Epigenetics and Human Health E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 575

Veröffentlichungsjahr: 2011

Beschreibung

After first introducing the concept of epigenetics, this handbook and ready reference provides an overview of the main research on epigenetics. It adopts a multidisciplinary approach, involving molecular biology, molecular epidemiology and nutritional science, with a special focus of the book is on disease prevention and treatment. Of interest to all healthcare-related professionals as well as nutritionists, and the medical community focusing on disease prevention.

Leseprobe

Contents

Preface

List of Contributors

Part I General Introduction

1 The Research Program in Epigenetics: The Birth of a New ParadigmPaolo Vineis

References

2 Interactions Between Nutrition and HealthIbrahim Elmadfa

2.1 Introduction

2.2 Epigenetic Effects of the Diet

2.3 Current Nutrition Related Health Problems

References

3 Epigenetics: Comments from an EcologistFritz Schiemer

References

4 Interaction of Hereditary and Epigenetic Mechanisms in the Regulation of Gene ExpressionThaler Roman, Eva Aumüller, Carotin Berner, and Alexander C. Haslberger

4.1 Hereditary Dispositions

4.2 The Epigenome

4.3 Epigenetic Mechanisms

4.4 Environmental Influences

4.5 Dietary Effects

4.6 Inheritance and Evolutionary Aspects

4.7 Conclusion

References

Part II Hereditary Aspects

5 Methylenetetrahydrofolate Reductase C677T and A1298C Polymorphisms and Cancer Risk: A Review of the Published Meta-AnalysesStefania Boccia

5.1 Key Concepts of Population-Based Genetic Association Studies

5.2 Methylenetetrahydrofolate Reductase Gene Polymorphisms (C677T and A1298C) and Its Association with Cancer Risk

5.3 Meta-Analyses of Methylenetetrahydrofolate Reductase C677T and A1298C Polymorphisms and Cancer

References

6 The Role of Biobanks for the Understanding of Gene-Environment InteractionsChristian Viertler, Michaela Mayrhofer, and Kurt Zatloukal

6.1 Background

6.2 The Investigation of Gene-Environment Interactions as a Challenge for Biobanks

References

7 Case Studies on Epigenetic InheritanceGunnar Kaati

7.1 Introduction

7.2 Methodology

7.3 Patterns of Transgenerational Responses

7.4 Epigenetic Inheritance

7.5 Future Directions

7.6 Conclusions

References

Part III Environmental and Toxicological Aspects

8 Genotoxic, Non-Genotoxic and Epigenetic Mechanisms in Chemical Hepatocarcinogenesis: Implications for Safety EvaluationWilfried Bursch

8.1 Introduction

8.2 Genotoxic and Non-Genotoxic Chemicals in Relation to the Multistage Model of Cancer Development

8.3 Concluding Remarks

References

9 Carcinogens in Foods: Occurrence, Modes of Action and Modulation of Human Risks by Genetic Factors and Dietary ConstituentsM. Misik, A. Nersesyan, W. Parzefall, and S. Knasmüller

9.1 Introduction

9.2 Genotoxic Carcinogens in Human Foods

9.3 Contribution of Genotoxic Dietary Carcinogens to Human Cancer Risks

9.4 Protective Effects of Dietary Components Towards DNA-Reactive Carcinogens

9.5 Gene Polymorphisms Affecting the Metabolism of Genotoxic Carcinogens

9.6 Concluding Remarks, Epigenetics and Outlook

References

Part IV Nutritional Aspects

10 From Molecular Nutrition to Nutritional Systems BiologyCuy Vergères

10.1 Impact of Life Sciences on Molecular Nutrition Research

10.2 Nutrigenomics 229

10.3 Nutrigenetics

10.4 Nutri-Epigenetics

10.5 Nutritional Systems Biology

10.6 Ethics and Socio-Economics of Modern Nutrition Research

References

11 Effects of Dietary Natural Compounds on DNA Methylation Related to Cancer Chemoprevention and Anticancer Epigenetic TherapyBarbara Maria Stefanska and Krystyna Fabianowska-Majewska

11.1 Introduction

11.2 DNA Methylation Reaction

11.3 Implication of the Selected Natural Compounds in DNA Methylation Regulation

11.4 Conclusions and Future Perspectives

References

12 Health Determinants Throughout the Life CyclePetra Rust

12.1 Introduction

12.2 Pre- and Postnatal Determinants

12.3 Determinants During Infancy and Adulthood

12.4 Determinants in Adults and Older People

12.5 Interactions Throughout the Lifecycle

12.6 Intergenerational Effects

References

Part V Case Studies

13 Viral Infections and Epigenetic Control MechanismsKlaus R. Huber

13.1 The Evolutionary Need for Control Mechanisms

13.2 Control by RNA Silencing

13.3 Viral Infections and Epigenetic Control Mechanisms

13.4 Epigenetics and Adaptive Immune Responses

References

14 Epigenetics Aspects in Gyneacology and Reproductive MedicineAlexander Just and Johannes Huber

References

15 Epigenetics and TumorigenesisHeidrun Karlic and Franz Varga

15.1 Introduction

15.2 Role of Metabolism Within the Epigenetic Network

15.3 Epigenetic Modification by DNA Methylation During Lifetime

15.4 Interaction of Genetic and Epigenetic Mechanisms in Cancer

15.5 DNA Methylation in Normal and Cancer Cells

15.6 Promoter Hypermethylation in Hematopoietic Malignancies

15.7 Hypermethylated Gene Promoters in Solid Cancers

15.8 Interaction DNA Methylation and Chromatin

References

16 Epigenetic Approaches in OncologySabine Zöchbauer-Müller and Robert M. Mader

16.1 Introduction

16.2 DNA Methylation, Chromatin and Transcription

16.3 Methods for Detecting Methylation

16.4 The Paradigm of Lung Cancer

16.5 Epigenetics and Therapy

16.6 Epigenetic Alterations Under Cytotoxic Stress

16.7 Therapeutic Applications of Inhibitors of DNA Methylation

16.8 How May Methylation Become Relevant to Clinical Applications?

16.9 Conclusions

References

17 Epigenetic Dysregulation in Aging and CancerDespina Komninou and John P. Richie

17.1 Introduction

17.2 The Cancer-Prone Metabolic Phenotype of Aging

17.3 Age-Related Epigenetic Silencing Via DNA Methylation

17.4 Inflammatory Control of Age-Related Epigenetic Regulators

17.5 Lessons from Anti-Aging Modalities

17.6 Conclusions

References

18 The Impact of Genetic and Environmental Factors in Neurodegeneration: Emerging Role of EpigeneticsLucia Migliore and Fabio Coppedè

18.1 Neurodegenerative Diseases

18.2 The Role of Causative and Susceptibility Genes in Neurodegenerative Diseases

18.3 The Contribution of Environmental Factors to Neurodegenerative Diseases

18.4 Epigenetics, Environment and Susceptibility to Human Diseases

18.5 Epigenetics and Neurodegenerative Diseases

18.6 The Epigenetic Role of the Diet in Neurodegenerative Diseases

18.7 Concluding Remarks

References

19 Epigenetic Biomarkers in Neurodegenerative DisordersBorut Peterlin

19.1 Introduction

19.2 Epigenetic Marks in Inherited Neurological and Neurodegenerative Disorders

19.3 Epigenetic Dysregulation in Neurodegenerative Disorders

19.4 Gene Candidates for Epigenetic Biomarkers

19.5 Conclusions

References

20 Epigenetic Mechanisms in AsthmaRachel L. Miller and Julie Herbstman

20.1 Introduction

20.2 Epigenetic Mechanisms

20.3 Fetal Basis of Adult Disease

20.4 Fetal Basis of Asthma

20.5 Experimental Evidence

20.6 Epigenetic Mechanisms in Asthma

20.7 Cell-Specific Responses

20.8 Conclusion

References

Part VI Ways to Translate the Concept

21 Public Health Cenomics - Integrating Cenomics and Epigenetics into National and European Health Strategies and PoliciesTobias Schutte in den Baumen and Angela Brand

21.1 Public Health and Cenomics

21.2 The Bellagio Model of Public Health Cenomics

21.3 The Public Health Cenomics European Network

21.4 From Public Health Cenomics to Public Health and Epigenetics/ Epigenomics

21.5 Health in All Policies-Translating Epigenetics/Epigenomics into Policies and Practice

21.6 Health in All Policies as a Guiding Concept for European Policies

21.7 Relative Risk and Risk Regulation - A Model for the Regulation of Epigenetic Risks?

21.8 Attributable Risks and Risk Regulation

21.9 Translating Attributable Risks into Policies

21.10 Limits to the Concept of Health in All Policies in Genomics and Epigenetics

21.11 Conclusion

References

22 Taking a First Step: Epigenetic Health and ResponsibilityAstrid H. Cesche

22.1 Introduction

22.2 Responding to Epigenetic Challenges

22.3 Responsibility and Public Health Care Policy

22.4 Conclusion

References

Index

Related Titles

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The Editor

Dr. Alexander C. HaslbergerUniversity of ViennaDepartment of Nutritional SciencesAlthanstrasse 141090 ViennaAustria

The Co-editorMag. Sabine CresslerBarichgasse 30/4/541030 ViennaAustria

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For Conny

Preface

We all know only too well that our way of life, the food we eat, smoking, stress or environmental toxins influence our health. But we have just started to learn how these environmental factors cooperate with our hereditary genetic dispositions to determine health or the development of diseases.

Moreover, we did not know until recently that all these factors may also influ-ence the health of our children and grandchildren to whom we may transmit functional changes of our genes. Are we really responsible for the well - being of our unborn descendants?

Does nutrition or stress in our early childhood and in our daily life determine functions of genes and tissues by epigenetic mechanisms? And how does this influence change during life affecting ageing and longevity? To what extent is there an inheritance of environmentally acquired characteristics? These are main questions in epigenetics, a new and exciting hot topic in natural sciences linking multiple hereditary and environmental impacts on our health ( http://www.integratedhealthcare.eu ).

It has been noted in an article “Epigenetics: The Science of Change ” of the Environmental Health Perspectives , that interest in epigenetics is increasing “as it has become clear that understanding epigenetics and epigenomics– the genome-wide distribution of epigenetic changes– will be essential in work related to many other topics requiring a thorough understanding of all aspects of genetics, such as stem cells, cloning, aging, synthetic biology, species conservation, evolution, and agri culture” (http://www.ehponline.org/members/2006/114-3/focus.xhtml). Because of this interaction of epigenetics with so many scientific and technological fields, epigenetics will be at the center of public, governmental and scientific interest.

There are now great books available which thoroughly describe mechanisms of epigenetics. The idea for this book was born at a meeting at the University of Vienna where participants from different areas of nutrition, environmental and molecular biology stressed the need of more discussion on concepts towards environmental health interactions between scientists of these disciplines.

Clearly the more optimistic aspect of the possibility to prevent, interfere or even correct epigenetic marks which could result in hazards for diseases, e.g. by dietary concepts or changes of our personal environment and lifestyle, encourages the work in epigenetics. In contrast many results from the analysis of hereditary genetic dispositions can only be respected.

This book picks a transdisciplinary approach focusing on the new understanding of epigenetic and gene - environment interactions for scientific, biomedical, toxicological, environmental, nutritional, evolutionary and regulatory aspects. It focuses on the views of the many exceptional scientists working in these different areas towards epigenetics and health environmental interactions.

The articles in Part I of the book emphasize the interactions between concepts of genetic diversity, epigenetics, environmental health, molecular epidemiology, nutrition and evolution theory. Part II focuses on hereditary aspects, Part III on environmental and toxicological aspects. Part IV extends on nutritional aspects. In Part V the new understanding of epigenetics and environmental health interactions is detailed in case studies of fields such as gynecology, oncology, infectious diseases, asthma, or neurodegenerative diseases. The last Part VI explores concepts to translate the new understanding into public health policies and strategies including principal ethical aspects.

The book is targeted at scientists, environmental, nutritional and health experts, geneticists, experts in science communication, policy makers, experts from standard setting authorities, teachers as well as scientifically experienced consumers interested in interdisciplinary aspects in this area.

The major objective of the book is to strengthen the understanding of interactions between hereditary, genetic and environmental interactions and to bridge gaps which often have evolved between scientific disciplines of molecular, genetic and biotechnological areas on one side and environmental oriented sciences, conservation biology and environmental health on the other.

We thank all the brilliant authors who have contributed, as the summary of their distinguished views on this complex area is the essence of this book.

We do hope that you all enjoy the rather rough ride through the newly emerging and exciting fields of epigenetics!

Vienna, September 2009

Alexander G. Haslberger

Acknowledgment

We thank the Austrian Federal Ministry of Science and Research and the Forum of Austrian Scientists for Environmental Protection ( http://www.fwu.at/english.htm ) for support and many dedicated scientists and colleagues, especially MR Dr. Christian Smoliner for stimulating discussions.

List of Contributors

Eva AumükrUniversity of ViennaDepartment of NutritionalSciencesAlthanstrasse 141090 ViennaAustria

Tobias Schutte in den BaumenMaastricht UniversityEuropean Centre for PublicHealth GenomicsFaculty of HealthMedicine and Life SciencesUniversiteitssingel 40 West6229 ER Maastricht-RandwijckThe Netherlands

Carotin BernerUniversity of ViennaDepartment of NutritionalSciencesAlthanstrasse 141090 ViennaAustria

Stefania BocciaUniversité Cattolica del Sacro CuoreInstitute of HygieneGenetic Epidemiology andMolecular Biology UnitLargo Francesco Vito, 100168 RomeItaly

Angela BrandMaastricht UniversityEuropean Centre for PublicHealth GenomicsFaculty of HealthMedicine and Life SciencesUniversiteitssingel 40 West6229 ER Maastricht-RandwijckThe Netherlands

Wilfried BunchMedical University of ViennaDepartment of MedicineInstitute of Cancer ResearchChemical Safety and CancerPreventionBorschkegasse 8a1090 ViennaAustria

Fabio CoppedèUniversity of PisaDepartment of NeuroscienceVia Roma 6756126 PisaItaly

Ibrahim ElmadfaUniversity of ViennaDepartment of NutritionalSciencesAlthanstrasse 141090 ViennaAustria

Krystyna Fabianowska-MajewskaMedical University of LodzDepartment of BiomedicalChemistryLindleya 690–131 LodzPoland

Ast rid H. CescheUniversity of New EnglandFaculty of Arts and SciencesArmidale, NSW2351Australia

AlexanderC.HaslbergerUniversity of ViennaDepartment of NutritionalSciencesAlthanstrasse 141090 ViennaAustria

Julie HerbstmanColumbia UniversityMailman School of Public HealthDepartment of EnvironmentalHealth Sciences100 Haven Ave #25 FNew York, NY 10032USA

Johannes HuberUniversity Hospital ViennaDepartment of GynecologicalEndocrinology and ReproductiveMedicineWãhringer Giirtel 18–201090 ViennaAustria

Klaus R. HuberDanube Hospital ViennaInstitute of Laboratory MedicineLangobardenstrasse 1221120 ViennaAustria

Alexander JustUniversity Hospital ViennaDepartment of GynecologicalEndocrinology and ReproductiveMedicineWãhringer Giirtel 18–201090 ViennaAustria

Gunnar KaatiUniversity of UmeåDepartment of Public Health andClinical MedicineBuilding 1A90185 UmeaSweden

Heidrun KarlicHanusch HospitalLudwig Boltzmann Institutefor Leukemia ResearchHeinrich Collin Strasse 301140 ViennaAustria

Siegfried KnasmüllerMedical University of ViennaDepartment of MedicineInstitute of CancerResearch Chemical Safety and CancerPreventionBorschkegasse 8A1090 ViennaAustria

Despina KomninouNutrition and DiseasePrevention Center31–11, 31st AvenueLong Island City, NY 11106USA

Robert M. MaderMedical University of ViennaDepartment of MedicineDivision of OncologyWãhringer Giirtel 18–201090 ViennaAustria

Michaela Theresia MayrhoferMedical University of GrazInstitute of PathologyAuenbrugger Platz 258036 GrazAustria

Lucia MigiioreUniversity of PisaDepartment of Human andEnvironmental ScienceVia San Giuseppe 2256126 PisaItaly

Rachel L MillerColumbia UniversityCollege of Physicians and SurgeonsDepartment of MedicineDivision of Pulmonary Allergyand Critical Care Medicine630 West 168th StreetNew York, NY 10032USA

Miroslav MisikMedical University of ViennaDepartment of MedicineInstitute of Cancer ResearchChemical Safety and CancerPreventionBorschkegasse 8A1090 ViennaAustria

Armen NersesyanMedical University of ViennaDepartment of MedicineInstitute of Cancer ResearchChemical Safety and CancerPreventionBorschkegasse 8A1090 ViennaAustria

Wolfram ParzefallMedical University of ViennaDepartment of MedicineInstitute of Cancer ResearchChemical Safety and Cancer PreventionBorschkegasse 8A1090 ViennaAustria

Borut PeterlinUniversity Medical CenterLjubljanaInstitute of Medical GeneticsDepartment of Obstetrics andGynecologySlajmerjeva 31000 LjubljanaSlovenia

John P. RichiePennsylvauia State UniversityCollege of MedicineDepartment of Public HealthSciences500 University DriveHershey, PA 17033USA

Thaler RomanUniversity of ViennaDepartment of NutritionalSciencesAlthanstrasse 141090 ViennaAustria

Petra RustUniversity of ViennaDepartment of NutritionalSciencesAlthanstrasse 141090 ViennaAustria

Fritz SchiemerUniversity of ViennaCenter for EcologyAlthanstrasse 141090 ViennaAustria

Barbara Maria StefanskaMedical University of LodzDepartment of Biomédical ChemistryLindleya 690–131 LodzPoland

Franz VargaHanusch HospitalLudwig Boltzmann Institute ofOsteologyHeinrich Collin Strasse 301140 ViennaAustria

Guy VergèresFederal Department of EconomicsAffairsAgroscope Liebefeld-PosieuxResearch StationSchwarzenburgstrasse 1613003 BerneSwitzerland

Christian ViertlerMedical University of GrazInstitute of PathologyAuenbrugger Platz 258036 GrazAustria

Paolo MinéisImperial College LondonMRC Centre for Environmentand HealthSt Mary’s CampusNorfolk PlaceLondon W2 1PGUK

Kurt ZatloukalMedical University of GrazInstitute of PathologyAuenbrugger Platz 258036 GrazAustria

Sabine Zöchbauer-MüllerMedical University of ViennaDepartment of MedicineDivision of OncologyWahringer Giirtel 18–201090 ViennaAustria

Part I

General Introduction

1

The Research Program in Epigenetics: The Birth of a New Paradigm

Paolo Vineis

Abstract

This introductory chapter sketches a short history of the concept of epigenetics, from Waddington to today. The chapter outlines the promises associated with the development of epigenetic research, particularly in the field of cancer, and the still unmet challenges, with several examples.

The recent discovery that humans and chimpanzees have essentially the same DNA sequence is simply revolutionary. The obvious question is “why then do they differ so widely”? Obviously, there is something else other than the DNA sequence that explains differences among species. An even more revolutionary advancement could then be the discovery that what makes the difference is a certain pattern of methylation of CpG islands in key genes, for example for the olfactory receptors in chimpanzees (unmethylated) and for brain development in humans. Though this is still speculation, there are great expectations from epigenetics/omics to fill the gaps left by genetics/omics.

If we consider Thomas Kuhn’s description of the advancement of science through a sequence of revolutions (leading to paradigmatic leaps), we can probably conclude that epigenetics is definitely a new paradigm. According to Kuhn there are several ways in which a new paradigm arises. Usually this implies a more or less profound crisis of the existing theory, the development of alternative theories–without sound observations yet–and possibly a technological leap forward. These three conditions hold for the shift from genetics to epigenetics, though not necessarily in the order I have suggested.

In a way, a theoretical model for epigenetics (the one by Waddington, who coined the term) came first historically, when genetics was still flourishing. Then several signs of crisis emerged, and now the technological developments allow one to study epigenetic changes properly. To be clear, when I say that the genetic paradigm is in a crisis, this may seem at odds with the successes of genome-wide association studies (GWAS) in 2007–2008. In fact, by crisis I mean (i) the obvious gap–referred to above–between DNA sequencing and the ability to explain, for example, differences between species; and (ii) the emerging failures of the paradigm that until very recently strictly separated genes from the environment, according to the neo-Darwinian view. On the one hand we had the environmental exposures, that could cause somatic mutations, or cause chronic diseases by several mechanisms not involving DNA. On the other hand, we had inherited variation, but the link between the two was not straightforward. Recently, to fill the gap the theory of gene–environment interactions (GEI) was coined, with not much success, or at least not the kind of success that was expected. Not many good examples of hona fide GEI are available today. Ten years ago, for example, people expected that variants in DNA repair could explain much of cancer variation, in particular in relation to exposure to carcinogens, but a recent synopsis on DNA repair variants in cancer done by us [1] showed surprisingly few associations. Also GWAS led to the discovery of not many variants strongly associated with cancer (with relative risks usually lower than 1.5). In addition, the patterns of association were rather unusual with some regions or SNP associated with several cancers or several diseases, like in the case of 5pl5 [2]. Ironically, for 8q24 not only have multiple associations been found, but also the implicated regions are non-coding regions, shedding light probably on some regulatory mechanisms involved, that is, exactly epigenetics.

Well before the gene–environment divide fell into a crisis, Waddington coined his theory of phenotypic plasticity and epigenetics. Waddington referred to epigenetics as an amalgam between genetics and epigenesis, where the latter is the progressive development of new structures. Waddington related epigenetics very much to embryonic development, and put forward the idea that the latter is not entirely due to the “program” encoded in DNA, but depends on environmental influences [3]. His definition of epigenetics is extremely modern: “the causal interactions between genes and their products, which bring the phenotype into being”, that echoes a contemporary definition: “the inheritance of DNA activity that does not depend on the naked DNA sequence” [4].

Coming to the present time, the study of epigenetics has definitely been enabled by recent technological advancements, that allow us to investigate DNA methylation, histone acetylation, RNA interference, chromatine formation and other signs of epigenetic events.

What is new in this paradigm? First, it refers not to structural but to functional changes in DNA (gene regulation). Second, we are observing continuous quantitative changes, that is, nature seems to work in degrees, not according to leaps like mutations: the ratio between hypo- and hyper-methylation, for example, seems to be very relevant to cancer. Third, epigenetic changes are reversible: as some chapters in this book show, nice animal experiments have been conducted with dietary supplements that were able to reverse methylation patterns. Fourth, epigenetic patterns seem to be heritable (though this may be the weakest part, since the evidence is not entirely persuasive). Fifth, epigenetic changes fill the gap between genes and the environment: the mysterious relationships between (spontaneous) heritable mutations and selection in neo-Darwinian theory may be overcome by a more sophisticated paradigm that resembles Lamarck’s research program–but of course we have to be cautious. Sixth, a successful new theory according to Popper, Lakatos and Kuhn is one that explains unexplained findings in the previous theory and is able to predict new findings.

Are we already in the position to say that the epigenetic theory is able to overcome the old divide between genetics and the environment? I am not aware of any prediction made by epigenetics on theoretical grounds that was subsequently verified, but we can wait. One good candidate is what I said at the start about humans and chimpanzees.

To be sure, some recent research involving epigenetics is extremely promising [5]. In addition to the studies mentioned above, it is worth mentioning the fact that Inuit populations exposed to persistent organic pollutants (POPs) also had detectable hypomethylation of their DNA [6]; this kind of investigation can prove very effective in finding a link between low-level environmental exposures and the risk of disease, through the investigation of sensitive intermediate markers. Exposures that have been found to interact with “metastable epialleles” are, for example, genistein, a component of diet that seems to protect from epigenetic damage, the drug valproic acid, arsenic, and of course vinclozoline (see the current book). But the research is just in its infancy, and many more examples are likely to follow.

In addition to clarifying the relationships between genes and the environment, there is a further dimension in epigenetics, that is the fact that it may explain a feature of evolution that has been slightly neglected, except in developmental studies: self-organization of the living being. In fact a modern theory of evolution should encompass two big chapters, both the selection–adaptation component, and the self-organization component (the latter very often overlooked). This is in fact a promising component of the new revolutionary paradigm of epigenetics; for example, one might speculate that cancer is explained by a Darwinian paradigm (since it is due to selective advantage of mutated/epimutated cells) [7] but without the self-organization element that has characterized the evolution of organisms and species.

The next years will probably show the ability of the new paradigm to explain unexplained findings, and to make correct predictions.

References

1 Vineis, P., Manuguerra, M., Kavvoura, F.K., Guarrera, S., Allione, A., Rosa, F., Di Gregorio, A., Polidoro, S., Saletta, F., Ioannidis, J.P., and Matullo, G. (2009) A field synopsis on low-penetrance variants in DNA repair genes and cancer susceptibility. J. Natl. Cancer Inst., 101 (1), 24–36.

2 Rafnar, T., Sulem, P., Stacey, S.N., Geller, F., Gudmundsson, J., Sigurdsson, A., Jakobsdottir, M., Helgadottir, H., Thorlacius, S., Aben, K.K., Blöndal, T., Thorgeirsson, T.E., Thorleifsson, G., Kristjansson, K., Thorisdottir, K., Ragnarsson, R., Sigurgeirsson, B., Skuladottir, H., Gudbjartsson, T., Isaksson, H.J., Einarsson, G.V., Benediktsdottir, K.R., Agnarsson, B.A., Olafsson, K., Salvarsdottir, A., Bjarnason, H., Asgeirsdottir, M., Kristinsson, K.T., Matthiasdottir, S., Sveinsdottir, S.G., Polidoro, S., Höiom, V., Botella-Estrada, R., Hemminki, K., Rudnai, P., Bishop, D.T., Campagna, M., Kellen, E., Zeegers, M.P., de Verdier, P., Ferrer, A., Isla, D., Vidal, M.J., Andres, R., Saez, B., Juberias, P., Banzo, J., Navarrete, S., Tres, A., Kan, D., Lindblom, A., Gurzau, E., Koppova, K., de Vegt, F., Schalken, J.A., van der Heijden, H.F., Smit, H.J., Termeer, R.A., Oosterwijk, E., van Hooij, O., Nagore, E., Porru, S., Steineck, G., Hansson, J., Buntinx, F., Catalona, W.J., Matullo, G., Vineis, P., Kiltie, A.E., Mayordomo, J.I., Kumar, R., Kiemeney, L.A., Frigge, M.L., Jonsson, T., Saemundsson, H., Barkardottir, R.B., Jonsson, E., Jonsson, S., Olafsson, J.H., Gulcher, J.R., Masson, G., Gudbjartsson, D.F., Kong, A., Thorsteinsdottir, U., and Stefansson, K. ( 2009 ) Sequence variants at the TERT -CLPTM1L locus associated with many cancer types . Nat. Genet., 41 (2), 221–227.

3 Feinberg, A.P. (2007) Phenotypic plasticity and the epigenetics of human diseases . Nature, 447, 433–440.

4 Esteller, M. (2008) Epigenetics in evolution and disease . Lancet, 372, S90–S96.

5 Jirtle, R.L., and Skinner, M.K. (2007) Environmental epigenomics and disease susceptibility. Nat. Rev. Genet., 8, 253–262.

6 Rusiecki, J.A., Baccarelli, A., Bollati, V., Tarantini, L., Moore, L., and Bonefeld-Jorgensen, E.C. (2008) Global DNA hypomethylation is associated with high serum-persistent organic pollutants in Greenlandic Inuits . Environ. Health Perspect., 116, 1547–1552.

7 Vineis, P., and Berwick, M. (2006) The population dynamics of cancer: a Darwinian perspective. Int. J. Epidemiol., 35 (5), 1151–1159.

2

Interactions Between Nutrition and Health

Ibrahim Elmadfa

Abstract

Nutrition is a major contributor to health providing the organism with the energy, essential nutrients and biologically active plant cell components necessary for its maintenance and proper functioning. More recently, food components have also been discovered as regulators of a number of physiological pathways often involving their own metabolism. This regulation is to a large extent mediated via gene expression in which epigenetic effects play an important part. Methylation of DNA is a major regulatory mechanism in the transcription of genes and is influenced by food components providing methyl groups. Due to the universality of this mechanism and depending on the genes and tissues involved, alterations of DNA methylation can have a number of consequences. There is evidence that they play a role in the development of certain cancer types that are related to exposure to carcinogens. Epigenetic alterations of gene expression were also shown to be involved in some animal models of obesity. As many of these changes are inheritable, the diet of the parents could have a far-reaching influence on their offspring and possibly contribute to the recent rise in the prevalence of overweight and related metabolic diseases.

In light of the impact of nutrition on gene regulation, molecular approaches will contribute to our understanding of the relationship between nutrition and health.

2.1 Introduction

The close relationship between nutrition and health is not a recent discovery. In fact, the deep impact of food on health has been known for centuries and even millennia. However, knowledge about the effects of health status on the metabolism of food is more recent. Insights in genetic make-up and regulations show that alterations in nutrient processing are not necessarily restricted to certain diseases but can also occur in healthy subjects. Epigenetic modifications are important determinants of such variances and can be influenced by food and nutrient intake beside other environmental factors.

2.2 Epigenetic Effects of the Diet

The pathways of nutrient metabolism are encoded in the genes. Hence, mutations can lead to disturbances in the breakdown of a certain compound, as is the case in galactose or fructose intolerance. However, the regulation of gene expression is as important and is directly influenced by dietary components. A well-known example for the epigenetic effects of a nutrient is the methylation of DNA, a major regulatory mechanism, by methyl group donors like folie acid, vitamin Bi2, betain and choline. It was shown that, in mice, supplementation of these nutrients to pregnant dams had an influence on the offspring, manifesting in alterations of the coat color [1].

2.3 Current Nutrition Related Health Problems

In wealthy societies, the major health problems arising from nutrition are overweight and obesity. Both have been increasing at an alarming rate for the past 50 years. While unlimited access to food provides the residents of industrialized nations with the necessary energy sources, this wide choice is not the only cause of increased body weight. Lack of physical activity is another important contributor. However, although both account for the majority of cases of overweight, additional factors play a role. As the increase in obesity has occurred very rapidly, changes in the genome itself are unlikely. Therefore, epigenetic modifications might be involved. Maternal obesity and nutrition may lead to epigenetic modifications that establish overweight in the infant as well [2]. For example, hypomethyl-ation of the agouti gene in mice causes an over-expression of the agouti protein that, by binding antagonistically to the melanocortin receptor (MCR) 4, induces hyperphagia [3]. Differences in gene expression were also observed between low and high weight gainers in a diet-induced obesity study in mice [4, 5].

There is evidence that diseases associated with obesity, like cardiovascular diseases and diabetes mellitus type II, also have epigenetic backgrounds [6, 7]. Thus, a subject’s exposure to food scarcity correlated with a lower risk for cardiovascular death and diabetes mellitus in his grandchildren. Interestingly, this legacy was transmitted through the male line [8].

The role of epigenetic modifications in cancer development is well established. Altered methylation patterns are observed in many tumors with hypo- and hyper-methylation occurring at the same time. This methylation is partly influenced by nutritional factors. Notably, hypermetliylation is particularly frequent in gastrointestinal tumors and this may be related to exposure to carcinogens [9, 10].

Nutrition has an important influence on health and disease. While this knowledge is not new, novel technologies allow insights into the mechanisms behind this relationship revealing nutrients not only as building material for body tissues and co-factors of enzymes butas modulators of gene expression. The involvement of epigenetic events is supported by the apparent heredity of certain diet-related diseases.

Understanding the influence of an individual’s genetic make-up on the metabolism of nutrients and of nutrients on gene regulation presents a great challenge to modern nutritional scienctists. Molecular genetic approaches have found their way into research in nutritional sciences adding to its interdisciplinarity. Applied nutrition and dietetics will be increasingly shaped by the emerging field of nutri-genetics and nutrigenomics. In this sense, the following chapters are meant to give an overview of the plethora of health conditions that are influenced by the interplay of nutrition and the genome.

References

1 Cropley, J.E., Suter, C.M., Beekman, K.B., and Martin, D.I. (2006) Germ-line epigenetic modification of the murine A vy alíele by nutritional supplementation. Proc. Nati. Acad. Sri. USA,103, 17308–17312.

2 Waterland, R.A., and Michels, K.B. (2007) Epigenetic epidemiology of the developmental origins hypothesis. Annu. Rev. Nutr., 27, 363–388.

3 Wolff, G.L., Roberts, D.W., and Mountjoy, K.G. (1999) Physiological consequences of ectopic agouti gene expression: the yellow obese mouse syndrome. Physiol. Genomics, 1, 151–163.

4 Samama, P., Rumennik, L, and Grippo, J.F. (2003) The melanocortin receptor MCR4 controls fat consumption. Regid. Pept.,113, 85–88.

5 Koza, R.A., Nikonova, L, Hogan, J., Rim, J.S., Mendoza, T., Faulk, C, Skaf, J., and Kozak, LP. (2006) Changes in gene expression foreshadow diet-induced obesity in genetically identical mice. PIoS Genet.2, e81.

6 Lund, G., Andersson, L, Lauria, M., Lindholm, M., Fraga, M.F., Villar-Garea, A., Ballestar, E., Esteller, M., and Zaina, S. (2004) DNA methylation polymorphisms precede any histological sign of atherosclerosis in mice lacking apolipoprotein E. J. Eiol. Chem., 279, 29147–29154.

7 Wren, J.D., and Garner, H.R. (2005) Data-mining analysis suggests an epigenetic pathogenesis for type 2 diabetes. J. Eiomed. Eiotechnol., 2, 104–112.

8 Kaati, G., Bygren, L.O., and Edvinsson, S. (2002) Cardiovascular and diabetes mortality determined by nutrition during parents’ and grandparents’ slow growth period. Eur. J. Hum. Genet., 2, 682–688.

9 Lopez, J., Percharde, M., Coley, H.M., Webb, A., and Crook, T. (2009) The context and potential of epigenetics in oncology. Er. J. Cancer,100, 571–577.

10 Nyström, M., and Mutanen, M. (2009) Diet and epigenetics in colon cancer. World J. Gastroenterol, 15, 257–263.

3

Epigenetics: Comments from an Ecologist

Fritz Schiemer

Abstract

The “Comments from an Ecologist” are based on the results of a workshop initiated by the “Forum of Austrian Scientists for Environmental Protection”. It emphasizes epigenetics as a main research priority for an improved understanding of the interactions between human societies and their environment.

In 2004 Leslie Pray summarized new scientific findings in the area of epigenetics [1] saying that the environmental lability of epigenetic inheritance may not necessarily bring to mind Lamarckian ideas but it does give researchers reason to reconsider long-refuted notions about the inheritance of acquired characteristics.