogenomics 25
Deepti Deobagkar
3.1 Introduction 25
3.2 Toxicology 26
3.3 Toxicogenomics 27
3.4 Epigenetics 29
3.5 DNA methylation 30
3.6 DNA methyltransferases 34
3.7 DNA methylation is alteres upon exposure to chemicals and toxins 35
3.8 Toxicogenomics and epigenetics 40
3.9 Hydroxymethyl cytosine and toxicogenomics 42
3.10 MicroRNAs 42
3.11 DNA methylation in cancer 42
3.12 Bioinformatics approach 44
3.13 Summary 45
Acknowledgments 46
References 46
4 Chromatin at the Intersection of Disease and Therapy 51
Delphine Quénet, Marcin Walkiewicz, and Yamini Dalal
4.1 Epigenetic marks on chromatin: a complex pathway with high flexibility 51
4.2 Epigenetic approaches to treatment of cancer 55
4.3 Epigenetic modifications and potential therapy in other diseases 60
4.4 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. Sepúlveda
5.1 Introduction 73
5.2 Mechanisms of molecular epigenetic changes 74
5.3 Epigenetic assays 76
5.4 Epigenetic changes induced by organic chemicals 78
5.5 Epigenetic changes induced by metals 90
5.6 Concluding remarks 101
References 102
6 Epigenetic Mediation of Environmental Exposures to Polycyclic Aromatic Hydrocarbons 111
Bekim Sadikovic and David I. Rodenhiser
6.1 Introduction 111
6.2 Epigenetic modifications: DNA methylation 112
6.3 DNA methylation and cancer 113
6.4 Epigenetic histone modifications 114
6.5 Benzo(a)pyrene – a prototype PAH and environmental carcinogen 115
6.6 Molecular mechanisms of benzopyrene carcinogenicity: geno- and epigeno-toxicity 115
6.7 Epigenetic effects of multiple/synergistic carcinogen exposures 120
6.8 Summary and future considerations 122
Acknowledgments 123
References 123
7 Epigenomic Actions of Environmental Arsenicals 129
Paul L. Severson and Bernard W. Futscher
7.1 Introduction 129
7.2 Arsenicals in relation to human health 130
7.3 Arsenical mechanisms of action 131
7.4 Models to study arsenical action 133
7.5 Models used to study epigenetic action 134
7.6 Epigenetic effects of arsenicals 135
7.7 Perspectives 140
References 141
8 Arsenic-Induced Changes to the Epigenome 149
Kathryn A. Bailey and Rebecca C. Fry
8.1 Introduction 149
8.2 Arsenic exposure and DNA methylation 152
8.3 DNA methylation changes associated with arsenic exposure 154
8.4 Histone modifications associated with arsenic exposure 173
8.5 MicroRNA (miRNA) alterations associated with arsenic exposure 180
8.6 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
9.1 Introduction 191
9.2 Asthma environmental toxicants associated with epigenetic regulation 193
9.3 Epigenetic changes and asthma phenotype 197
9.4 ‘Pharmacoepigenetics’ 200
9.5 Conclusion 200
References 201
10 miRNAs in Human Prostate Cancer 205
Ernest K. Amankwah and Jong Y. Park
10.1 Introduction 205
10.2 Biogenesis, function, and target of miRNA 206
10.3 miRNA and human cancer 208
10.4 miRNAs as oncogenes and tumor suppressors 209
10.5 Expression profile of miRNA in prostate cancer 210
10.6 miRNA as therapeutic targets for prostate cancer 213
10.7 Conclusion and future directions 213
References 213
11 Environment, Epigenetics, and Cardiovascular Health 219
Sanjukta Ghosh and Andrea Baccarelli
11.1 Introduction 219
11.2 Epidemiological evidence of environmental factors affecting cardiovascular health 220
11.3 Cause and effect relation between environmental exposure and cardiovascular diseases 222
11.4 Cardiovascular epigenetic signatures as risk factors and biomarkers for environmental exposure 232
11.5 Conclusion 233
References 233
12 Toxicology, Epigenetics, and Autoimmunity 241
Craig A. Cooney and Kathleen M. Gilbert
12.1 Introduction 241
12.2 Drugs and toxicants in epigenetics 243
12.3 Metabolic requirements for epigenetics 244
12.4 Autoimmunity and epigenetics 245
12.5 Conclusion 251
References 252
13 Toxicoepigenomics in Lupus 261
Donna Ray and Bruce C. Richardson
13.1 Introduction 261
13.2 Etiology of lupus 262
13.3 Epigenetics and lupus 264
13.4 Environmental contributions to lupus 267
13.5 Summary 270
References 270
14 Ocular Epigenomics: Potential Sites of Environmental Impact in Development and Disease 275
Kenneth P. Mitton
14.1 Introduction 275
14.2 Gene expression in ocular development 277
14.3 Epigenetic regulation in ocular development 280
14.4 DNA-methylation changes in ocular disease 283
14.5 Inherited and age-related diseases of the eye 286
14.6 Pharmacological effects on retinal function 287
14.7 Future research 289
References 289
15 Nuclear RNA Silencing and Related Phenomena in Animals 297
Radek Malik and Petr Svoboda
15.1 Introduction 297
15.2 Conclusion 310
Acknowledgments 310
References 310
16 Epigenetic Biomarkers in Cancer Detection and Diagnosis 317
Ashley G. Rivenbark and William B. Coleman
16.1 DNA methylation 317
16.2 Epigenetics of cancer 319
16.3 Epigenetic biomarkers for cancer diagnostics: DNA methylation 320
16.4 Application of aberrant DNA methylation to cancer diagnostics 323
16.5 Epigenetic biomarkers in breast cancer 323
16.6 Epigenetic biomarkers in prostate cancer 324
16.7 Epigenetic biomarkers in lung cancer 325
16.8 Epigenetic biomarkers in colorectal cancer 326
16.9 Epigenetic biomarkers in liver cancer 328
16.10 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
17.1 Introduction 339
17.2 Epigenetics and cancer 340
17.3 Epigenetics effects of arsenic 341
17.4 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
18.1 Introduction 357
18.2 Adverse effects of perinatally-exposed DES on the mouse vagina 358
18.3 MeDIP-ChIP 359
18.4 Future research needs 362
Acknowledgments 363
References 363
19 Epigenomics – Impact for Drug Safety Sciences 365
Harri Lempiäinen, Raphaëlle Luisier, Arne Müller, Philippe Marc, David Heard, Federico Bolognani,
Pierre Moulin, Philippe Couttet, Olivier Grenet, Jennifer Marlowe, Jonathan Moggs, and Rémi Terranova
19.1 Introduction – the dynamic epigenome and perturbations in disease 365
19.2 Relevance of epigenetics for toxicology 370
19.3 Towards identifying epigenetic biomarkers of drug-induced toxicity 371
19.4 Challenges of integrating epigenetic analysis into toxicity testing 373
19.5 Practical considerations 374
19.6 Bioinformatics and modeling of epigenomic data 376
19.7 Case study: identification of early mechanism and biomarkers for non-genotoxic carcinogenesis (NGC) 378
19.8 Conclusions 379
Acknowledgments 380
References 380
20 Archival Toxicoepigenetics: Molecular Analysis of Modified DNA from Preserved Tissues in Toxicology Studies 387
B. Alex Merrick
20.1 Introduction 387
20.2 Preservation of tissue: effects on protein and nucleic acids 388
20.3 Extraction of nucleic acids from fixed or embedded tissues 391
20.4 Analysis of methylated DNA for epigenetics 394
20.5 Survey of epigenetic studies using formalin preserved tissues 395
20.6 Prospects for toxicoepigenetics in preserved tissues 401
20.7 Conclusion 402
References 403
21 Nanoparticles and Toxicoepigenomics 409
Manasi P. Jain, Angela O. Choi, and Dusica Maysinger
21.1 Nanoparticles 409
21.2 Particles and the environment 410
21.3 Nanoparticles in soil 412
21.4 Nanoparticles in water 412
21.5 Nanoparticles in air 413
21.6 Nanoparticles in medicine 414
21.7 Nanotoxicology 414
21.8 Nanotoxicology in humans and experimental animals 414
21.9 Complications with nanotoxicological studies 416
21.10 Molecular mechanisms of nanoparticle toxicity and cellular defense mechanisms 417
21.11 Molecular mechanisms of nanoparticle-induced cytotoxicity 418
21.12 Nano-epigenomcs and epigenetics 419
21.13 Conclusion 421
References 422
22 Methods of Global Epigenomic Profiling 427
Michael W.Y. Chan, Zhengang Peng, Jennifer Chao Weber, Ying-Wei Li, Matthew T. Zuzolo, and Huey-Jen L. Lin
22.1 Introduction 427
22.2 DNA methylation 428
22.3 Histone modifications and chromatin remodeling 435
22.4 Noncoding RNA 439
22.5 Summary and discussion 440
Acknowledgments 440
References 440
23 Transcriptomics: Applications in Epigenetic Toxicology 445
Pius Joseph
23.1 Introduction 445
23.2 Microarray analysis of gene expression profiles 446
23.3 Gene expression studies – challenges 453
23.4 Conclusions 456
Acknowledgments 456
Disclaimer 457
References 457
24 Carcinogenic Metals Alter Histone Tail Modifications 459
Yana Chervona and Max Costa
24.1 Introduction 459
24.2 Epigenetics and histone tail modifications 460
24.3 Arsenic 462
24.4 Nickel 463
24.5 Hexavalent chromium (Cr [VI]) 466
24.6 Cadmium 468
24.7 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
25.1 Introduction – pathological profiling (diagnostic endpoint) and toxicological profiling (probabilistic endpoint) 475
25.2 Radiation exposure and dosimetric quantum biology 477
25.3 Common gene expression profiles after subacute and prolonged effects after radiation exposure 478
25.4 Stochastic expression gene profiles after radiation exposure 483
25.5 Conclusions 492
Appendix A 494
Appendix B 495
Appendix C 496
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
26.1 Introduction 511
26.2 Polycomb group (PcG) proteins 512
26.3 Trithorax group genes 516
26.4 Model for the transcriptional regulation of developmentally regulated genes by PcG and TrxG 526
26.5 PcG and TrxG proteins in disease 527
26.6 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
27.1 Introduction 539
27.2 Structure and organization of insulators 540
27.3 Insulators and chromatin architecture 543
27.4 Regulation of insulator function 552
27.5 Insulators and the external/internal cellular environment 555
27.6 Insulators and disease 557
27.7 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
28.1 Introduction 569
28.2 Evaluating environmental influences on the epigenome 570
28.3 Establishment of the field of environmental epigenomics 570
28.4 An evolutionary perspective: the case of genomic imprinting 571
28.5 Transitioning from epigenetics to epigenomics and related bioinformatics 572
28.6 Observational studies in epigenomics 576
28.7 Integrative analyses with epigenomics data 577
28.8 Gene set enrichment and concept tools for pathway analyses 578
28.9 Databases and resources 580
28.10 Illustrative applications from environmental exposures/perturbations 581
28.11 University of Michigan NIEHS center approach to Lifestage Exposures and Adult Disease (LEAD) 583
28.12 Future directions 584
Acknowledgments 584
References 584
29 Computational Methods in Toxicoepigenomics 589
Joo Chuan Tong
29.1 Introduction 589
29.2 Data sources 589
29.3 Computational tools 591
29.4 Conclusion 592
References 592
30 Databases and Tools for Computational Epigenomics 595
V. Umashankar and S. Gurunathan
30.1 Introduction 595
30.2 Epigenetics and computational epigenetics 596
30.3 Epigenomics and computational epigenomics 596
30.4 Human epigenome project (HEP) 596
30.5 Epigenome prediction mechanism 597
30.6 Epigenomics databases 599
30.7 Tools employed in computational epigenomics 606
30.8 Sophisticated algorithms 611
30.9 Conclusion 612
References 613
Website references 613
31 Interface of Epigenetics and Carcinogenic Risk Assessment 615
Paul Nioi
31.1 Introduction 615
31.2 Key epigenetic changes implicated in carcinogenesis 616
31.3 DNA methylation changes in chemical carcinogenesis 617
31.4 Methods of detecting alterations in the genomic methylome 623
31.5 Conclusions 624
References 627
32 Epigenetic Modifications in Chemical Carcinogenesis 631
Igor P. Pogribny, Igor Koturbash, and Frederick A. Beland
32.1 Introduction 631
32.2 Epigenetic alterations in cancer cells 632
32.3 Role of epigenetic alterations in chemical carcinogenesis 634
32.4 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
33.1 Introduction: epigenetic mechanisms and cancer 645
33.2 Toxicity and cancer epigenetics 646
33.3 Advantages of using a cohort consortia approach to studying toxicoepigenomics in cancer 649
33.4 Data integration 650
33.5 Challenges and future directions 650
References 651
Author Index 653
Subject Index 655
