Dr. Saura C. Sahu, Research Chemist, Division of Toxicology, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, US Food and Drug Administration.Dr. Sahu is the US Editor for the Journal of Applied Toxicology and the editor of Hepatotoxicity (Wiley, 2007), Toxicogenomics (Wiley, 2008), Nanotoxicity (Wiley, 2009), and Handbook of Systems Toxicology (Wiley, 2011).

“Despite some of the issues with the structure, Toxicology and Epigenetics is an important, timely book that provides world-class, expert opinion on a broad range of topics in a fast moving highly relevant branch of toxicology.”  (British Toxicology Society, 1 July 2013)

• Preface xxiAcknowledgments xxiiiList of Contributors xxv1 Introduction 1Saura C. SahuReferences 22 Environment, Epigenetics, and Diseases 5Robert Y.S. Cheng and Wan-yee Tang2.1 Perceptions of epigenetics 52.2 Environmental epigenetics and human diseases 82.3 Implications of environmental epigenetics and future prospects 162.4 Key questions to be answered 17Acknowledgments 17References 173 DNA Methylation and Toxicogenomics 25Deepti Deobagkar3.1 Introduction 253.2 Toxicology 263.3 Toxicogenomics 273.4 Epigenetics 293.5 DNA methylation 303.6 DNA methyltransferases 343.7 DNA methylation is alteres upon exposure to chemicals and toxins 353.8 Toxicogenomics and epigenetics 403.9 Hydroxymethyl cytosine and toxicogenomics 423.10 MicroRNAs 423.11 DNA methylation in cancer 423.12 Bioinformatics approach 443.13 Summary 45Acknowledgments 46References 464 Chromatin at the Intersection of Disease and Therapy 51Delphine Quénet, Marcin Walkiewicz, and Yamini Dalal4.1 Epigenetic marks on chromatin: a complex pathway with high flexibility 514.2 Epigenetic approaches to treatment of cancer 554.3 Epigenetic modifications and potential therapy in other diseases 604.4 Conclusion 66References 665 Molecular Epigenetic Changes Caused by Environmental Pollutants 73Solange S. Lewis, Gregory J. Weber, Jennifer L. Freeman, and Maria S. Sepúlveda5.1 Introduction 735.2 Mechanisms of molecular epigenetic changes 745.3 Epigenetic assays 765.4 Epigenetic changes induced by organic chemicals 785.5 Epigenetic changes induced by metals 905.6 Concluding remarks 101References 1026 Epigenetic Mediation of Environmental Exposures to Polycyclic Aromatic Hydrocarbons 111Bekim Sadikovic and David I. Rodenhiser6.1 Introduction 1116.2 Epigenetic modifications: DNA methylation 1126.3 DNA methylation and cancer 1136.4 Epigenetic histone modifications 1146.5 Benzo(a)pyrene – a prototype PAH and environmental carcinogen 1156.6 Molecular mechanisms of benzopyrene carcinogenicity: geno- and epigeno-toxicity 1156.7 Epigenetic effects of multiple/synergistic carcinogen exposures 1206.8 Summary and future considerations 122Acknowledgments 123References 1237 Epigenomic Actions of Environmental Arsenicals 129Paul L. Severson and Bernard W. Futscher7.1 Introduction 1297.2 Arsenicals in relation to human health 1307.3 Arsenical mechanisms of action 1317.4 Models to study arsenical action 1337.5 Models used to study epigenetic action 1347.6 Epigenetic effects of arsenicals 1357.7 Perspectives 140References 1418 Arsenic-Induced Changes to the Epigenome 149Kathryn A. Bailey and Rebecca C. Fry8.1 Introduction 1498.2 Arsenic exposure and DNA methylation 1528.3 DNA methylation changes associated with arsenic exposure 1548.4 Histone modifications associated with arsenic exposure 1738.5 MicroRNA (miRNA) alterations associated with arsenic exposure 1808.6 Conclusions and future directions 182Acknowledgments 183References 1839 Environmental Epigenetics, Asthma, and Allergy: Our Environment’s Molecular Footprints 191Stephanie Lovinsky-Desir and Rachel L. Miller9.1 Introduction 1919.2 Asthma environmental toxicants associated with epigenetic regulation 1939.3 Epigenetic changes and asthma phenotype 1979.4 ‘Pharmacoepigenetics’ 2009.5 Conclusion 200References 20110 miRNAs in Human Prostate Cancer 205Ernest K. Amankwah and Jong Y. Park10.1 Introduction 20510.2 Biogenesis, function, and target of miRNA 20610.3 miRNA and human cancer 20810.4 miRNAs as oncogenes and tumor suppressors 20910.5 Expression profile of miRNA in prostate cancer 21010.6 miRNA as therapeutic targets for prostate cancer 21310.7 Conclusion and future directions 213References 21311 Environment, Epigenetics, and Cardiovascular Health 219Sanjukta Ghosh and Andrea Baccarelli11.1 Introduction 21911.2 Epidemiological evidence of environmental factors affecting cardiovascular health 22011.3 Cause and effect relation between environmental exposure and cardiovascular diseases 22211.4 Cardiovascular epigenetic signatures as risk factors and biomarkers for environmental exposure 23211.5 Conclusion 233References 23312 Toxicology, Epigenetics, and Autoimmunity 241Craig A. Cooney and Kathleen M. Gilbert12.1 Introduction 24112.2 Drugs and toxicants in epigenetics 24312.3 Metabolic requirements for epigenetics 24412.4 Autoimmunity and epigenetics 24512.5 Conclusion 251References 25213 Toxicoepigenomics in Lupus 261Donna Ray and Bruce C. Richardson13.1 Introduction 26113.2 Etiology of lupus 26213.3 Epigenetics and lupus 26413.4 Environmental contributions to lupus 26713.5 Summary 270References 27014 Ocular Epigenomics: Potential Sites of Environmental Impact in Development and Disease 275Kenneth P. Mitton14.1 Introduction 27514.2 Gene expression in ocular development 27714.3 Epigenetic regulation in ocular development 28014.4 DNA-methylation changes in ocular disease 28314.5 Inherited and age-related diseases of the eye 28614.6 Pharmacological effects on retinal function 28714.7 Future research 289References 28915 Nuclear RNA Silencing and Related Phenomena in Animals 297Radek Malik and Petr Svoboda15.1 Introduction 29715.2 Conclusion 310Acknowledgments 310References 31016 Epigenetic Biomarkers in Cancer Detection and Diagnosis 317Ashley G. Rivenbark and William B. Coleman16.1 DNA methylation 31716.2 Epigenetics of cancer 31916.3 Epigenetic biomarkers for cancer diagnostics: DNA methylation 32016.4 Application of aberrant DNA methylation to cancer diagnostics 32316.5 Epigenetic biomarkers in breast cancer 32316.6 Epigenetic biomarkers in prostate cancer 32416.7 Epigenetic biomarkers in lung cancer 32516.8 Epigenetic biomarkers in colorectal cancer 32616.9 Epigenetic biomarkers in liver cancer 32816.10 Cancer detection and diagnosis 330References 33217 Epigenetic Histone Changes in the Toxicologic Mode of Action of Arsenic 339John F. Reichard and Alvaro Puga17.1 Introduction 33917.2 Epigenetics and cancer 34017.3 Epigenetics effects of arsenic 34117.4 Conclusions 348References 35018 Irreversible Effects of Diethylstilbestrol on Reproductive Organs and a Current Approach for Epigenetic Effects of Endocrine Disrupting Chemicals 357Shinichi Miyagawa, Ryohei Yatsu, Tamotsu Sudo, Katsuhide Igarashi, Jun Kanno, and Taisen Iguchi18.1 Introduction 35718.2 Adverse effects of perinatally-exposed DES on the mouse vagina 35818.3 MeDIP-ChIP 35918.4 Future research needs 362Acknowledgments 363References 36319 Epigenomics – Impact for Drug Safety Sciences 365Harri Lempiäinen, Raphaëlle Luisier, Arne Müller, Philippe Marc, David Heard, Federico Bolognani,Pierre Moulin, Philippe Couttet, Olivier Grenet, Jennifer Marlowe, Jonathan Moggs, and Rémi Terranova19.1 Introduction – the dynamic epigenome and perturbations in disease 36519.2 Relevance of epigenetics for toxicology 37019.3 Towards identifying epigenetic biomarkers of drug-induced toxicity 37119.4 Challenges of integrating epigenetic analysis into toxicity testing 37319.5 Practical considerations 37419.6 Bioinformatics and modeling of epigenomic data 37619.7 Case study: identification of early mechanism and biomarkers for non-genotoxic carcinogenesis (NGC) 37819.8 Conclusions 379Acknowledgments 380References 38020 Archival Toxicoepigenetics: Molecular Analysis of Modified DNA from Preserved Tissues in Toxicology Studies 387B. Alex Merrick20.1 Introduction 38720.2 Preservation of tissue: effects on protein and nucleic acids 38820.3 Extraction of nucleic acids from fixed or embedded tissues 39120.4 Analysis of methylated DNA for epigenetics 39420.5 Survey of epigenetic studies using formalin preserved tissues 39520.6 Prospects for toxicoepigenetics in preserved tissues 40120.7 Conclusion 402References 40321 Nanoparticles and Toxicoepigenomics 409Manasi P. Jain, Angela O. Choi, and Dusica Maysinger21.1 Nanoparticles 40921.2 Particles and the environment 41021.3 Nanoparticles in soil 41221.4 Nanoparticles in water 41221.5 Nanoparticles in air 41321.6 Nanoparticles in medicine 41421.7 Nanotoxicology 41421.8 Nanotoxicology in humans and experimental animals 41421.9 Complications with nanotoxicological studies 41621.10 Molecular mechanisms of nanoparticle toxicity and cellular defense mechanisms 41721.11 Molecular mechanisms of nanoparticle-induced cytotoxicity 41821.12 Nano-epigenomcs and epigenetics 41921.13 Conclusion 421References 42222 Methods of Global Epigenomic Profiling 427Michael W.Y. Chan, Zhengang Peng, Jennifer Chao Weber, Ying-Wei Li, Matthew T. Zuzolo, and Huey-Jen L. Lin22.1 Introduction 42722.2 DNA methylation 42822.3 Histone modifications and chromatin remodeling 43522.4 Noncoding RNA 43922.5 Summary and discussion 440Acknowledgments 440References 44023 Transcriptomics: Applications in Epigenetic Toxicology 445Pius Joseph23.1 Introduction 44523.2 Microarray analysis of gene expression profiles 44623.3 Gene expression studies – challenges 45323.4 Conclusions 456Acknowledgments 456Disclaimer 457References 45724 Carcinogenic Metals Alter Histone Tail Modifications 459Yana Chervona and Max Costa24.1 Introduction 45924.2 Epigenetics and histone tail modifications 46024.3 Arsenic 46224.4 Nickel 46324.5 Hexavalent chromium (Cr [VI]) 46624.6 Cadmium 46824.7 Summary 470References 47025 Prediction of Epigenetic and Stochastic Gene Expression Profiles of Late Effects after Radiation Exposure 475Yoko Hirabayashi and Tohru Inoue25.1 Introduction – pathological profiling (diagnostic endpoint) and toxicological profiling (probabilistic endpoint) 47525.2 Radiation exposure and dosimetric quantum biology 47725.3 Common gene expression profiles after subacute and prolonged effects after radiation exposure 47825.4 Stochastic expression gene profiles after radiation exposure 48325.5 Conclusions 492Appendix A 494Appendix B 495Appendix C 496References 50926 Modulation of Developmentally Regulated Gene Expression Programs through Targeting of Polycomb and Trithorax Group Proteins 511Marjorie Brand and F.J. Dilworth26.1 Introduction 51126.2 Polycomb group (PcG) proteins 51226.3 Trithorax group genes 51626.4 Model for the transcriptional regulation of developmentally regulated genes by PcG and TrxG 52626.5 PcG and TrxG proteins in disease 52726.6 Targeting PcG and TrxG proteins in disease 528References 52927 Chromatin Insulators and Epigenetic Inheritance in Health and Disease 539Jingping Yang and Victor G. Corces27.1 Introduction 53927.2 Structure and organization of insulators 54027.3 Insulators and chromatin architecture 54327.4 Regulation of insulator function 55227.5 Insulators and the external/internal cellular environment 55527.6 Insulators and disease 55727.7 Concluding remarks 560Acknowledgments 561References 56128 Bioinformatics for High-Throughput Toxico-Epigenomics Studies 569Maureen A. Sartor, Dana C. Dolinoy, Laura S. Rozek, and Gilbert S. Omenn28.1 Introduction 56928.2 Evaluating environmental influences on the epigenome 57028.3 Establishment of the field of environmental epigenomics 57028.4 An evolutionary perspective: the case of genomic imprinting 57128.5 Transitioning from epigenetics to epigenomics and related bioinformatics 57228.6 Observational studies in epigenomics 57628.7 Integrative analyses with epigenomics data 57728.8 Gene set enrichment and concept tools for pathway analyses 57828.9 Databases and resources 58028.10 Illustrative applications from environmental exposures/perturbations 58128.11 University of Michigan NIEHS center approach to Lifestage Exposures and Adult Disease (LEAD) 58328.12 Future directions 584Acknowledgments 584References 58429 Computational Methods in Toxicoepigenomics 589Joo Chuan Tong29.1 Introduction 58929.2 Data sources 58929.3 Computational tools 59129.4 Conclusion 592References 59230 Databases and Tools for Computational Epigenomics 595V. Umashankar and S. Gurunathan30.1 Introduction 59530.2 Epigenetics and computational epigenetics 59630.3 Epigenomics and computational epigenomics 59630.4 Human epigenome project (HEP) 59630.5 Epigenome prediction mechanism 59730.6 Epigenomics databases 59930.7 Tools employed in computational epigenomics 60630.8 Sophisticated algorithms 61130.9 Conclusion 612References 613Website references 61331 Interface of Epigenetics and Carcinogenic Risk Assessment 615Paul Nioi31.1 Introduction 61531.2 Key epigenetic changes implicated in carcinogenesis 61631.3 DNA methylation changes in chemical carcinogenesis 61731.4 Methods of detecting alterations in the genomic methylome 62331.5 Conclusions 624References 62732 Epigenetic Modifications in Chemical Carcinogenesis 631Igor P. Pogribny, Igor Koturbash, and Frederick A. Beland32.1 Introduction 63132.2 Epigenetic alterations in cancer cells 63232.3 Role of epigenetic alterations in chemical carcinogenesis 63432.4 Future perspectives: epigenetic alterations and cancer risk assessment 638References 63833 Application of Cancer Toxicoepigenomics in Identifying High-Risk Populations 645Mukesh Verma and Krishna K. Banaudha33.1 Introduction: epigenetic mechanisms and cancer 64533.2 Toxicity and cancer epigenetics 64633.3 Advantages of using a cohort consortia approach to studying toxicoepigenomics in cancer 64933.4 Data integration 65033.5 Challenges and future directions 650References 651Author Index 653Subject Index 655

Dr. Saura C. Sahu, Research Chemist, Division of Toxicology, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, US Food and Drug Administration.Dr. Sahu is the US Editor for the Journal of Applied Toxicology and the editor of Hepatotoxicity (Wiley, 2007), Toxicogenomics (Wiley, 2008), Nanotoxicity (Wiley, 2009), and Handbook of Systems Toxicology (Wiley, 2011).

“Despite some of the issues with the structure, Toxicology and Epigenetics is an important, timely book that provides world-class, expert opinion on a broad range of topics in a fast moving highly relevant branch of toxicology.”  (British Toxicology Society, 1 July 2013)

• Preface xxiAcknowledgments xxiiiList of Contributors xxv1 Introduction 1Saura C. SahuReferences 22 Environment, Epigenetics, and Diseases 5Robert Y.S. Cheng and Wan-yee Tang2.1 Perceptions of epigenetics 52.2 Environmental epigenetics and human diseases 82.3 Implications of environmental epigenetics and future prospects 162.4 Key questions to be answered 17Acknowledgments 17References 173 DNA Methylation and Toxicogenomics 25Deepti Deobagkar3.1 Introduction 253.2 Toxicology 263.3 Toxicogenomics 273.4 Epigenetics 293.5 DNA methylation 303.6 DNA methyltransferases 343.7 DNA methylation is alteres upon exposure to chemicals and toxins 353.8 Toxicogenomics and epigenetics 403.9 Hydroxymethyl cytosine and toxicogenomics 423.10 MicroRNAs 423.11 DNA methylation in cancer 423.12 Bioinformatics approach 443.13 Summary 45Acknowledgments 46References 464 Chromatin at the Intersection of Disease and Therapy 51Delphine Quénet, Marcin Walkiewicz, and Yamini Dalal4.1 Epigenetic marks on chromatin: a complex pathway with high flexibility 514.2 Epigenetic approaches to treatment of cancer 554.3 Epigenetic modifications and potential therapy in other diseases 604.4 Conclusion 66References 665 Molecular Epigenetic Changes Caused by Environmental Pollutants 73Solange S. Lewis, Gregory J. Weber, Jennifer L. Freeman, and Maria S. Sepúlveda5.1 Introduction 735.2 Mechanisms of molecular epigenetic changes 745.3 Epigenetic assays 765.4 Epigenetic changes induced by organic chemicals 785.5 Epigenetic changes induced by metals 905.6 Concluding remarks 101References 1026 Epigenetic Mediation of Environmental Exposures to Polycyclic Aromatic Hydrocarbons 111Bekim Sadikovic and David I. Rodenhiser6.1 Introduction 1116.2 Epigenetic modifications: DNA methylation 1126.3 DNA methylation and cancer 1136.4 Epigenetic histone modifications 1146.5 Benzo(a)pyrene – a prototype PAH and environmental carcinogen 1156.6 Molecular mechanisms of benzopyrene carcinogenicity: geno- and epigeno-toxicity 1156.7 Epigenetic effects of multiple/synergistic carcinogen exposures 1206.8 Summary and future considerations 122Acknowledgments 123References 1237 Epigenomic Actions of Environmental Arsenicals 129Paul L. Severson and Bernard W. Futscher7.1 Introduction 1297.2 Arsenicals in relation to human health 1307.3 Arsenical mechanisms of action 1317.4 Models to study arsenical action 1337.5 Models used to study epigenetic action 1347.6 Epigenetic effects of arsenicals 1357.7 Perspectives 140References 1418 Arsenic-Induced Changes to the Epigenome 149Kathryn A. Bailey and Rebecca C. Fry8.1 Introduction 1498.2 Arsenic exposure and DNA methylation 1528.3 DNA methylation changes associated with arsenic exposure 1548.4 Histone modifications associated with arsenic exposure 1738.5 MicroRNA (miRNA) alterations associated with arsenic exposure 1808.6 Conclusions and future directions 182Acknowledgments 183References 1839 Environmental Epigenetics, Asthma, and Allergy: Our Environment’s Molecular Footprints 191Stephanie Lovinsky-Desir and Rachel L. Miller9.1 Introduction 1919.2 Asthma environmental toxicants associated with epigenetic regulation 1939.3 Epigenetic changes and asthma phenotype 1979.4 ‘Pharmacoepigenetics’ 2009.5 Conclusion 200References 20110 miRNAs in Human Prostate Cancer 205Ernest K. Amankwah and Jong Y. Park10.1 Introduction 20510.2 Biogenesis, function, and target of miRNA 20610.3 miRNA and human cancer 20810.4 miRNAs as oncogenes and tumor suppressors 20910.5 Expression profile of miRNA in prostate cancer 21010.6 miRNA as therapeutic targets for prostate cancer 21310.7 Conclusion and future directions 213References 21311 Environment, Epigenetics, and Cardiovascular Health 219Sanjukta Ghosh and Andrea Baccarelli11.1 Introduction 21911.2 Epidemiological evidence of environmental factors affecting cardiovascular health 22011.3 Cause and effect relation between environmental exposure and cardiovascular diseases 22211.4 Cardiovascular epigenetic signatures as risk factors and biomarkers for environmental exposure 23211.5 Conclusion 233References 23312 Toxicology, Epigenetics, and Autoimmunity 241Craig A. Cooney and Kathleen M. Gilbert12.1 Introduction 24112.2 Drugs and toxicants in epigenetics 24312.3 Metabolic requirements for epigenetics 24412.4 Autoimmunity and epigenetics 24512.5 Conclusion 251References 25213 Toxicoepigenomics in Lupus 261Donna Ray and Bruce C. Richardson13.1 Introduction 26113.2 Etiology of lupus 26213.3 Epigenetics and lupus 26413.4 Environmental contributions to lupus 26713.5 Summary 270References 27014 Ocular Epigenomics: Potential Sites of Environmental Impact in Development and Disease 275Kenneth P. Mitton14.1 Introduction 27514.2 Gene expression in ocular development 27714.3 Epigenetic regulation in ocular development 28014.4 DNA-methylation changes in ocular disease 28314.5 Inherited and age-related diseases of the eye 28614.6 Pharmacological effects on retinal function 28714.7 Future research 289References 28915 Nuclear RNA Silencing and Related Phenomena in Animals 297Radek Malik and Petr Svoboda15.1 Introduction 29715.2 Conclusion 310Acknowledgments 310References 31016 Epigenetic Biomarkers in Cancer Detection and Diagnosis 317Ashley G. Rivenbark and William B. Coleman16.1 DNA methylation 31716.2 Epigenetics of cancer 31916.3 Epigenetic biomarkers for cancer diagnostics: DNA methylation 32016.4 Application of aberrant DNA methylation to cancer diagnostics 32316.5 Epigenetic biomarkers in breast cancer 32316.6 Epigenetic biomarkers in prostate cancer 32416.7 Epigenetic biomarkers in lung cancer 32516.8 Epigenetic biomarkers in colorectal cancer 32616.9 Epigenetic biomarkers in liver cancer 32816.10 Cancer detection and diagnosis 330References 33217 Epigenetic Histone Changes in the Toxicologic Mode of Action of Arsenic 339John F. Reichard and Alvaro Puga17.1 Introduction 33917.2 Epigenetics and cancer 34017.3 Epigenetics effects of arsenic 34117.4 Conclusions 348References 35018 Irreversible Effects of Diethylstilbestrol on Reproductive Organs and a Current Approach for Epigenetic Effects of Endocrine Disrupting Chemicals 357Shinichi Miyagawa, Ryohei Yatsu, Tamotsu Sudo, Katsuhide Igarashi, Jun Kanno, and Taisen Iguchi18.1 Introduction 35718.2 Adverse effects of perinatally-exposed DES on the mouse vagina 35818.3 MeDIP-ChIP 35918.4 Future research needs 362Acknowledgments 363References 36319 Epigenomics – Impact for Drug Safety Sciences 365Harri Lempiäinen, Raphaëlle Luisier, Arne Müller, Philippe Marc, David Heard, Federico Bolognani,Pierre Moulin, Philippe Couttet, Olivier Grenet, Jennifer Marlowe, Jonathan Moggs, and Rémi Terranova19.1 Introduction – the dynamic epigenome and perturbations in disease 36519.2 Relevance of epigenetics for toxicology 37019.3 Towards identifying epigenetic biomarkers of drug-induced toxicity 37119.4 Challenges of integrating epigenetic analysis into toxicity testing 37319.5 Practical considerations 37419.6 Bioinformatics and modeling of epigenomic data 37619.7 Case study: identification of early mechanism and biomarkers for non-genotoxic carcinogenesis (NGC) 37819.8 Conclusions 379Acknowledgments 380References 38020 Archival Toxicoepigenetics: Molecular Analysis of Modified DNA from Preserved Tissues in Toxicology Studies 387B. Alex Merrick20.1 Introduction 38720.2 Preservation of tissue: effects on protein and nucleic acids 38820.3 Extraction of nucleic acids from fixed or embedded tissues 39120.4 Analysis of methylated DNA for epigenetics 39420.5 Survey of epigenetic studies using formalin preserved tissues 39520.6 Prospects for toxicoepigenetics in preserved tissues 40120.7 Conclusion 402References 40321 Nanoparticles and Toxicoepigenomics 409Manasi P. Jain, Angela O. Choi, and Dusica Maysinger21.1 Nanoparticles 40921.2 Particles and the environment 41021.3 Nanoparticles in soil 41221.4 Nanoparticles in water 41221.5 Nanoparticles in air 41321.6 Nanoparticles in medicine 41421.7 Nanotoxicology 41421.8 Nanotoxicology in humans and experimental animals 41421.9 Complications with nanotoxicological studies 41621.10 Molecular mechanisms of nanoparticle toxicity and cellular defense mechanisms 41721.11 Molecular mechanisms of nanoparticle-induced cytotoxicity 41821.12 Nano-epigenomcs and epigenetics 41921.13 Conclusion 421References 42222 Methods of Global Epigenomic Profiling 427Michael W.Y. Chan, Zhengang Peng, Jennifer Chao Weber, Ying-Wei Li, Matthew T. Zuzolo, and Huey-Jen L. Lin22.1 Introduction 42722.2 DNA methylation 42822.3 Histone modifications and chromatin remodeling 43522.4 Noncoding RNA 43922.5 Summary and discussion 440Acknowledgments 440References 44023 Transcriptomics: Applications in Epigenetic Toxicology 445Pius Joseph23.1 Introduction 44523.2 Microarray analysis of gene expression profiles 44623.3 Gene expression studies – challenges 45323.4 Conclusions 456Acknowledgments 456Disclaimer 457References 45724 Carcinogenic Metals Alter Histone Tail Modifications 459Yana Chervona and Max Costa24.1 Introduction 45924.2 Epigenetics and histone tail modifications 46024.3 Arsenic 46224.4 Nickel 46324.5 Hexavalent chromium (Cr [VI]) 46624.6 Cadmium 46824.7 Summary 470References 47025 Prediction of Epigenetic and Stochastic Gene Expression Profiles of Late Effects after Radiation Exposure 475Yoko Hirabayashi and Tohru Inoue25.1 Introduction – pathological profiling (diagnostic endpoint) and toxicological profiling (probabilistic endpoint) 47525.2 Radiation exposure and dosimetric quantum biology 47725.3 Common gene expression profiles after subacute and prolonged effects after radiation exposure 47825.4 Stochastic expression gene profiles after radiation exposure 48325.5 Conclusions 492Appendix A 494Appendix B 495Appendix C 496References 50926 Modulation of Developmentally Regulated Gene Expression Programs through Targeting of Polycomb and Trithorax Group Proteins 511Marjorie Brand and F.J. Dilworth26.1 Introduction 51126.2 Polycomb group (PcG) proteins 51226.3 Trithorax group genes 51626.4 Model for the transcriptional regulation of developmentally regulated genes by PcG and TrxG 52626.5 PcG and TrxG proteins in disease 52726.6 Targeting PcG and TrxG proteins in disease 528References 52927 Chromatin Insulators and Epigenetic Inheritance in Health and Disease 539Jingping Yang and Victor G. Corces27.1 Introduction 53927.2 Structure and organization of insulators 54027.3 Insulators and chromatin architecture 54327.4 Regulation of insulator function 55227.5 Insulators and the external/internal cellular environment 55527.6 Insulators and disease 55727.7 Concluding remarks 560Acknowledgments 561References 56128 Bioinformatics for High-Throughput Toxico-Epigenomics Studies 569Maureen A. Sartor, Dana C. Dolinoy, Laura S. Rozek, and Gilbert S. Omenn28.1 Introduction 56928.2 Evaluating environmental influences on the epigenome 57028.3 Establishment of the field of environmental epigenomics 57028.4 An evolutionary perspective: the case of genomic imprinting 57128.5 Transitioning from epigenetics to epigenomics and related bioinformatics 57228.6 Observational studies in epigenomics 57628.7 Integrative analyses with epigenomics data 57728.8 Gene set enrichment and concept tools for pathway analyses 57828.9 Databases and resources 58028.10 Illustrative applications from environmental exposures/perturbations 58128.11 University of Michigan NIEHS center approach to Lifestage Exposures and Adult Disease (LEAD) 58328.12 Future directions 584Acknowledgments 584References 58429 Computational Methods in Toxicoepigenomics 589Joo Chuan Tong29.1 Introduction 58929.2 Data sources 58929.3 Computational tools 59129.4 Conclusion 592References 59230 Databases and Tools for Computational Epigenomics 595V. Umashankar and S. Gurunathan30.1 Introduction 59530.2 Epigenetics and computational epigenetics 59630.3 Epigenomics and computational epigenomics 59630.4 Human epigenome project (HEP) 59630.5 Epigenome prediction mechanism 59730.6 Epigenomics databases 59930.7 Tools employed in computational epigenomics 60630.8 Sophisticated algorithms 61130.9 Conclusion 612References 613Website references 61331 Interface of Epigenetics and Carcinogenic Risk Assessment 615Paul Nioi31.1 Introduction 61531.2 Key epigenetic changes implicated in carcinogenesis 61631.3 DNA methylation changes in chemical carcinogenesis 61731.4 Methods of detecting alterations in the genomic methylome 62331.5 Conclusions 624References 62732 Epigenetic Modifications in Chemical Carcinogenesis 631Igor P. Pogribny, Igor Koturbash, and Frederick A. Beland32.1 Introduction 63132.2 Epigenetic alterations in cancer cells 63232.3 Role of epigenetic alterations in chemical carcinogenesis 63432.4 Future perspectives: epigenetic alterations and cancer risk assessment 638References 63833 Application of Cancer Toxicoepigenomics in Identifying High-Risk Populations 645Mukesh Verma and Krishna K. Banaudha33.1 Introduction: epigenetic mechanisms and cancer 64533.2 Toxicity and cancer epigenetics 64633.3 Advantages of using a cohort consortia approach to studying toxicoepigenomics in cancer 64933.4 Data integration 65033.5 Challenges and future directions 650References 651Author Index 653Subject Index 655

Dr. Saura C. Sahu, Research Chemist, Division of Toxicology, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, US Food and Drug Administration.Dr. Sahu is the US Editor for the Journal of Applied Toxicology and the editor of Hepatotoxicity (Wiley, 2007), Toxicogenomics (Wiley, 2008), Nanotoxicity (Wiley, 2009), and Handbook of Systems Toxicology (Wiley, 2011).

“Despite some of the issues with the structure, Toxicology and Epigenetics is an important, timely book that provides world-class, expert opinion on a broad range of topics in a fast moving highly relevant branch of toxicology.”  (British Toxicology Society, 1 July 2013)

• Preface xxiAcknowledgments xxiiiList of Contributors xxv1 Introduction 1Saura C. SahuReferences 22 Environment, Epigenetics, and Diseases 5Robert Y.S. Cheng and Wan-yee Tang2.1 Perceptions of epigenetics 52.2 Environmental epigenetics and human diseases 82.3 Implications of environmental epigenetics and future prospects 162.4 Key questions to be answered 17Acknowledgments 17References 173 DNA Methylation and Toxicogenomics 25Deepti Deobagkar3.1 Introduction 253.2 Toxicology 263.3 Toxicogenomics 273.4 Epigenetics 293.5 DNA methylation 303.6 DNA methyltransferases 343.7 DNA methylation is alteres upon exposure to chemicals and toxins 353.8 Toxicogenomics and epigenetics 403.9 Hydroxymethyl cytosine and toxicogenomics 423.10 MicroRNAs 423.11 DNA methylation in cancer 423.12 Bioinformatics approach 443.13 Summary 45Acknowledgments 46References 464 Chromatin at the Intersection of Disease and Therapy 51Delphine Quénet, Marcin Walkiewicz, and Yamini Dalal4.1 Epigenetic marks on chromatin: a complex pathway with high flexibility 514.2 Epigenetic approaches to treatment of cancer 554.3 Epigenetic modifications and potential therapy in other diseases 604.4 Conclusion 66References 665 Molecular Epigenetic Changes Caused by Environmental Pollutants 73Solange S. Lewis, Gregory J. Weber, Jennifer L. Freeman, and Maria S. Sepúlveda5.1 Introduction 735.2 Mechanisms of molecular epigenetic changes 745.3 Epigenetic assays 765.4 Epigenetic changes induced by organic chemicals 785.5 Epigenetic changes induced by metals 905.6 Concluding remarks 101References 1026 Epigenetic Mediation of Environmental Exposures to Polycyclic Aromatic Hydrocarbons 111Bekim Sadikovic and David I. Rodenhiser6.1 Introduction 1116.2 Epigenetic modifications: DNA methylation 1126.3 DNA methylation and cancer 1136.4 Epigenetic histone modifications 1146.5 Benzo(a)pyrene – a prototype PAH and environmental carcinogen 1156.6 Molecular mechanisms of benzopyrene carcinogenicity: geno- and epigeno-toxicity 1156.7 Epigenetic effects of multiple/synergistic carcinogen exposures 1206.8 Summary and future considerations 122Acknowledgments 123References 1237 Epigenomic Actions of Environmental Arsenicals 129Paul L. Severson and Bernard W. Futscher7.1 Introduction 1297.2 Arsenicals in relation to human health 1307.3 Arsenical mechanisms of action 1317.4 Models to study arsenical action 1337.5 Models used to study epigenetic action 1347.6 Epigenetic effects of arsenicals 1357.7 Perspectives 140References 1418 Arsenic-Induced Changes to the Epigenome 149Kathryn A. Bailey and Rebecca C. Fry8.1 Introduction 1498.2 Arsenic exposure and DNA methylation 1528.3 DNA methylation changes associated with arsenic exposure 1548.4 Histone modifications associated with arsenic exposure 1738.5 MicroRNA (miRNA) alterations associated with arsenic exposure 1808.6 Conclusions and future directions 182Acknowledgments 183References 1839 Environmental Epigenetics, Asthma, and Allergy: Our Environment’s Molecular Footprints 191Stephanie Lovinsky-Desir and Rachel L. Miller9.1 Introduction 1919.2 Asthma environmental toxicants associated with epigenetic regulation 1939.3 Epigenetic changes and asthma phenotype 1979.4 ‘Pharmacoepigenetics’ 2009.5 Conclusion 200References 20110 miRNAs in Human Prostate Cancer 205Ernest K. Amankwah and Jong Y. Park10.1 Introduction 20510.2 Biogenesis, function, and target of miRNA 20610.3 miRNA and human cancer 20810.4 miRNAs as oncogenes and tumor suppressors 20910.5 Expression profile of miRNA in prostate cancer 21010.6 miRNA as therapeutic targets for prostate cancer 21310.7 Conclusion and future directions 213References 21311 Environment, Epigenetics, and Cardiovascular Health 219Sanjukta Ghosh and Andrea Baccarelli11.1 Introduction 21911.2 Epidemiological evidence of environmental factors affecting cardiovascular health 22011.3 Cause and effect relation between environmental exposure and cardiovascular diseases 22211.4 Cardiovascular epigenetic signatures as risk factors and biomarkers for environmental exposure 23211.5 Conclusion 233References 23312 Toxicology, Epigenetics, and Autoimmunity 241Craig A. Cooney and Kathleen M. Gilbert12.1 Introduction 24112.2 Drugs and toxicants in epigenetics 24312.3 Metabolic requirements for epigenetics 24412.4 Autoimmunity and epigenetics 24512.5 Conclusion 251References 25213 Toxicoepigenomics in Lupus 261Donna Ray and Bruce C. Richardson13.1 Introduction 26113.2 Etiology of lupus 26213.3 Epigenetics and lupus 26413.4 Environmental contributions to lupus 26713.5 Summary 270References 27014 Ocular Epigenomics: Potential Sites of Environmental Impact in Development and Disease 275Kenneth P. Mitton14.1 Introduction 27514.2 Gene expression in ocular development 27714.3 Epigenetic regulation in ocular development 28014.4 DNA-methylation changes in ocular disease 28314.5 Inherited and age-related diseases of the eye 28614.6 Pharmacological effects on retinal function 28714.7 Future research 289References 28915 Nuclear RNA Silencing and Related Phenomena in Animals 297Radek Malik and Petr Svoboda15.1 Introduction 29715.2 Conclusion 310Acknowledgments 310References 31016 Epigenetic Biomarkers in Cancer Detection and Diagnosis 317Ashley G. Rivenbark and William B. Coleman16.1 DNA methylation 31716.2 Epigenetics of cancer 31916.3 Epigenetic biomarkers for cancer diagnostics: DNA methylation 32016.4 Application of aberrant DNA methylation to cancer diagnostics 32316.5 Epigenetic biomarkers in breast cancer 32316.6 Epigenetic biomarkers in prostate cancer 32416.7 Epigenetic biomarkers in lung cancer 32516.8 Epigenetic biomarkers in colorectal cancer 32616.9 Epigenetic biomarkers in liver cancer 32816.10 Cancer detection and diagnosis 330References 33217 Epigenetic Histone Changes in the Toxicologic Mode of Action of Arsenic 339John F. Reichard and Alvaro Puga17.1 Introduction 33917.2 Epigenetics and cancer 34017.3 Epigenetics effects of arsenic 34117.4 Conclusions 348References 35018 Irreversible Effects of Diethylstilbestrol on Reproductive Organs and a Current Approach for Epigenetic Effects of Endocrine Disrupting Chemicals 357Shinichi Miyagawa, Ryohei Yatsu, Tamotsu Sudo, Katsuhide Igarashi, Jun Kanno, and Taisen Iguchi18.1 Introduction 35718.2 Adverse effects of perinatally-exposed DES on the mouse vagina 35818.3 MeDIP-ChIP 35918.4 Future research needs 362Acknowledgments 363References 36319 Epigenomics – Impact for Drug Safety Sciences 365Harri Lempiäinen, Raphaëlle Luisier, Arne Müller, Philippe Marc, David Heard, Federico Bolognani,Pierre Moulin, Philippe Couttet, Olivier Grenet, Jennifer Marlowe, Jonathan Moggs, and Rémi Terranova19.1 Introduction – the dynamic epigenome and perturbations in disease 36519.2 Relevance of epigenetics for toxicology 37019.3 Towards identifying epigenetic biomarkers of drug-induced toxicity 37119.4 Challenges of integrating epigenetic analysis into toxicity testing 37319.5 Practical considerations 37419.6 Bioinformatics and modeling of epigenomic data 37619.7 Case study: identification of early mechanism and biomarkers for non-genotoxic carcinogenesis (NGC) 37819.8 Conclusions 379Acknowledgments 380References 38020 Archival Toxicoepigenetics: Molecular Analysis of Modified DNA from Preserved Tissues in Toxicology Studies 387B. Alex Merrick20.1 Introduction 38720.2 Preservation of tissue: effects on protein and nucleic acids 38820.3 Extraction of nucleic acids from fixed or embedded tissues 39120.4 Analysis of methylated DNA for epigenetics 39420.5 Survey of epigenetic studies using formalin preserved tissues 39520.6 Prospects for toxicoepigenetics in preserved tissues 40120.7 Conclusion 402References 40321 Nanoparticles and Toxicoepigenomics 409Manasi P. Jain, Angela O. Choi, and Dusica Maysinger21.1 Nanoparticles 40921.2 Particles and the environment 41021.3 Nanoparticles in soil 41221.4 Nanoparticles in water 41221.5 Nanoparticles in air 41321.6 Nanoparticles in medicine 41421.7 Nanotoxicology 41421.8 Nanotoxicology in humans and experimental animals 41421.9 Complications with nanotoxicological studies 41621.10 Molecular mechanisms of nanoparticle toxicity and cellular defense mechanisms 41721.11 Molecular mechanisms of nanoparticle-induced cytotoxicity 41821.12 Nano-epigenomcs and epigenetics 41921.13 Conclusion 421References 42222 Methods of Global Epigenomic Profiling 427Michael W.Y. Chan, Zhengang Peng, Jennifer Chao Weber, Ying-Wei Li, Matthew T. Zuzolo, and Huey-Jen L. Lin22.1 Introduction 42722.2 DNA methylation 42822.3 Histone modifications and chromatin remodeling 43522.4 Noncoding RNA 43922.5 Summary and discussion 440Acknowledgments 440References 44023 Transcriptomics: Applications in Epigenetic Toxicology 445Pius Joseph23.1 Introduction 44523.2 Microarray analysis of gene expression profiles 44623.3 Gene expression studies – challenges 45323.4 Conclusions 456Acknowledgments 456Disclaimer 457References 45724 Carcinogenic Metals Alter Histone Tail Modifications 459Yana Chervona and Max Costa24.1 Introduction 45924.2 Epigenetics and histone tail modifications 46024.3 Arsenic 46224.4 Nickel 46324.5 Hexavalent chromium (Cr [VI]) 46624.6 Cadmium 46824.7 Summary 470References 47025 Prediction of Epigenetic and Stochastic Gene Expression Profiles of Late Effects after Radiation Exposure 475Yoko Hirabayashi and Tohru Inoue25.1 Introduction – pathological profiling (diagnostic endpoint) and toxicological profiling (probabilistic endpoint) 47525.2 Radiation exposure and dosimetric quantum biology 47725.3 Common gene expression profiles after subacute and prolonged effects after radiation exposure 47825.4 Stochastic expression gene profiles after radiation exposure 48325.5 Conclusions 492Appendix A 494Appendix B 495Appendix C 496References 50926 Modulation of Developmentally Regulated Gene Expression Programs through Targeting of Polycomb and Trithorax Group Proteins 511Marjorie Brand and F.J. Dilworth26.1 Introduction 51126.2 Polycomb group (PcG) proteins 51226.3 Trithorax group genes 51626.4 Model for the transcriptional regulation of developmentally regulated genes by PcG and TrxG 52626.5 PcG and TrxG proteins in disease 52726.6 Targeting PcG and TrxG proteins in disease 528References 52927 Chromatin Insulators and Epigenetic Inheritance in Health and Disease 539Jingping Yang and Victor G. Corces27.1 Introduction 53927.2 Structure and organization of insulators 54027.3 Insulators and chromatin architecture 54327.4 Regulation of insulator function 55227.5 Insulators and the external/internal cellular environment 55527.6 Insulators and disease 55727.7 Concluding remarks 560Acknowledgments 561References 56128 Bioinformatics for High-Throughput Toxico-Epigenomics Studies 569Maureen A. Sartor, Dana C. Dolinoy, Laura S. Rozek, and Gilbert S. Omenn28.1 Introduction 56928.2 Evaluating environmental influences on the epigenome 57028.3 Establishment of the field of environmental epigenomics 57028.4 An evolutionary perspective: the case of genomic imprinting 57128.5 Transitioning from epigenetics to epigenomics and related bioinformatics 57228.6 Observational studies in epigenomics 57628.7 Integrative analyses with epigenomics data 57728.8 Gene set enrichment and concept tools for pathway analyses 57828.9 Databases and resources 58028.10 Illustrative applications from environmental exposures/perturbations 58128.11 University of Michigan NIEHS center approach to Lifestage Exposures and Adult Disease (LEAD) 58328.12 Future directions 584Acknowledgments 584References 58429 Computational Methods in Toxicoepigenomics 589Joo Chuan Tong29.1 Introduction 58929.2 Data sources 58929.3 Computational tools 59129.4 Conclusion 592References 59230 Databases and Tools for Computational Epigenomics 595V. Umashankar and S. Gurunathan30.1 Introduction 59530.2 Epigenetics and computational epigenetics 59630.3 Epigenomics and computational epigenomics 59630.4 Human epigenome project (HEP) 59630.5 Epigenome prediction mechanism 59730.6 Epigenomics databases 59930.7 Tools employed in computational epigenomics 60630.8 Sophisticated algorithms 61130.9 Conclusion 612References 613Website references 61331 Interface of Epigenetics and Carcinogenic Risk Assessment 615Paul Nioi31.1 Introduction 61531.2 Key epigenetic changes implicated in carcinogenesis 61631.3 DNA methylation changes in chemical carcinogenesis 61731.4 Methods of detecting alterations in the genomic methylome 62331.5 Conclusions 624References 62732 Epigenetic Modifications in Chemical Carcinogenesis 631Igor P. Pogribny, Igor Koturbash, and Frederick A. Beland32.1 Introduction 63132.2 Epigenetic alterations in cancer cells 63232.3 Role of epigenetic alterations in chemical carcinogenesis 63432.4 Future perspectives: epigenetic alterations and cancer risk assessment 638References 63833 Application of Cancer Toxicoepigenomics in Identifying High-Risk Populations 645Mukesh Verma and Krishna K. Banaudha33.1 Introduction: epigenetic mechanisms and cancer 64533.2 Toxicity and cancer epigenetics 64633.3 Advantages of using a cohort consortia approach to studying toxicoepigenomics in cancer 64933.4 Data integration 65033.5 Challenges and future directions 650References 651Author Index 653Subject Index 655