Integrating Epigenetics, Medicine, and Evolution Scott F. Gilbert David Epel Swarthmore College Hopkins Marine Station, Stanford University Sinauer Associates, Inc. • Publishers Sunderland, Massachusetts U.S.A. © Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written permission from the publisher. Brief Contents PART 1 Environmental Signals and Normal Development CHAPTER 1 The Environment as a Normal Agent in Producing Phenotypes 3 CHAPTER 2 How Agents in the Environment Effect Molecular Changes in Development 37 CHAPTER 3 Developmental Symbiosis: Co-Development as a Strategy for Life 79 CHAPTER 4 Embryonic Defenses: Survival in a Hostile World 119 PART 2 Ecological Developmental Biology and Disease States CHAPTER 5 Teratogenesis: Environmental Assaults on Development 167 CHAPTER 6 Endocrine Disruptors 197 CHAPTER 7 The Epigenetic Origin of Adult Diseases 245 PART 3 Toward a Developmental Evolutionary Synthesis CHAPTER 8 The Modern Synthesis: Natural Selection of Allelic Variation 289 CHAPTER 9 Evolution through Developmental Regulatory Genes 323 CHAPTER 10 Environment, Development, and Evolution: Toward a New Synthesis 369 CODA Philosophical Concerns Raised by Ecological Developmental Biology 403 APPENDIX A Lysenko, Kammerer, and the Truncated Tradition of Ecological Developmental Biology 421 APPENDIX B The Molecular Mechanisms of Epigenetic Change 433 APPENDIX C Writing Development Out of the Modern Synthesis 441 APPENDIX D Epigenetic Inheritance Systems: The Inheritance of Environmentally Induced Traits 447 © Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written permission from the publisher. Contents PART 1 Environmental Signals and Normal Development CHAPTER 1 The Environment as a CHAPTER 2 How Agents in the Normal Agent in Producing Phenotypes 3 Environment Effect Molecular Changes in Development 37 Plasticity Is a Normal Part of Development 6 BONELLIA VIRIDIS: WHEN THE ENVIRONMENT Regulation of Gene Transcription 38 DETERMINES SEX 6 Differential gene expression 38 A century of studies 7 DNA methylation 42 A contextually integrated view of life 8 Environmental agents and direct DNA “Eco-Devo” and Developmental Plasticity 9 methylation 43 Reaction norms and polyphenisms 11 The effects of maternal behavior on gene Epigenetics 12 methylation 44 Agents of developmental plasticity 13 Signal Transduction from Environment to Temperature-Dependent Phenotypes 13 Genome via the Neuroendocrine System 46 Enzyme activity as a function of temperature 13 VERNALIZATION: TEMPERATURE-DEPENDENT CHROMATIN CHANGES 47 Seasonal polyphenism in butterflies 16 Neuroendocrine regulation of temperature- Temperature and sex 17 dependent polyphenism in insects 49 Nutritional Polyphenism: What You Eat Becomes Neuroendocrine regulation of sex determi- You 20 nation 51 Royal jelly and egg-laying queens 20 SEX, AROMATASE, AND CONSERVATION BIOLOGY 54 Horn length in the male dung beetle 21 An extreme phenotype for extreme times: Gravity and Pressure 23 Stress and cannibalism 57 Predator-Induced Polyphenisms 26 “We will pump you up”: Muscle hypertrophy 59 Predator-induced polyphenism in inverte- ANABOLIC STEROIDS 62 brates 27 Signal Transmission from Environment to Predator-induced polyphenism in Genome through Direct Induction 64 vertebrates 27 Microbial induction of gene expression in The Presence of Conspecifics: It’s Who You vertebrate intestines 64 Know 29 Microbial induction of the vertebrate immune A swarm of locusts: Polyphenism through response 65 touch 30 Transgenerational Effects 67 POLYPHENISMS AND CONSERVATION BIOLOGY 31 Transgenerational polyphenism in locusts 68 Sexual polyphenism by the community Transgenerational predator-induced environment 32 polyphenisms 68 Convergence on Favorable Phenotypes 32 Methylation and transgenerational continuity: Summary 32 Toadflax 70 References 33 Methylation and transgenerational continuity: Mice and rats 71 Summary 74 References 74 © Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written permission from the publisher. viii Contents CHAPTER 3 Developmental Symbiosis: CHAPTER 4 Embryonic Defenses: Survival Co-Development as a Strategy for Life 79 in a Hostile World 119 Symbiosis: An Overview 80 Characteristics of Embryo Defense 122 The “Grand” Symbioses 81 Developmental robustness: A necessary but Nitrogen-fixing nodules 81 paradoxical defense 122 ENDOPHYTES 83 Early embryonic cells differ from adult cells 125 Mycorrhizae 83 SPECULATIONS ON CELL DEFENSES IN EARLY Life Cycle Symbioses 85 DEVELOPMENT 127 THE LARGE BLUE BUTTERFLY 86 Strategies for Embryo Defense 129 Getting Symbionts Together with Their Hosts 87 Strategy 1: Induced polyphenism 129 The Squid and the Microbe: A Paradigm of Strategy 2: Parental protection 129 Symbiont Influence 89 Strategy 3: Dormancy and diapause 130 Evolution of the Symbiotic Regulation of THE DAUERLARVA OF C. ELEGANS 132 Development: Wolbachia 91 Strategy 4: Defense physiologies 133 Sex determination by infection 92 A general strategy: “Be prepared” 134 Evolution of dependence on Wolbachia for sex- ual development 95 Mechanisms of Embryo Defense 134 MUTUALISTIC CONSORTIA 97 Protection against Toxic Substances 135 The Mutualistic Bacteria of the Mammalian Gut The general plan: “Bouncers,” “chemists,” and 98 “policemen” 135 Toxic metals 138 Introduction to the gut microbiota 98 Problems with metal detoxification 140 Maintaining the gut microbial community: The biofilm model 99 Protection against Physical Damage 141 Inheritance of the gut bacteria 100 Shells and extracellular coats 141 Gut Bacteria and Normal Mammalian Cytoplasmic sealing 145 Development 101 Protection against Oxidative Damage 147 An important role for symbiotic bacteria in the Protection against Damage to DNA 150 normal development of the host’s gut: Sunscreens prevent DNA damage 150 Angiogenesis induction 101 Repairing damaged DNA 153 The impact of symbiotic gut bacteria on the Protection against Pathogens 154 development of the host immune system: Antimicrobial secretions 103 Parental behavior 155 Chemical protection 155 IMMUNITY THROUGH DEVELOPMENTAL SYMBIOSIS 104 Embryonic immune responses 155 B lymphocytes and the GALT 105 Symbiosis and protection from fungi 156 IMMUNE SYSTEM CELL TYPES 105 Protection from Predation 158 Gut Bacteria Symbiosis and Human Health 107 Summary 160 Bacterial regulation of the immune response References 161 107 The role of the gut bacteria in fat storage: Implications for human obesity 110 Further implications of the enteric gut bacteria for human health 112 Summary 114 References 115 © Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written permission from the publisher. Contents ix PART 2 Ecological Developmental Biology and Disease States CHAPTER 5 Teratogenesis: Environmental Plastics and Plasticity 220 Assaults on Development 167 Bisphenol A 221 The dose-response curve of BPA action 225 Medical Embryology and Teratology 168 The molecular biology of the BPA effect 226 Wilson’s principles of teratology 169 Epigenetic effects of BPA 228 Thalidomide and the window of Polychlorinated biphenyls 229 susceptibility 170 Possible mechanisms for the effects of PCBs 230 Teratogenic Agents 172 Transgenerational Effects of Endocrine Chemical teratogens: Industrial mercury and Disruptors 230 Minamata disease 172 Summary 233 Alcohol as a teratogen 173 REGULATORY AND POLICY DECISIONS ON BPA Retinoic acid 180 AND OTHER ENDOCRINE DISRUPTORS 234 TERATOGENS AND COGNITIVE FUNCTION 182 References 237 Other teratogenic agents 183 Natural Killers: Teratogens from Plants 185 CHAPTER 7 The Epigenetic Origin of Veratrum alkaloids 185 Adult Diseases 245 Plant juvenile hormones 187 Deformed Frogs: A Teratological Enigma 189 The Developmental Origins of Health and Disease 246 A combination of factors 189 The radiation hypothesis 190 Instructing the Fetus 247 Pesticides and herbicides 190 Maternal-fetal co-development 248 CONSERVATION BIOLOGY: SAVING THE FROGS 191 Fetal plasticity in humans 250 Summary 191 Gene methylation and the fetal phenotype 253 References 192 Predictive Adaptive Responses 256 The environmental mismatch hypothesis 260 CHAPTER 6 Endocrine Disruptors 197 Environment-genotype interactions in diabetes 263 The Nature of Endocrine Disruptors 198 PATERNAL EPIGENETIC EFFECTS 264 The endocrine disruptor hypothesis 199 Developmental Plasticity and Public Health 266 DDT: The start of it all 200 Aging and Cancer as Diseases of Epigenesis 267 ESTABLISHING A CHAIN OF CAUSATION 202 Epigenetic Methylation, Disease, and Aging 267 Estrogen and Endocrine Disruptors 203 Evidence from identical twins 268 The structure and mechanisms of estrogen Aging and random epigenetic drift 270 receptors 204 Epigenetic Origins of Cancer 273 Diethylstilbestrol 206 Cancer as caused by altered epigenetic methy- Mechanisms of DES action 208 lation 274 Soy estrogens 212 The reciprocity of epigenetic and genetic cau- Declining sperm counts and testicular dysgen- sation in cancer 277 esis syndrome 213 The tissue organization field hypothesis 278 Pesticides and infertility in males 215 Summary 283 SENSITIVITY TO DISRUPTION: A GENETIC References 283 COMPONENT 216 Atrazine, again 217 © Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written