Toxicology and Epigenetics E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 1632

Veröffentlichungsjahr: 2012

Beschreibung

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.

Leseprobe

Table of Contents

Title Page

Copyright

Dedication

Preface

Acknowledgments

List of Contributors

Chapter 1: Introduction

References

Chapter 2: Environment, Epigenetics, and Diseases

2.1 Perceptions of epigenetics

2.2 Environmental epigenetics and human diseases

2.3 Implications of environmental epigenetics and future prospects

2.4 Key questions to be answered

Acknowledgments

References

Chapter 3: DNA Methylation and Toxicogenomics

3.1 Introduction

3.2 Toxicology

3.3 Toxicogenomics

3.4 Epigenetics

3.5 DNA methylation

3.6 DNA methyltransferases

3.7 DNA methylation is alteres upon exposure to chemicals and toxins

3.8 Toxicogenomics and epigenetics

3.9 Hydroxymethyl cytosine and toxicogenomics

3.10 MicroRNAs

3.11 DNA methylation in cancer

3.12 Bioinformatics approach

3.13 Summary

Acknowledgments

References

Chapter 4: Chromatin at the Intersection of Disease and Therapy

4.1 Epigenetic marks on chromatin: a complex pathway with high flexibility

4.2 Epigenetic approaches to treatment of cancer

4.3 Epigenetic modifications and potential therapy in other diseases

4.4 Conclusion

References

Chapter 5: Molecular Epigenetic Changes Caused by Environmental Pollutants

5.1 Introduction

5.2 Mechanisms of molecular epigenetic changes

5.3 Epigenetic assays

5.4 Epigenetic changes induced by organic chemicals

5.5 Epigenetic changes induced by metals

5.6 Concluding remarks

References

Chapter 6: Epigenetic Mediation of Environmental Exposures to Polycyclic Aromatic Hydrocarbons

6.1 Introduction

6.2 Epigenetic modifications: DNA methylation

6.3 DNA methylation and cancer

6.4 Epigenetic histone modifications

6.5 Benzo(a)pyrene – a prototype PAH and environmental carcinogen

6.6 Molecular mechanisms of benzopyrene carcinogenicity: geno- and epigeno-toxicity

6.7 Epigenetic effects of multiple/synergistic carcinogen exposures

6.8 Summary and future considerations

Acknowledgments

References

Chapter 7: Epigenomic Actions of Environmental Arsenicals

7.1 Introduction

7.2 Arsenicals in relation to human health

7.3 Arsenical mechanisms of action

7.4 Models to study arsenical action

7.5 Models used to study epigenetic action

7.6 Epigenetic effects of arsenicals

7.7 Perspectives

References

Chapter 8: Arsenic-Induced Changes to the Epigenome

8.1 Introduction

8.2 Arsenic exposure and DNA methylation

8.3 DNA methylation changes associated with arsenic exposure

8.4 Histone modifications associated with arsenic exposure

8.5 MicroRNA (miRNA) alterations associated with arsenic exposure

8.6 Conclusions and future directions

Acknowledgments

References

Chapter 9: Environmental Epigenetics, Asthma, and Allergy: Our Environment's Molecular Footprints

9.1 Introduction

9.2 Asthma environmental toxicants associated with epigenetic regulation

9.3 Epigenetic changes and asthma phenotype

9.4 ‘Pharmacoepigenetics’

9.5 Conclusion

References

Chapter 10: miRNAs in Human Prostate Cancer

10.1 Introduction

10.2 Biogenesis, function, and target of miRNA

10.3 miRNA and human cancer

10.4 miRNAs as oncogenes and tumor suppressors

10.5 Expression profile of miRNA in prostate cancer

10.6 miRNA as therapeutic targets for prostate cancer

10.7 Conclusion and future directions

References

Chapter 11: Environment, Epigenetics, and Cardiovascular Health

11.1 Introduction

11.2 Epidemiological evidence of environmental factors affecting cardiovascular health

11.3 Cause and effect relation between environmental exposure and cardiovascular diseases

11.4 Cardiovascular epigenetic signatures as risk factors and biomarkers for environmental exposure

11.5 Conclusion

References

Chapter 12: Toxicology, Epigenetics, and Autoimmunity

12.1 Introduction

12.2 Drugs and toxicants in epigenetics

12.3 Metabolic requirements for epigenetics

12.4 Autoimmunity and epigenetics

12.5 Conclusion

References

Chapter 13: Toxicoepigenomics in Lupus

13.1 Introduction

13.2 Etiology of lupus

13.3 Epigenetics and lupus

13.4 Environmental contributions to lupus

13.5 Summary

References

Chapter 14: Ocular Epigenomics: Potential Sites of Environmental Impact in Development and Disease

14.1 Introduction

14.2 Gene expression in ocular development

14.3 Epigenetic regulation in ocular development

14.4 DNA-methylation changes in ocular disease

14.5 Inherited and age-related diseases of the eye

14.6 Pharmacological effects on retinal function

14.7 Future research

References

Chapter 15: Nuclear RNA Silencing and Related Phenomena in Animals

15.1 Introduction

15.2 Conclusion

Acknowledgments

References

Chapter 16: Epigenetic Biomarkers in Cancer Detection and Diagnosis

16.1 DNA methylation

16.2 Epigenetics of cancer

16.3 Epigenetic biomarkers for cancer diagnostics: DNA methylation

16.4 Application of aberrant DNA methylation to cancer diagnostics

16.5 Epigenetic biomarkers in breast cancer

16.6 Epigenetic biomarkers in prostate cancer

16.7 Epigenetic biomarkers in lung cancer

16.8 Epigenetic biomarkers in colorectal cancer

16.9 Epigenetic biomarkers in liver cancer

16.10 Cancer detection and diagnosis

References

Chapter 17: Epigenetic Histone Changes in the Toxicologic Mode of Action of Arsenic

17.1 Introduction

17.2 Epigenetics and cancer

17.3 Epigenetics effects of arsenic

17.4 Conclusions

References

Chapter 18: Irreversible Effects of Diethylstilbestrol on Reproductive Organs and a Current Approach for Epigenetic Effects of Endocrine Disrupting Chemicals

18.1 Introduction

18.2 Adverse effects of perinatally-exposed DES on the mouse vagina

18.3 MeDIP-ChIP

18.4 Future research needs

Acknowledgments

References

Chapter 19: Epigenomics – Impact for Drug Safety Sciences

19.1 Introduction – the dynamic epigenome and perturbations in disease

19.2 Relevance of epigenetics for toxicology

19.3 Towards identifying epigenetic biomarkers of drug-induced toxicity

19.4 Challenges of integrating epigenetic analysis into toxicity testing

19.5 Practical considerations

19.6 Bioinformatics and modeling of epigenomic data

19.7 Case study: identification of early mechanism and biomarkers for non-genotoxic carcinogenesis (NGC)

19.8 Conclusions

Acknowledgments

References

Chapter 20: Archival Toxicoepigenetics: Molecular Analysis of Modified DNA from Preserved Tissues in Toxicology Studies

20.1 Introduction

20.2 Preservation of tissue: effects on protein and nucleic acids

20.3 Extraction of nucleic acids from fixed or embedded tissues

20.4 Analysis of methylated DNA for epigenetics

20.5 Survey of epigenetic studies using formalin preserved tissues

20.6 Prospects for toxicoepigenetics in preserved tissues

20.7 Conclusion

References

Chapter 21: Nanoparticles and Toxicoepigenomics

21.1 Nanoparticles

21.2 Particles and the environment

21.3 Nanoparticles in soil

21.4 Nanoparticles in water

21.5 Nanoparticles in air

21.6 Nanoparticles in medicine

21.7 Nanotoxicology

21.8 Nanotoxicology in humans and experimental animals

21.9 Complications with nanotoxicological studies

21.10 Molecular mechanisms of nanoparticle toxicity and cellular defense mechanisms

21.11 Molecular mechanisms of nanoparticle-induced cytotoxicity

21.12 Nano-epigenomcs and epigenetics

21.13 Conclusion

References

Chapter 22: Methods of Global Epigenomic Profiling

22.1 Introduction

22.2 DNA methylation

22.3 Histone modifications and chromatin remodeling

22.4 Noncoding RNA

22.5 Summary and discussion

Acknowledgments

References

Chapter 23: Transcriptomics: Applications in Epigenetic Toxicology

23.1 Introduction

23.2 Microarray analysis of gene expression profiles

23.3 Gene expression studies – challenges

23.4 Conclusions

Acknowledgments

Disclaimer

References

Chapter 24: Carcinogenic Metals Alter Histone Tail Modifications

24.1 Introduction

24.2 Epigenetics and histone tail modifications

24.3 Arsenic

24.4 Nickel

24.5 Hexavalent chromium (Cr [VI])

24.6 Cadmium

24.7 Summary

References

Chapter 25: Prediction of Epigenetic and Stochastic Gene Expression Profiles of Late Effects after Radiation Exposure

25.1 Introduction – pathological profiling (diagnostic endpoint) and toxicological profiling (probabilistic endpoint)

25.2 Radiation exposure and dosimetric quantum biology

25.3 Common gene expression profiles after subacute and prolonged effects after radiation exposure

25.4 Stochastic expression gene profiles after radiation exposure

25.5 Conclusions

Appendix A

Appendix B

Appendix C

References

Chapter 26: Modulation of Developmentally Regulated Gene Expression Programs through Targeting of Polycomb and Trithorax Group Proteins

26.1 Introduction

26.2 Polycomb group (PcG) proteins

26.3 Trithorax group genes

26.4 Model for the transcriptional regulation of developmentally regulated genes by PcG and TrxG

26.5 PcG and TrxG proteins in disease

26.6 Targeting PcG and TrxG proteins in disease

References

Chapter 27: Chromatin Insulators and Epigenetic Inheritance in Health and Disease

27.1 Introduction

27.2 Structure and organization of insulators

27.3 Insulators and chromatin architecture

27.4 Regulation of insulator function

27.5 Insulators and the external/internal cellular environment

27.6 Insulators and disease

27.7 Concluding remarks

Acknowledgments

References

Chapter 28: Bioinformatics for High-Throughput Toxico-Epigenomics Studies

28.1 Introduction

28.2 Evaluating environmental influences on the epigenome

28.3 Establishment of the field of environmental epigenomics

28.4 An evolutionary perspective: the case of genomic imprinting

28.5 Transitioning from epigenetics to epigenomics and related bioinformatics

28.6 Observational studies in epigenomics

28.7 Integrative analyses with epigenomics data

28.8 Gene set enrichment and concept tools for pathway analyses

28.9 Databases and resources

28.10 Illustrative applications from environmental exposures/perturbations

28.11 University of Michigan NIEHS center approach to Lifestage Exposures and Adult Disease (LEAD)

28.12 Future directions

Acknowledgments

References

Chapter 29: Computational Methods in Toxicoepigenomics

29.1 Introduction

29.2 Data sources

29.3 Computational tools

29.4 Conclusion

References

Chapter 30: Databases and Tools for Computational Epigenomics

30.1 Introduction

30.2 Epigenetics and computational epigenetics

30.3 Epigenomics and computational epigenomics

30.4 Human epigenome project (HEP)

30.5 Epigenome prediction mechanism

30.6 Epigenomics databases

30.7 Tools employed in computational epigenomics

30.8 Sophisticated algorithms

30.9 Conclusion

References

Website references

Chapter 31: Interface of Epigenetics and Carcinogenic Risk Assessment

31.1 Introduction

31.2 Key epigenetic changes implicated in carcinogenesis

31.3 DNA methylation changes in chemical carcinogenesis

31.4 Methods of detecting alterations in the genomic methylome

31.5 Conclusions

References

Chapter 32: Epigenetic Modifications in Chemical Carcinogenesis

32.1 Introduction

32.2 Epigenetic alterations in cancer cells

32.3 Role of epigenetic alterations in chemical carcinogenesis

32.4 Future perspectives: epigenetic alterations and cancer risk assessment

References

Chapter 33: Application of Cancer Toxicoepigenomics in Identifying High-Risk Populations

33.1 Introduction: epigenetic mechanisms and cancer

33.2 Toxicity and cancer epigenetics

33.3 Advantages of using a cohort consortia approach to studying toxicoepigenomics in cancer

33.4 Data integration

33.5 Challenges and future directions

References

Author Index

Subject Index

This edition first published 2012

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Library of Congress Cataloging-in-Publication Data

Toxicology and epigenetics / editor, Saura C. Sahu.

p. cm.

Includes bibliographical references and index.

ISBN 978-1-119-97609-7 (cloth)

1. Genetic toxicology. 2. Environmental toxicology. 3. Epigenetics. I. Sahu, Saura C.

RA1224.3.T698 2012

615.9′02–dc23

Dedicated to

My parents, Gopinath and Ichhamoni, for their gift of life, love and living example.

My wife, Jharana, for her lifelong friendship, love and support.

My children, Megha, Sudhir and Subir, for their love and care.

Preface

Toxicology, an old discipline of science, is undergoing a rapid transformation in recent years following the new ‘epigenetic’ revolution. ‘Epigenetics’, an emerging major scientific discipline, is growing rapidly. This monograph builds a bridge between toxicology and epigenetics at a level designed to take the reader to the forefront of research in this area. The importance of this field of research is evidenced by the increasing number of contributions published each year. It becomes increasingly clear that developments in this field are moving so rapidly that new means are needed to report the status of ongoing research activities. The contributions presented in this monograph represent a collaborative effort by international experts working in this emerging field of science.

The main purpose of this book is to assemble up-to-date, state-of-the-art information on toxicoepigenetics presented by internationally recognized experts in a single edition. Therefore, I sincerely hope that this book will provide an authoritative source of current information in this area of research and prove useful to the scientists interested in this scientific discipline throughout the world. However, it should be of interest to a variety of other scientific disciplines including toxicology, genetics, medicine and pharmacology, as well as drug and food sciences. Also, it should be of interest to federal regulators and safety assessors of drugs, food, environment, and consumer products.

Saura C. SahuLaurel, Maryland, USA

Acknowledgments

I express my sincere gratitude to the following individuals, who have influenced me directly or indirectly, for writing this book.

I must admit that writing this book was a challenge. I am indebted to the internationally recognized experts, who shared my enthusiasm for this field of science and contributed generously to this book. Their work speaks for itself and I am grateful to them for their cooperation and excellent contributions in their own areas of expertise.

I thank Dr Thomas A. Cebula, Dr Joseph E. LeClerc, Dr Daniel A. Casciano, Dr Philip W. Harvey, Dr Harry Salem and Dr Tohru Inoue for their encouragement, inspiration and support.

Finally, I thank my publishers; Paul Deards, Rebecca Ralf and Sarah Tilley of the publishing company, John Wiley & Sons, Ltd, for their cooperation and excellent support in the timely publication of this book.

List of Contributors

Ernest K. Amankwah Division of Cancer Prevention and Control, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

Kathryn A. Bailey Environmental Sciences and Engineering, The University of North Carolina Gillings School of Global Public Health, UNC-Chapel Hill, Chapel Hill, NC, USA

Andrea Baccarelli Environmental Health, Harvard School of Public Health, Boston, MA, USA

Krishna K. Banaudha Biochemistry and Molecular Biology Department, The George Washington University, Washington, DC, USA

Frederick A. Beland Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR, USA

Federico Bolognani Novartis Institutes for BioMedical Research, Preclinical Safety, Discovery and Investigative Safety, Basel, Switzerland

Marjorie Brand Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute; Departments of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada

Michael W.Y. Chan Department of Life Science and Human Epigenomics Center, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, ROC

Robert Y.S. Cheng Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

Yana Chervona Department of Environmental Medicine, NYU School of Medicine, Tuxedo, NY, USA

Angela O. Choi Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada

William B. Coleman Department of Pathology and Laboratory Medicine, Curriculum in Toxicology, Program in Translational Medicine, UNC Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA

Craig A. Cooney Research and Development, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA

Victor G. Corces Department of Biology, Emory University, Atlanta, GA, USA

Max Costa Department of Environmental Medicine, NYU School of Medicine, Tuxedo, NY, USA

Philippe Couttet Novartis Institutes for BioMedical Research, Preclinical Safety, Discovery and Investigative Safety, Basel, Switzerland

Yamini Dalal Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, Bethesda, MD, USA

Deepti Deobagkar Center of Advanced Studies, Department of Zoology and Bioinformatics Center, University of Pune, Pune, India

F.J. Dilworth Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute; Departments of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada

Dana C. Dolinoy Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA

Jennifer L. Freeman School of Health Sciences, Purdue University, West Lafayette, IN, USA

Rebecca C. Fry Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, The University of North Carolina-Chapel Hill, NC, USA

Bernard W. Futscher Department of Pharmacology & Toxicology, College of Pharmacy and The University of Arizona Cancer Center, The University of Arizona, Tucson, AZ, USA

Sanjukta Ghosh Departments of Molecular and Integrative Physiological Sciences, Harvard School of Public Health, Boston, MA, USA

Kathleen M. Gilbert Arkansas Children's Hospital Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA

Olivier Grenet Novartis Institutes for BioMedical Research, Preclinical Safety, Discovery and Investigative Safety, Basel, Switzerland

S. Gurunathan Department of Bioinformatics, Faculty of Sciences and Humanities, SRM University, Chennai, India

David Heard Novartis Institutes for BioMedical Research, Preclinical Safety, Discovery and Investigative Safety, Basel, Switzerland

Yoko Hirabayashi Division of Cellular and Molecular Toxicology, National Center for Biological Safety and Research, National Institute of Health Sciences, Setagaya, Tokyo, Japan

Katsuhide Igarashi Division of Cellular and Molecular Toxicology, National Center for Biological Safety and Research, National Institute of Health Sciences, Setagaya, Tokyo, Japan

Taisen Iguchi Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, and Department of Basic Biology, The Graduate University for Advanced Studies, Okazaki, Aichi, Japan

Tohru Inoue Department of Biological Function and Structural Medicine, Nihon University School of Medicine, Itabashi, Tokyo, Japan

Manasi P. Jain Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada

Pius Joseph Molecular Carcinogenesis Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health (NIOSH), Morgantown, WV, USA

Jun Kanno Division of Cellular and Molecular Toxicology, National Center for Biological Safety and Research, National Institute of Health Sciences, Setagaya, Tokyo, Japan

Igor Koturbash Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR, USA

Harri Lempiäinen Novartis Institutes for BioMedical Research, Preclinical Safety, Discovery and Investigative Safety, Basel, Switzerland

Solange S. Lewis Department of Forestry and Natural Resources, Purdue University, West Lafayette, IN, USA

Ying-Wei Li Division of Medical Technology, School of Allied Medical Professions; Molecular Biology and Cancer Genetics Program, College of Medicine, Comprehensive Cancer Center; The Ohio State University, Columbus, OH, USA

Huey-Jen L. Lin Division of Medical Technology, School of Allied Medical Professions; Molecular Biology and Cancer Genetics Program, Comprehensive Cancer Center; The Ohio State University, Columbus, Ohio; Department of Medical Technology, University of Delaware, Newark, DE, USA

Stephanie Lovinsky-Desir Division of Pediatric Pulmonary, Department of Pediatrics, Columbia University College of Physicians and Surgeons; Children's Hospital of New York Presbyterian, New York City, NY, USA

Raphaëlle Luisier Novartis Institutes for BioMedical Research, Preclinical Safety, Discovery and Investigative Safety, Basel, Switzerland

Radek Malik Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic

Philippe Marc Novartis Institutes for BioMedical Research, Preclinical Safety, Discovery and Investigative Safety, Basel, Switzerland

Jennifer Marlowe Novartis Institutes for BioMedical Research, Preclinical Safety, Discovery and Investigative Safety, Basel, Switzerland

Dusica Maysinger Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada

B. Alex Merrick Molecular Toxicology and Informatics Group, Biomolecular Screening Branch, National Toxicology Program Division, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

Rachel L. Miller Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine; Division of Pediatric Pulmonary, Department of Pediatrics; Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University College of Physicians and Surgeons, Columbia University, New York City, NY, USA

Kenneth P. Mitton Eye Research Institute, Control of Gene Expression Laboratory and the Pediatric Retinal Research Laboratory, Oakland University, Rochester, MI, USA

Shinichi Miyagawa Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, and Department of Basic Biology, The Graduate University for Advanced Studies, Okazaki, Aichi, Japan

Jonathan Moggs Novartis Institutes for BioMedical Research, Preclinical Safety, Discovery and Investigative Safety, Basel, Switzerland

Pierre Moulin Novartis Institutes for BioMedical Research, Preclinical Safety, Discovery and Investigative Safety, Basel, Switzerland

Arne Müller Novartis Institutes for BioMedical Research, Preclinical Safety, Discovery and Investigative Safety, Basel, Switzerland

Paul Nioi Amgen Inc, Thousand Oaks, California, CA, USA

Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, Medical School; Department of Internal Medicine, Human Genetics and School of Public Health, Medical School, University of Michigan, Ann Arbor, MI, USA

Jong Y. Park Division of Cancer Prevention and Control, H. Lee Moffitt Cancer Center and Research Institute, Tampa; College of Medicine, University of Florida, FL, USA

Zhengang Peng Division of Medical Technology, School of Allied Medical Professions; Molecular Biology and Cancer Genetics Program, College of Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

Igor P. Pogribny Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR, USA

Alvaro Puga Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

Delphine Quénet Laboratory of Receptor Biology & Gene Expression, National Cancer Institute, Bethesda, MD, USA

Donna Ray Department of Medicine; School of Public Health, University of Michigan, Ann Arbor, MI, USA

John F. Reichard Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

Bruce Richardson Department of Medicine; Veteran Affairs, Ann Arbor Healthcare System, University of Michigan, Ann Arbor, MI, USA

Ashley G. Rivenbark Department of Pathology and Laboratory Medicine, UNC Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA

David I. Rodenhiser Departments of Paediatrics, Biochemistry and Oncology, University of Western Ontario; The EpiGen Western Research Group at The Children's Health Research Institute; London Regional Cancer Program at the London Health Sciences Centre, London, Ontario, Canada

Laura S. Rozek Department of Environmental Health Sciences, School of Public Health; Department of Otolaryngology, Medical School, University of Michigan, Ann Arbor, MI, USA

Bekim Sadikovic Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

Saura C. Sahu Division of Toxicology, Center for Food Safety and Applied Nutrition, Food and Drug Administration, Laurel, MD, USA

Maureen A. Sartor Department of Computational Medicine and Bioinformatics, Medical School; Department of Biostatistics, School of Public Health, University of Michigan, MI, USA

Maria S. Sepúlveda Department of Forestry and Natural Resources and School of Health Sciences, Purdue University, West Lafayette, IN, USA

Paul L. Severson Department of Pharmacology and Toxicology, College of Pharmacy and The University of Arizona Cancer Center, The University of Arizona, Tucson, AR, USA

Tamotsu Sudo Section of Translational Research and Development of Gynecological Oncology, Hyogo Cancer Center, Akashi, Hyogo, Japan

Petr Svoboda Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic

Wan-yee Tang Division of Molecular and Translational Toxicology, Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

Rémi Terranova Novartis Institutes for BioMedical Research, Preclinical Safety, Discovery and Investigative Safety, Basel, Switzerland

Joo Chuan Tong Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore; Data Mining Department, Institute for Infocomm Research, Connexis, Singapore

V. Umashanker Center for Bioinformatics, Vision Research Foundation, Sankara Nethralaya, Chennai, India

Mukesh Verma Methods and Technologies Branch, Epidemiology and Genetics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA

Marcin Walkiewicz Laboratory of Receptor Biology & Gene Expression, National Cancer Institute, Bethesda, MD, USA

Gregory J. Weber School of Health Sciences, Purdue University, West Lafayette, IN, USA

Jennifer Chao Weber College of Medicine, University of Arizona, Phoenix, AZ, USA

Jingping Yang Department of Biology, Emory University, Atlanta, GA, USA

Ryohei Yatsu Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, and Department of Basic Biology, The Graduate University for Advanced Studies, Okazaki, Aichi, Japan

Matthew T. Zuzolo Division of Medical Technology, School of Allied Medical Professions; Molecular Biology and Cancer Genetics Program, College of Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

Chapter 1

Introduction

Saura C. Sahu

Division of Toxicology, Center for Food Safety and Applied Nutrition, Food and Drug Administration, Laurel, MD, USA

Toxicoepigenomics is a rapidly developing new branch of toxicology. Currently it is a hot discipline of toxicological sciences (Trosko and Chang, 2010; Csoka and Szyf, 2009; Goldberg, Allis, and Bernstein, 2007; Watson and Goodman, 2002). Genetics is defined as heritable changes in the gene expression profiles caused by the modification of genomic DNA due to the alterations in sequence of its bases. It is long accepted that aging and various human diseases including cancer are caused by the changes in the genomic DNA sequence. This long-held ‘genetic’ mechanism of human diseases focuses on the genetic changes induced by the direct alterations in the genomic DNA sequence itself. Genetics, environmental factors, and xenobiotics contribute to toxicity and human disease. Recent ‘omics’ technologies opened the way to a systemic understanding of toxicology and pathogenesis (Waters and Fostel, 2004). Thus, they gave birth to a new branch of toxicology called toxicogenomics. Toxicogenomics is the integration of traditional toxicology and genomics leading to toxicity and pathogenicity induced by the heritable changes in the genomic DNA sequence itself. However, recent discoveries show that this is not always the case. It has been demonstrated that heritable gene expression, both in the disease states and induced by environmental exposures, is also altered by the DNA modifications without any direct alteration in genomic DNA sequence itself. Environmental factors such as diet, smoking, alcohol intake, environmental toxicants, and stress are capable of altering gene expression profiles that can be inherited by the future generations and such genes altered by the environmental factors without any alteration in the genomic DNA sequence can cause human diseases. This observation led to the discovery of an alternate complementary mechanism of human inheritance and disease called ‘epigenetic’ mechanism that does not involve any change in the genomic DNA sequence itself. Therefore, a new scientific discipline ‘epigenetics’ was born with the definition that it is the heritable changes in the expression of the gene without any direct alteration in the DNA sequence itself (Egger et al., 2004). The heritable epigenetic modifications induced by environmental factors involve DNA, histone, and chromosomes. The most common observations reported in the epigenetic inheritance process are DNA methylation, histone modification, and noncoding small RNAs (Bonasio, Tu, and Reinberg, 2010). These discoveries led to the increasing recognition of the importance of epigenetics in the mechanisms of toxicity. Therefore, another new branch of toxicology called toxicoepigenomics was born. Toxicoepigenomics is the integration of traditional toxicology and epigenetics leading to toxicity and pathogenicity induced by heritable alterations in the gene expression without any direct changes in the genomic DNA sequence itself.

An increasing body of evidence demonstrates that epigenetic patterns, altered by environmental factors, are associated with human diseases such as cancer, neurodevelopmental disorders, cardiovascular diseases, type-2 diabetes, obesity, and infertility (Meaney, 2010; Csoka and Szyf, 2009; Nicholls, 2000). Epigenetic changes have been observed in virus-associated human cancers (Li, Leu, and Chang, 2005). It is believed that early epigenetic molecular events lead to cancer development (Herceg, 2007). Epigenetic drug therapy has become an increased focus in the treatment of complex diseases including cancer (Jian, 2011). Understanding of epigenetic pathways and rapid development of sensitive detection technologies will help the development of drug therapies for these diseases, especially cancers. A systems-biology approach employing microarray analyses of epigenetic gene expression patterns have been suggested for the safety assessment of drugs (Csoka and Szyf, 2009; Trosko and Upham, 2010). More and more this approach is being used for epigenetic toxicological studies (Lefèvre and Mann, 2008; Chernov et al., 2010). Computational epigenomics, an emerging new discipline, will make significant contributions to toxicoepigenomics research. Chromatin immunoprecipitation (ChIP) is a useful tool for epigenetic studies. Recent technical advances such as ChIP-on-chip and ChIP-seq convert epigenetic research into a high-throughput endeavor (Bock and Lengauer, 2008). Bioinformatic methods will be useful in these efforts. Understanding the role of toxicity in pathogenesis is important. Control of the epigenetic diseases requires the identification of chemical and biological modulators of epigenetic targets. However, very little information on the potential toxicological consequence of such modulations is currently available and, therefore, requires further investigations. Better understanding of the epigenetic mechanism of human diseases, caused by environmental exposures, holds great promise for the future treatment of human diseases.

As the Editor of this monograph, Toxicology and Epigenetics, it gives me great pride to introduce a unique book which encompasses many aspects of toxicoepigenomics never published together before. It is only recently that epigenetic research has attracted the attention of toxicologists. The toxicoepigenomic research work, actively pursued throughout the world, will lead to major discoveries of fundamental importance and of great clinical significance. This monograph brings together the ideas and work of investigators of international reputation who have pioneered in this area of research. This book reflects the remarkable blossoming of the discipline of toxicoepigenetics in recent years. New ideas and new approaches are being brought to bear on explorations of epigenetic mechanisms in toxicology. Therefore, exciting times are ahead for the future research on toxicoepigenomics. I sincerely hope that this book will stimulate the creativity of all the investigators who are actively engaged in this rapidly developing emerging new field of research.

References

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Bonasio, R., Tu, S., and Reinberg, D. (2010) Molecular signals of epigenetic states. Science, 330, 612–616.

Chernov, A.V., Baranovskaya, S., Golubkov, V.S. et al. (2010) Microarray-based transcriptional and epigenetic profiling of matrix metalloproteinases, collagens, and related genes in cancer. J. Biol. Chem., 285, 19647–19659.

Csoka, A.B. and Szyf, M. (2009) Epigenetic side-effects of common pharmaceuticals: a potential new field in medicine and pharmacology. Med. Hypotheses, 73, 770–780.

Egger, G., Liang, G., Aparicio, A., and Jones, P.A. (2004) Epigenetics in human disease and prospects for epigenetic therapy: a review. Nature, 429, 457–463.

Goldberg, A.D., Allis, C.D., and Bernstein, E. (2007) Epigenetics: a landscape takes shape. Cell, 128, 635–638.

Herceg, Z. (2007) Epigenetics and cancer: towards an evaluation of the impact of environmental and dietary factors. Mutagenesis, 22, 91–103.

Jian, T. (2011) DNA methylation topology: potential of a chromatin landmark for epigenetic drug toxicology. Epigenomics, 3, 761–770.

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Li, H.P., Leu, Y.W., and Chang, Y.S. (2005) Epigenetic changes in virus-associated human cancers. Cell Res., 15, 262–271.

Meaney, M.J. (2010) Epigenetics and the biological definition of gene x environment interactions. Child Dev., 81, 41–79.

Nicholls, R.D. (2000) The impact of genomic imprinting for neurobehavioural and developmental disorders. J. Clin. Invest., 105, 413–418.

Trosko, J.E. and Chang, C.C. (2010) Factors to consider in the use of stem cells for pharmaceutic drug development and for chemical safety assessment. Toxicology, 270, 18–34.

Trosko, J.E. and Upham, B.L. (2010) A paradigm shift is required for the risk assessment of potential human health after exposure to low level chemical exposures: a response to the toxicity testing in the 21st century report. Int. J. Toxicol., 29, 344–357.

Waters, M.D. and Fostel, J.M. (2004) Toxicogenomics and systems toxicology: aims and prospects. Nat. Rev. Genet., 5, 936–948.

Watson, R.E. and Goodman, J.I. (2002) Epigenetics and DNA methylation come of age. Toxicol. Sci., 67, 11–16.

Chapter 2

Environment, Epigenetics, and Diseases

Robert Y.S.1 Cheng and Wan-yee Tang2

1Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

2Division of Molecular and Translational Toxicology, Johns Hopkins Bloomberg School of Public Health, Department of Environmental Health Sciences, Baltimore, MD, USA

2.1 Perceptions of epigenetics

2.1.1 Definition of epigenetics

Disease susceptibility has now been recognized as a complex interplay between one's genetic make-up and epigenetic modulations induced by endogenous or exogenous environmental factors (Ho and Tang, 2007; Tang and Ho, 2007). Epigenetic disruption of gene expression has been shown to play an equally important role as genetic predisposition (such as polymorphisms, mutations, deletions, and insertions) in the development of disease (Dolinoy, Weidman, and Jirtle, 2007b; Godfrey et al., 2007; Jiang, Bressler, and Beaudet, 2004). ‘Epigenetics’ itself is defined as ‘outside conventional genetics’ (Jaenisch and Bird, 2003). Epigenetic changes are reversible, heritable modifications that are mitotically stable (Skinner, Manikkam, and Guerrero-Bosagna, 2010) and do not involve alterations in the primary DNA sequence (Bird, 2007; Rakyan et al., 2003; Whitelaw and Whitelaw, 2006). This dynamic nature makes the epigenome more responsive to environmental stimuli (Aguilera et al., 2010; Foley et al., 2009; Skinner, 2011; Tang and Ho, 2007). There are three distinct and intertwined mechanisms that are now known to regulate the epigenome: non-coding RNAs (ncRNAs), DNA methylation, and histone modifications (Cheung and Lau, 2005; Esteller, 2005; Morris, 2005). These processes singularly or jointly affect transcript stability, DNA folding, nucleosome positioning, chromatin compaction, and ultimately nuclear organization. They determine whether a gene is silenced or activated and when and where this occurs. Hence, they are known to be essential for normal cell development, maintenance of tissue-specific gene expression patterns in mammals, regulation of genome stability, X-chromosome inactivation, and gene imprinting (Bernstein, Meissner, and Lander, 2007).