THE EPIGENOME AND DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE Edited by Cheryl S Rosenfeld AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, UK 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 225 Wyman Street, Waltham, MA 02451, USA The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK Copyright © 2016 Elsevier Inc All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein) Notices Knowledge and best practice in this field are constantly changing As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein ISBN: 978-0-12-801383-0 British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress For information on all Academic Press publications visit our website at http://store.elsevier.com/ Typeset by TNQ Books and Journals www.tnq.co.in Printed and bound in the United States of America Dedication I dedicate this book to my father, Robert L ­Rosenfeld, who passed away on February 5, 2005 From early childhood onwards, he ­encouraged me to pursue my interests in science and medicine and taught me that a good start and supportive environment can last a lifetime List of Contributors Roger Brown  School of Nursing, University of Wisconsin-Madison, Madison, WI, USA Sara Fneich  INRA, UMR1198 Biologie du Développement et Reproduction, Jouy-en-Josas, France Tatjana Buklijas  Liggins Institute, The University of Auckland, Auckland, New Zealand Anne Gabory  INRA, UMR1198 Biologie du Développement et Reproduction, Jouy-en-Josas, France Douglas T Carrell  Department of Surgery (Urology), University of Utah School of Medicine, Salt Lake City, UT, USA Jeffrey S Gilbert  Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA Vivette Glover  Institute of Reproductive and Development Biology, Imperial College London, London, UK Mei-Wei Chang  Michigan State University College of Nursing, East Lansing, MI, USA Ana Cheong  Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, USA Quetzal A Class  Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA Jane K Cleal  Institute of Developmental Sciences, University of Southampton, Southampton, UK James S.M Cuffe  School of Biomedical Science, The University of Queensland, St Lucia, QLD, Australia Elysia Poggi Davis  Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA; Department of Psychology, University of Denver, Denver, CO, USA Rodney R Dietert  Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA M Jean Brancheau Egan  Michigan Department of Community Health, WIC Division, Lansing, MI, USA Kobra Eghtedary  Michigan Department of Community Health, WIC Division, Lansing, MI, USA Tom P Fleming  Centre for Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK Peter D Gluckman  Liggins Institute, The University of Auckland, Auckland, New Zealand Laura M Glynn  Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA; Department of Psychology, Chapman University, Orange, CA, USA Amrie C Grammer  University of Virginia Research Park, VA, USA Carlos Guerrero-Bosagna  Avian Behavioral Genomics and Physiology Group, IFM Biology, Linköping University, Linköping, Sweden Mark A Hanson Institute of Developmental Sciences, University of Southampton and NIHR ­ Nutrition Biomedical Research Centre, University Hospital Southampton, Southampton, UK Shuk-Mei Ho  Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, USA; Cincinnati Cancer Center, Cincinnati, OH, USA; Cincinnati Veteran Affairs Medical Center, Cincinnati, OH, USA Vinothini Janakiram  Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, USA xiii xiv LIST OF CONTRIBUTORS Timothy G Jenkins Department of Surgery (Urology), University of Utah School of Medicine, Salt Lake City, UT, USA Claudine Junien  INRA, UMR1198 Biologie du Développement et Reproduction, Jouy-en-Josas, France J.P Lallès Institut National de la Recherche Agronomique, UR1341 ADNC, Saint Gilles, France; Centre de Recherche en Nutrition Humaine-Ouest, Nantes, France Yuet-Kin Leung  Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, USA; Cincinnati Cancer Center, Cincinnati, OH, USA Rohan M Lewis  Institute of Developmental Sciences, University of Southampton, Southampton, UK Michele Loi  Centro de Estudos Humanísticos, Universidade Minho, Campus de Gualtar, Braga, Portugal C Michel  Centre de Recherche en Nutrition Humaine-Ouest, Nantes, France; Institut National de la Recherche Agronomique/Université de Nantes, UMR1280, Nantes, France; Institut des Maladies de l’Appareil Digestif, Nantes, France Karen M Moritz  School of Biomedical Science, The University of Queensland, St Lucia, QLD, Australia Kristin E Murphy Department of Surgery (Urology), University of Utah School of Medicine, Salt Lake City, UT, USA Susan Nitzke  Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA Marianna Nobile Universita’ degli Studi di Milano-Bicocca, Dipartimento dei Sistemi Giuridici, Milano, Italy Kieran J O’Donnell  The Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental University Institute, McGill University, Montreal, QC, Canada Polina Panchenko  INRA, UMR1198 Biologie du Développement et Reproduction, Jouy-en-Josas, France Sara E Pinney  Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA Ken Resnicow  University of Michigan School of Public Health, University of Michigan, Ann Arbor, MI, USA Lynette K Rogers  Center for Perinatal Research, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio Cheryl S Rosenfeld  Department of Bond Life Sciences Center, Department of Biomedical Sciences, Genetics Area Program, Thompson Center for Autism and Neurobehavioral Disorders, University of Missouri, Columbia, MO, USA Lewis P Rubin  Department of Pediatrics, Texas Tech University Health Sciences Center El Paso, Paul L Foster School of Medicine, El Paso, TX, USA Curt A Sandman  Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA J.P Segain  Centre de Recherche en Nutrition Humaine-Ouest, Nantes, France; Institut National de la Recherche Agronomique/Université de Nantes, UMR1280, Nantes, France; Institut des Maladies de l’Appareil Digestif, Nantes, France Congshan Sun  Centre for Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK Martha Susiarjo  Department of Cell and Developmental Biology, Perelman School of ­Medicine, University of Pennsylvania, Philadelphia, PA, USA Pheruza Tarapore  Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, USA; Cincinnati Cancer Center, Cincinnati, OH, USA V Theodorou  Institut National de la Recherche Agronomique, UMR Toxalim, Toulouse, France Sarah To  Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA Steve Turner  Child Health, Royal Aberdeen Children’s Hospital, Aberdeen, UK LIST OF CONTRIBUTORS Mehmet Uzumcu  Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA Miguel A Velazquez  Centre for Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK Markus Velten  Department of Anesthesiology and Intensive Care Medicine, Rheinische FriedrichWilhelms-University Bonn, Germany xv Sarah Voisin  INRA, UMR1198 Biologie du Développement et Reproduction, Jouy-en-Josas, France Sarah L Walton  School of Biomedical Science, The University of Queensland, St Lucia, QLD, Australia Aparna Mahakali Zama  Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA Acknowledgments This book would not have been possible without all of the coauthors who kindly shared their knowledge and passion for the various areas Ms Lisa Eppich and Ms Catherine A Van Der Laan at Elsevier were integral in making this book come to life The concept of developmental origins of health and disease (DOHaD) was first clearly articulated by the late Sir David Barker It was thus appropriate that it was originally termed the “Barker hypothesis” but subsequently changed to “fetal origin of adult disease (FOAD),” and most recently to “developmental origins of adult health and disease.” Since its conception, the DOHaD concept has gained currency and led to paradigm shifts in how scientists and clinicians view a variety of noncommunicable diseases Correspondingly, it has paved the way for new avenues of diagnosis, prevention, and treatment strategies I am grateful to the many teachers, mentors, colleagues, and friends who along the way fostered my interests and curiosity in science and medicine In particular, I am grateful to the late Mrs Patricia Murphy whose enthusiasm and wonderment for biology were contagious My PhD mentor, Dr Dennis Lubahn, was incredibly supportive of me and my research ideas The lessons I learned in his laboratory have stayed with me all of these years Most of all, I am thankful to Dr R Michael Roberts For over 20 years, he has been a wonderful mentor, colleague, and friend I am thankful to Dr Deborah Wagner, my friend and former classmate, for allowing me over various holidays to serve as a relief veterinarian at her animal hospital As veterinary students, we made a “Forrest Gump” pact that if she were to ever open her animal hospital, I would be her first mate It has been rewarding to be able to indulge my veterinary interests and keep in touch with advances in clinical medicine These experiences have helped shape my thinking and research directions Finally, I am grateful to my mother, sister, brother, nieces and nephews, and other family members who walk on two and four legs xvii Cheryl S Rosenfeld C H A P T E R The Developmental Origins of Health and Disease (DOHaD) Concept: Past, Present, and Future Peter D Gluckman1, Tatjana Buklijas1, Mark A Hanson2 1Liggins Institute, The University of Auckland, Auckland, New Zealand; 2Institute of Developmental Sciences, University of Southampton and NIHR Nutrition Biomedical Research Centre, University Hospital Southampton, Southampton, UK O U T L I N E Introduction1 The Wider DOHaD Research Agenda The Origins of the Field DOHaD and Public Policy Conceptual Developments and Experimental Observations5 DOHaD and Epigenetics 10 References11 INTRODUCTION preconceptional, prenatal, and/or early postnatal periods The emphasis has been on obesity, type diabetes mellitus, and cardiovascular disease, but a significant body of work has also been focused on endocrine cancers, osteoporosis and frailty in the elderly, mental health, cognitive function, respiratory disease, immune function, and allergy While the field as currently The overarching argument of the conceptual paradigm and the research field of developmental origins of health and disease (DOHaD) is that the state of health and risk from disease in later childhood and adult life is significantly affected by environmental factors acting during the The Epigenome and Developmental Origins of Health and Disease http://dx.doi.org/10.1016/B978-0-12-801383-0.00001-3 Copyright © 2016 Elsevier Inc All rights reserved 1.  DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE CONCEPT constructed is just over two decades old, it is based on research that goes back to the 1930s In this chapter, we bring together research traditions, concepts, and approaches that, over the last 80 years, have explored the question of prenatal and early postnatal environmental influences that impact health and disease in later life and look forward to emergent areas of attention and application of the concept THE ORIGINS OF THE FIELD The idea that experiences in early life influence health in later life may be found throughout the history of Western medicine: well into the 1800s, it was believed that anything that a mother saw, touched, ate, or even imagined— collectively known as “maternal impressions”— had a capacity to permanently influence the developing organism [1,2] In the early 1800s, the common view was that a new organism was created in a process called “generation,” out of maternal and paternal contributions as well as various experiences that the mother had during (and even before) pregnancy [3] But in the nineteenth century, “generation” was replaced with “reproduction,” built on the new idea of “heredity.” The noun “heredity” was first used in the 1830s, to describe the transmission of parental qualities during conception, and at the same time to make a distinction between those inherited qualities and the properties that emerged during development [4] Scientists studied where heredity resided within the cell; how hereditary particles were distributed among cells and their quantity was prevented from doubling in each successive generation; and to what extent were hereditary elements in the cells sensitive to developmental influences [5] August Weismann’s work provided the conceptual basis for new thinking about heredity and development: while germ cells produced somatic cells, he argued, they were not affected by anything that somatic cells acquired or learned [6] It followed that each individual was born with a certain predisposition toward disease; no environmental modifications could improve one’s outlook The best one could to improve one’s offspring’s chances was to reproduce with a person of “better heredity.” The early 1900s were the heyday of “hard heredity,” exemplified by the emergence of genetics, an experimental discipline concerned with mechanisms of heredity, and the dominance of the social program of eugenics, seeking to reform society through rationalizing human reproduction [7] But the deep economic crisis of the 1930s made it obvious that environmental conditions had a strong influence on the emergence and prevalence of disease [8] New epidemiological work suggested that the conditions of early life played a role at least as important as heredity A landmark paper by the Scottish epidemiologist William Ogilvy Kermack and colleagues in 1934 argued that “the data behaved as if the expectation of life was determined by the conditions existing during the years 0–15 (…) the health of the man is determined preponderantly by the physical constitution which the child has built up” [9] The recognition of the importance of environmental conditions and the apparent demise of eugenics did not, however, mean the fall of the genetic model, which remained dominant through the twentieth century [8] The Second World War was a pivotal event in the making of the developmental approach to the study of health and disease, conceptualized in the early twenty-first century as DOHaD Even before the war, physiologists, teratologists, and agricultural scientists collected experimental evidence showing that manipulating the life conditions of pregnant animals permanently affected the patterns of growth and the phenotype of their offspring [10–12] Interventions in humans were, for obvious reasons, too subtle to produce substantial differences, and they also focused on maternal mortality and morbidity rather than longer-term outcomes in the offspring [13] But wartime famines provided rare The Origins of the Field “natural experiments” by exposing thousands of women to periods of severe undernutrition, in some cases sharply delineated [14,15] The longest and the most severe famine took place in Leningrad under German siege (between September 1941 and January 1944) [14], but the clearest data came from Rotterdam and The Hague, two cities in northwestern Holland that had suffered food shortages during German reprisals from September 1944 to May 1945, in what became known as the Dutch Winter Famine [15,16] Data collected showed that starvation in the last trimester of pregnancy caused a reduction in the birth weight of the offspring, while famine around conception increased the chance of miscarriage and malformation Postwar Germany provided an opportunity for the British team working on the intersection of physiology, nutritional science, and pediatrics (Robert McCance, Elsie Widdowson, and Rex Dean) to study how low food rations and lack of food variety influenced lactation in new mothers, infant birth weight, and childhood growth [17] Back in their Cambridge laboratories, Widdowson and McCance tested their clinical findings in animal experiments and demonstrated that the size of the litter and the rate of offspring growth depended on maternal nutrition Interestingly, prenatal and early postnatal (preweaning) nutrition did not affect just the weight that the pups attained by adulthood: it also influenced susceptibility to infections, body proportions, and timing of reproductive maturation, as well as behavior [18] Their results supported the theory of “critical” or “sensitive periods,” popular across disciplines as diverse as ethology (behavioral studies), linguistics, child psychology, and physiology, according to which each organ or tissue has a distinctive period of critical differentiation as well as a period of maximum growth, during which these organs and tissues are highly sensitive to injury [11] But, as the world recovered from the wartime trauma, in the 1960s and 1970s interest in the relationship between prenatal and perinatal influences and later health and disease waned In this period, fetal physiologists largely focused on questions that emphasized fetal autonomy rather than interplay between the environment and the developing organism They studied, for example, fetal respiratory movements, fetal endocrine growth mechanisms, or fetal control of the onset of labor [19] It was mostly researchers with a strong interest in socioeconomic determinants of health inequalities who pursued questions of the interaction between environment and development At the University of Birmingham’s Department of Social Medicine, under Professor Thomas McKeown, a young David Barker completed his PhD thesis on “Prenatal influences and subnormal intelligence” (1966) [20] He found that children of all levels of “subnormal” intelligence (classified as IQ under 75) had a birth weight lower than expected Interestingly, the “normal” siblings of all but the most severely “subnormal” children (IQ less than 50) were born at low birth weight too These low birth weights of both “normal” and “subnormal” children, Barker suggested, reflected “influences which affect the intra-uterine lives of all children in their families.” At the same time, a pair of South African political immigrants to the United States (via the University of Manchester’s Department of Social Medicine), the Columbia University epidemiologists Zena Stein and Mervyn Susser, undertook a large program of study of the influence of maternal nutrition on “mental competence” [21,22] One part of their research was an intervention study of providing food supplements to pregnant women drawn from a population with a high frequency of low birth weight; the other, an observational study based on the Dutch Winter Famine cohort While both of these studies produced negative results, they rekindled interest in the Dutch Winter Famine cohort, which from then onwards would play a key role in the study of developmental, as well as transgenerational, influences upon adult health 528 EDC See Endocrine disruptor compound (EDC); Endocrine-disrupting chemicals (EDC) EGFR See Epidermal growth factor receptor (EGFR) eGFR See estimated glomerular filtration rate (eGFR) Emb-LPD, 37–38 Embryo, 33–34 Embryonic day 18 (E18), 66 Embryonic epigenetic reprogramming, 58–59 Embryonic stem cells (ES cells), 52, 280, 364 Emotional regulation See also Cognitive regulation birth phenotype, 239–240 intrauterine exposures, 240–242 Emotional stress, 490–491 ENaC See Epithelial sodium channel (ENaC) End-stage renal disease (ESRD), 292 Endo-siRNAs See Endogenous small interfering RNAs (Endo-siRNAs) Endocrine disrupters, 379–380 Endocrine disruption of normal brain programming, 75 BPA, 77 EDC-induced epimutations, 76–77 HPA axis, 76 hypothetical model, 77f ncRNAs, 77–78 neural ESR and AR, 76 steroidogenic pathway disruptions, 76 testosterone and estrogen depression, 76 Endocrine disruptor compound (EDC), 130–132 Endocrine Society, 507–508 Endocrine-disrupting chemicals (EDC), 64–65, 144, 323–324, 379 affecting ovary, 149–150 developmental effects, 144 critical roles of endogenous hormones, 144 DOHaD, 144 evidence, 144–145 ovarian development and function, 145–151 on female reproduction and ovary, 151 INDEX DES, 160–161 dioxins, 158–159 organochlorine pesticides, 155–158 phthalates, 151–155 Endogenous factors See also Exogenous factors endogenous hormones, 327 fatty acids, 327–328 glucose, 327–328 oxidants, 326 vitamins, 326–327 Endogenous glucocorticoids, 74 Endogenous hormones, 327 Endogenous small interfering RNAs (Endo-siRNAs), 181 Endothelial cell (EC), 134–135 Endothelial nitric oxide synthase (eNOS), 134–135 Enhancer of zeste homolog (EZH2), 317 ENO See Exhaled nitric oxide (ENO) eNOS See Endothelial nitric oxide synthase (eNOS) Environmental exposures, 378 Environmental perturbations, 268 Environmental Protection Agency (EPA), 324–325 Environmental toxicants, 171–172, 175, 177, 179, 328, 429–430 Environmental toxins, 447–448 Environmentally induced ­transgenerational epigenetic effects, 177–178 EPA See Environmental Protection Agency (EPA) Epidemiology, 321–322 colorectal cancer, 347 IBD, 344 IBS, 345 Epidermal growth factor receptor (EGFR), 318–319, 323 Epigenetic alterations, 212, 215–216, 227–228 Epigenetic analyses, 157–158 Epigenetic changes, 378 Epigenetic disruption, 179 Epigenetic inheritance, germline in, 427–428 Epigenetic mechanisms, 49–50 accumulating data, 50 DNA methylation, 50–51 bimodal distribution, 51 changes, 52–53 5-mC, 52 molecular biology-based techniques, 52 states of, 51–52 embryonic epigenetic ­reprogramming, 58–59 ncRNAs, 55 lncRNAs, 55 miRNAs, 56 sncRNAs, 55–56 nucleosome remodeling, 56 BAF complex, 57–58 complexes, 56–57 gene promoters, 57 nucleosome remodelers, 57 PGC, 50 posttranslational histone ­modifications, 53 acetylation of histone lysines, 53–54 changes in histone modification patterns, 54–55 ChIP-seq, 54 histone-modifying enzymes, 54 primordial germ cell reprogramming, 59 and transcription factors, 50 Epigenetic patterns, developmental environment and establishment of, 173–174 Epigenetic processes, gut microbiota and, 342 Epigenetic regulation, 281 contributing to adipocyte development, 282f of PPARγ, 283 of preadipocyte determination, 281–283 Epigenetic regulation in cancer, 316 DNA methylation, 316–317 ncRNA, 317–318 Epigenetics, 18–19, 25, 96, 128, 192–193, 362 See also Sperm epigenetics clinical and experimental ­investigations, 128 developmental programming, periods of susceptibility to, 128 adolescence, 129 adulthood, 129 fetal and early postnatal, 129 periconceptional and embryonic, 129 DOHaD and, DNA sequence, exposures, INDEX gene transcription, RXRα promoter region, 8–9 environmental factors and, 345–346 and gene expression, 399–400 sex-specific epigenetic marks, 400 sex-specific impact of ­environmental influences, 400–401 X/Y pairs of paralogues, 401–402 generational transfer and, 346–347 maternal prenatal stress, 110 chromatin dynamics influence gene transcription, 110f DNA, 110 DNA methylation, 111–112 dynamic alteration of chromatin structure, 111 modifications, 110–111 mechanisms of DOHaD in CVD, 133–136 programming stimuli, 130 clinical conditions, 132–133 diet and nutritional factors, 130–131 EDCs, 131–132 Xenobiotics, 131–132 Epigenome, 133 genetic and gene-by-environment influences on, 113 DOHaD, 115 genetic polymorphisms, 113–114 genotype-methylation interdependency, 114 GUSTO cohort, 114–115 prenatal stress and ­posttranscriptional regulation of gene expression, 115 transcription factor remodeling of DNA methylome, 114f prenatal stress and regulators of, 116–117 Epithelial sodium channel (ENaC), 305 Epstein–Barr virus (EBV), 225 ER See Estrogen receptors (ESR) ERK See Extracellular signalregulated kinase (ERK) ES cells See Embryonic stem cells (ES cells) ESR See Estrogen receptors (ESR) ESRD See End-stage renal disease (ESRD) estimated glomerular filtration rate (eGFR), 292 Estrogen, 70, 327, 383 Estrogen receptors (ESR), 64–65, 116 Esr1, 68, 323 Esr2, 68–69 Estrogen-containing hormone replacement therapy, 224 ESTRs See Expanded simple tandem repeats (ESTRs) Ethnicity, 22 Euchromatin, 69 Exclusion criteria, 498 Exhaled nitric oxide (ENO), 205 Exogenous factors See also Endogenous factors AO, 325 endocrine-disrupting chemicals, 323–324 heavy metals, 323 insecticides, 324–325 light, 325–326 pesticides, 324–325 xenoestrogens, 324 Exogenous glucocorticoids, 74 Expanded simple tandem repeats (ESTRs), 369 Expression analysis, 401 Extracellular matrix (ECM), 318–319 Extracellular signal-regulated kinase (ERK), 320–321 Extraembryonic tissues epigenetic features and and placenta, 402–403 features, 403–404 sex differences, 404 EZH2 See Enhancer of zeste homolog (EZH2) F Fabp4 See Fatty acid binding protein (Fabp4) Facebook, 506, 511 Fas-associated protein with death domain (Fadd), 321 Father contribution to DOHaD, 361–362 See also Bad mother criminalization epigenetic mechanisms of inheritance from father, 363f epigenetics, 362 paternal aging, 368 paternally driven environmental effects, 368–370 sperm epigenetics DNA methylation, 362–364 histone modifications, 364 mRNA, 364–365 529 protamines, 364 proteins, 364–365 sncRNA, 364–365 variants, 364 transgenerational epigenetic inheritance, 370 zygotic epigenetic reprogramming, 365–368 Fathers in Motion (FIM), 482–483 See also Mothers in Motion (MIM) Fatty acid binding protein (Fabp4), 318–319 Fatty acids, 327–328 5fC See 5-formyl-cytosine (5fC) Featured mothers, 492 in DVDs, 494–495 Female reproductive abnormalities, 429 Fetal alcohol spectrum disorder, 301–302 Fetal development, 448 Fetal epigenetics, placental influences on, 451–452 Fetal organ development, 239 Fetal origins hypothesis, 24 Fetal origins of adult disease (FOAD), 5, 94, 200–201 hypothesis, 381 Fetal programming, 108 effects on neurobehavioral outcomes, 236–237 role in anxiety disorders, 240 Fetal rights, 467–468 legal recognition, 465 “born alive” rule, 466–467 contingent legal personhood, 466 maternal–fetal conflict, 465 Roe v Wade, 466 Fetus, 127–128 placental epigenetics influences on, 450–451 Fibroblast growth factor receptor (FGFR), 318–319 FIM See Fathers in Motion (FIM) Fish, 431 fMRI See functional magnetic resonance imaging (fMRI) FOAD See Fetal origins of adult disease (FOAD) Follicle stimulating hormone (FSH), 148 Follicular assembly See Primordial follicle formation Folliculogenesis, 148 Food allergies, 221–222 530 Food and epigenetics, GI epithelium, 347–348 dietary modulators/epigenetic enzymes inhibitors allyl compounds from garlic, 350–351 dietary isoflavones, 351 dietary polyphenols, 351 food compounds and interactions, 351–352 HDAC inhibitors, 348–350 on epigenome of gastrointestinal epithelium, 352f methyl donors and precursors, 348 Forkhead box E3 (Foxe3), 319–320 Forkhead box O3 (FOXO3), 147–148 5-formyl-cytosine (5fC), 364 Foxe3 See Forkhead box E3 (Foxe3) FOXO3 See Forkhead box O3 (FOXO3) FoxP3+ Tregs See CD4+ forkhead box P3-positive Tregs (FoxP3+ Tregs) FreeSurfer software, 251–252 FSH See Follicle stimulating hormone (FSH) functional magnetic resonance imaging (fMRI), 250 Functional teratology, Future generations, 464, 476 G G × E associations See Gene-byenvironment associations (G × E associations) G protein-coupled receptor 81 (Gpr81), 318–319 G-6-P See Glucose-6-phosphate (G-6-P) G-protein coupled receptor 14 (Gpcr14), 320–321 GAD See Generalized anxiety disorder (GAD) Garlic, allyl compounds from, 350–351 Gastrointestinal tract (GI tract), 338 developmental origins of GI diseases, 343–344 colorectal cancer, 347 IBD, 344–345 IBS, 345–347 epigenetics and GI tract development and maturation, 339–340 GI epithelium, 341 gut epithelium, 340 stem cells, 340–341 INDEX transgenic expression of DNMT3b, 341 GI epithelium food and epigenetics, 347–352 gut microbiota and programming, 341–343 IECs, 339 Gastrulation, 408 GATA binding protein (Gata4), 319–320 Gata4 See GATA binding protein (Gata4) GCs See Glucocorticoids (GCs) GD See Gestational day (GD) GDF9 See Growth differentiation factor (GDF9) GDM See Gestational diabetes mellitus (GDM) GEN See Genistein (GEN) Gene promoters, 57 Gene-by-environment associations (G × E associations), 114 Generalized anxiety disorder (GAD), 109 Generation, Genetic inheritance, germline in, 427–428 Genetic polymorphisms, 113–114 Genistein (GEN), 318–319 Genome-wide association studies (GWAS), 117, 220, 225–226 Genomic imprinting, 26, 451 Genotype-methylation interdependency, 114 Germ cell nests, 145–147 Germline development, 427–428 in epigenetic and genetic inheritance, 427–428 environmental exposures affecting male, 433–434 Gestational day (GD), 318–319 Gestational diabetes mellitus (GDM), 129, 276, 382–383, 440–441 epigenetic programming of gene expression exposed to, 277–279 in pregnancy, 275–276 effect on offspring, 276–277 epigenetic programming of gene expression exposed to GDM, 277–279 link between diabetes and chromatin remodeling in offspring, 277 GFR See Glomerular filtration rate (GFR) GI tract See Gastrointestinal tract (GI tract) Gini Index, 19 Gitelman syndrome, 305 Glomerular filtration rate (GFR), 302–303 Glucagon-like peptide (GLP-1), 272 Glucocorticoid receptor (GR), 52–53, 73, 113–114 Glucocorticoids (GCs), 107, 253, 447 Glucose, 327–328 Glucose transporters (GLUT), 272–274 GLUT3, 449 GLUT4, 269–270, 272–274 Glucose-6-phosphate (G-6-P), 271 GLUT See Glucose transporters (GLUT) Glutathione, 213 Glycogen synthase kinase (GSK-3), 97–98 Google scholar, 510 Gpcr14 See G-protein coupled receptor 14 (Gpcr14) GR See Glucocorticoid receptor (GR) Growing Up in Singapore Towards healthy Outcomes cohort (GUSTO cohort), 114–115 Growth differentiation factor (GDF9), 148 GSK-3 See Glycogen synthase kinase (GSK-3) GUSTO cohort See Growing Up in Singapore Towards healthy Outcomes cohort (GUSTO cohort) Gut microbiota and programming butyrate in GI epithelium epigenetic modulation, 343 and epigenetic processes, 342 as long-term memory of perinatal life, 343 and metabolic activities, 341–342 GWAS See Genome-wide association studies (GWAS) H H2K27me2 See Dimethylated lysine 27 histone (H2K27me2) H3Ac See Histone acetylation (H3Ac) H3K14 See Histone lysine 14 (H3K14) INDEX H3K27me3 See Trimethylation at lysine 27 of histone (H3K27me3) H3K4 methylation, 284 H3K4 trimethylation (H4K4me3), 271–272 H3K4 See Trimethylation at lysine of histone (H3K4) H3K4me See Methylated lysine residue of the histone H3 tail (H3K4me) H3K4me3 See Trimethylation of lysine of histone H3 (H3K4me3) H3K9me2 See Dimethylation at lysine of histone (H3K9me2) H4K4me3 See H3K4 trimethylation (H4K4me3); Trimethylation at lysine of histone (H4K4me3) HAPO study See Hyperglycemia and adverse pregnancy outcome study (HAPO study) Hard heredity, HATs See Histone acetyl transferases (HATs) Hay fever See Allergic rhinitis (AR) HDAC See Histone deacetylase (HDAC) Heart, 129 Heavy metals, 323 Hedgehog interacting protein (HHIP), 304 Hepatic glucose production (HGP), 271 Hepatocyte nuclear factor 4, alpha (Hnf4α), 270 Heredity, Heterochromatin, 69 Heterochromatin protein (HP1), 317 HFD See High-fat diet (HFD) HGP See Hepatic glucose production (HGP) HHIP See Hedgehog interacting protein (HHIP) High mobility group A hook (HMGA1), 317–318 High mobility group A hook (HMGA2), 317–318 High-fat diet (HFD), 39, 41–42, 319, 395 Hippocalcin-like protein (Hpcal1), 320–321 Hispanic paradox, 22–24 Histone acetylation (H3Ac), 135 Histone lysine 14 (H3K14), 274 Histone acetyl transferases (HATs), 69, 338 Histone acetylation, 411 Histone acetyltransferases, 135 Histone deacetylase (HDAC), 51–52, 67, 111, 134–135, 338 HDAC1, 271–272, 283 HDAC3, 283 HDAC4, 274 Histone demethylase enzymes, 51–52 Histone methylation in adipogenesis, 284 Histone methyltransferases (HMTs), 317, 338 Histone modifications, 135, 179–181, 308–309, 364 Histone tails, 53 Histone-modifying enzymes, 54 HIV See Human immunodeficiency virus (HIV) HLA complex See Human leukocyte antigen complex (HLA complex) 5-hmC See 5hydroxymethylcytosine (5-hmC) HMGA1 See High mobility group A hook (HMGA1) HMTs See Histone methyltransferases (HMTs) Hnf4α See Hepatocyte nuclear factor 4, alpha (Hnf4α) Homeobox A10 (HOXA10), 323–324 HOXA10 See Homeobox A10 (HOXA10) HP1 See Heterochromatin protein (HP1) HPA axis See Hypothalamicpituitary-adrenal axis (HPA axis) Hpcal1 See Hippocalcin-like protein (Hpcal1) 11β-HSD2 See 11β-hydroxysteroid dehydrogenase (11β-HSD2) HSD11B1 See 11-beta-hydroxysteroid dehydrogenase type (HSD11B1) 5-HT See 5-hydroxytryptamine (5-HT) hTERT See Human telomerase reverse transcriptase (hTERT) Human brain, 247 fetal, 247–248, 248f 531 Human immunodeficiency virus (HIV), 442–443 Human leukocyte antigen complex (HLA complex), 223 Human studies, 132 Human telomerase reverse transcriptase (hTERT), 327–328 Humans, DOHaD in, 17–18 acculturation, 22–24 African American health disparities, 21–22 allostasis, 20–21 allostatic load, 20–21 biopsychosocial stress, 18 critical period, 18 environmental factors, 18 epigenetic regulation and effects of psychosocial stress, 25 death knell for Lamarckian influence, 25 DNA methylation, 25–26 HPA stress axis, 25–26 inherited variations, 26 miRNAs, 27 paternal factors, 27 posttranslational modifications of histone tails, 27 Gini Index, 19 health effects of income inequality, 19–20 health vulnerabilities, 27 hispanic paradox, 22–24 integrated approaches, 19 life course approach and, 24–25 relative deprivation, 20 socioeconomic stressors and infant and child health, 19–20 “thrifty phenotype” hypothesis, 18 weathering, 18–19 weathering, 21–22 Humans, transgenerational epigenetic inheritance in, 431–433 Hydroxymethylation, 134–135 5hydroxymethylcytosine (5-hmC), 52, 111–112, 317, 364 11β-hydroxysteroid dehydrogenase (11β-HSD2), 65, 107 11β-hydroxysteroid dehydrogenase enzymes, 72 5-hydroxytryptamine (5-HT), 108–109 Hyperdynamic chromatin, 281 532 Hyperglycemia and adverse pregnancy outcome study (HAPO study), 276 Hypertension, 292, 294–295, 298, 300–301 Hypothalamic-pituitary-adrenal axis (HPA axis), 21, 37, 64–65, 72, 106, 346, 381, 433 Hypoxia, 135 I IAP See Intestinal alkaline phosphatase (IAP) iAs See inorganic arsenic (iAs) IBD See Inflammatory Bowel disease (IBD) IBS See Irritable Bowel syndrome (IBS) ICM cells See Inner cell mass cells (ICM cells) ICV See Intracranial volumes (ICV) IECs See Intestinal epithelial cells (IECs) IGF See Insulin-like growth factor (IGF) IGFR See Insulin-growth factor receptor (IGFR) IGT See Impaired glucose tolerance (IGT) IL See Interleukin (IL) Immune disorders See also Autoimmune disorders; Inflammatory disorders; Metabolic disorders and communicable diseases, 217–218 and DIT, 214t–215t interlinkage of, 216–217 co-occurrence of ­immunosuppression, 217 and noncommunicable diseases, 218–222 Impaired glucose tolerance (IGT), 277–278 In motion program, 493–494 In utero cortisol, 108 In utero environmental changes and preterm birth linkages chemicals, 378–380 environmental exposures, 378 epigenetic changes, 378 maternal health, 381–384 particles/air pollution, 380–381 In utero exposure, 452 In vitro fertilization (IVF), 34 INDEX In vitro models of periconceptional programming, 39–40 ART, 40 cryopreservation, 40–41 culture medium and duration, 40 maternal age, 41 In vivo maternal nutritional models of periconceptional programming maternal overnutrition, 39 maternal protein deficiency in rodents, 37 Emb-LPD, 38 LPD model, 37 maternal serum reductions in insulin and BCAAs, 37–38 maternal undernutrition in sheep, 38–39 obesity models, 39 Inclusion criteria, 498 Independent from gestational age, 249 Infectome, 225 Infertility, epigenetic marks of, 179–181 Inflammatory Bowel disease (IBD), 338, 344 animal studies, 344–345 epidemiology, 344 Inflammatory disorders, 227 See also Autoimmune disorders; Immune disorders; Metabolic disorders atherosclerosis, 227–228 depression, 228 psoriasis, 228 sleep disorders, 228 Initial recruitment See Primordial-toprimary follicular transition Inner cell mass cells (ICM cells), 37, 408 inorganic arsenic (iAs), 320, 322 Insecticides, 324–325 Institutional Review Board (IRB), 488 Insulin receptor substrate (IRS2), 271, 284–285 Insulin-growth factor receptor (IGFR), 325–326 Insulin-like growth factor (IGF), 148–149, 339 IGF-2, 96–97, 269 Interactive information, 496 Interleukin (IL), 204 IL-1, 220 IL-6, 109 IL-8, 327–328 Intervention culturally sensitive DVDs, 494–496 peer support group teleconference, 496–497 Intestinal alkaline phosphatase (IAP), 343 Intestinal epithelial cells (IECs), 338–339 Intracranial volumes (ICV), 249 Intrauterine exposures cognitive regulation, 243 fetal exposure to maternal HPA axis, 244 fetal exposure to maternal psychological distress, 243–244 to early life stress, 250–251 emotional regulation, 240 fetal exposure to maternal HPA axis and placental hormones, 240–241 fetal exposure to maternal psychological distress, 240–241 neuronal consequences, 249–253 exposure to early life stress, 250–251 fetal exposure to maternal HPA axis, 252–253 fetal exposure to maternal psychological distress, 251–252 timing of, 239 Intrauterine growth restriction (IUGR), 5–6, 128, 268, 381, 443 epigenetic changes at Pdx-1 promoter, 273f induced by maternal dietary protein restriction, 268–270 induced by maternal total calorie restriction, 272–275 rodent models, 275t UPI model, 270–272 Intravenous glucose tolerance testing (IVGTT), 269 Invertebrates, 431 IRB See Institutional Review Board (IRB) Iron (Fe), 351 Irritable Bowel syndrome (IBS), 338, 345 animal studies, 346 environmental factors and epigenetics, 345–346 epidemiology, 345 generational transfer and epigenetics, 346–347 INDEX IRS2 See Insulin receptor substrate (IRS2) IUGR See Intrauterine growth restriction (IUGR) IVF See In vitro fertilization (IVF) IVGTT See Intravenous glucose tolerance testing (IVGTT) J JCEM See Journal of Clinical Endocrinology & Metabolism (JCEM) Jean-Baptiste Lamarck, 391b Jet propellant-8 (JP-8), 321 JHDM1a See Jumonji domain– containing histone demethylase 1a (JHDM1a) JMJD1C See Jumonji domaincontaining 1c (JMJD1C) JMJD3 See Lysine specific demethylase 6B (JMJD3) Journal of Clinical Endocrinology & Metabolism (JCEM), 507–508 JP-8 See Jet propellant-8 (JP-8) Jumonji domain-containing 1c (JMJD1C), 69 Jumonji domain–containing histone demethylase 1a (JHDM1a), 51–52 K KDM1 See Lysine (K) specific demethylase (KDM1) KDM2a See Jumonji domain– containing histone demethylase 1a (JHDM1a) KDM3A See Lysine specific demethylase 3A (KDM3A) Keratin (KRT5), 325–326 Kidney development, 293–294 See also Nephron endowment KIT ligand (KL), 147–148 KL See KIT ligand (KL) KLF6 See Kruppel-like factor (KLF6) KRT5 See Keratin (KRT5) Kruppel-like factor (KLF6), 327–328 L Lactoferrin, 161 Lactogen, 383 Lamarckian mechanisms, 391b Large offspring syndrome, 408 Latency model, 18 Latina epidemiologic paradox, 22–23 LBW See Low birth weight (LBW) Ldlr See Low-density lipoprotein receptor (Ldlr) Lead, 323, 379 Leptin (lep), 277–278 LG See Licking/grooming (LG) LH See Luteinizing hormone (LH) LHR See Luteinizing hormone receptor (LHR) Licking/grooming (LG), 7–8 Life course approach, 10, 24–25 Life Sciences and Society Program (LSSP), 511–517 Light, 325–326 LINE-1 See Long interspersed nucleotide element (LINE-1) lncRNAs See Long noncoding RNAs (lncRNAs) Long interspersed nucleotide element (LINE-1), 326–327, 449 Long noncoding RNAs (lncRNAs), 26, 55, 134, 401–402 Low birth weight (LBW), 19, 269–270 Low protein (LP), 268–269 Low-density lipoprotein receptor (Ldlr), 318–319 Low-income women, 486 Low-MWPs, 151 Low-protein diet (LPD), 37 LP See Low protein (LP) LPD See Low-protein diet (LPD) LSSP See Life Sciences and Society Program (LSSP) Luteinizing hormone (LH), 148 Luteinizing hormone receptor (LHR), 149 Lysine (K) specific demethylase (KDM1), 277 Lysine specific demethylase 3A (KDM3A), 277 Lysine specific demethylase 6B (JMJD3), 277 M 2M fetuses See Two male fetuses (2M fetuses) Magic doll analogy, 470–472 Major depressive disorder (MDD), 228 Major histocompatibility complex (MHC), 223 Male offspring, 269 533 Male reproductive pathologies, 171–172 aspects, 172 developmental environment and establishment of epigenetic patterns, 173–174 developmental exposures and incidence of male reproductive abnormalities, 174 compounds, 175 DES, 176 examples, 174–175 exposure to natural compounds, 176 exposure to pesticides, 176 fetal exposures, 175 maternal exposures, 177 plastic compounds, 175–176 TDS, 175 vinclozolin, 176 developmental timing and emergent properties, 172 environmental factors correlating with male reproductive dysfunction, 173 environmentally induced ­transgenerational epigenetic effects, 177–178 epigenetic marks of infertility, 179–181 epigenetic patterns in genome, 172 germ line to somatic epigenetic effects, 178–179 small non-coding RNAs, 181–182 Male-specific Y chromosome genes, 399 Male/female gametogenesis differences conception for future father and mother, 404–407 life cycle of mammalian ­gametogenesis and ­embryogenesis, 407f routes for biological transmission of effects of exposure, 405f Malnutrition, 89–90 epigenetics and prenatal programming by, 96 GSK-3, 97–98 IGF-2 gene, 96–97 MAPK See Mitogen-activated protein kinase (MAPK) Marsupials, 66 Maternal age, 22, 41 Maternal and fetal signals, 444 Maternal body composition, 444–445 Maternal child health, 18, 22–23 534 Maternal depression, 251–252 Maternal diet, 445–446 Maternal distress, neurobehavioral consequences of, 241 Maternal exercise, 447 Maternal glucocorticoid exposure, 300–301 Maternal health, 381 diabetes, 382–383 nutrition, 383–384 obesity, 382 Maternal hypoxia, 299–300 Maternal impressions, Maternal nutrient restriction (MNR), 130 Maternal nutrition, 296–299 Maternal obesity, 298 Maternal overnutrition, 39 Maternal prenatal stress, 103–104 BDNF, 109 biological maternal mediators, 109 BSID, 108 child, effects, 105 associations, 106 increased risk of schizophrenia, 106 independent groups, 106 Neonatal Behavioral Assessment Scale, 106 outcomes, 105 early life stress and 5mC, 112 epigenetic changes, 112 genetic and gene-by-environment influences on epigenome, 113–116 genome-wide approaches, 113 methodological considerations, 117–119 methylation levels, 113 epigenetics, 110 chromatin dynamics influence gene transcription, 110f DNA, 110 DNA methylation, 111–112 dynamic alteration of chromatin structure, 111 modifications, 110–111 exposure, 104 associations with adverse child outcomes, 105 effects of acute disasters, 105 emotional and behavioral measures, 104–105 well-controlled animal studies, 105 INDEX fetal overexposure to glucocorticoids, 107–108 fetal programming, 108 glucocorticoids, 107 HPA axis and cortisol, 108–109 IL6, 109 maternal stress, anxiety, or depression, 109 timing of exposure, 106–107 in utero cortisol, 108 Maternal stress, 73, 447 Maternal substance exposure, 301–302 Maternal undernutrition, 446 Maternal/paternal genome reprogramming, differences in environmental and metabolic programming, 408 epigenetic changes during in vivo reprogramming, 409f mysterious intermediaries, 411–412 ncRNAs, 412 persistence, 413 phases and twists of mark erasure, 408–411 skip in generation, 412–413 Maternal–fetal conflict, 465 MBD See Methyl-CpG-binding domain (MBD) MBDs See Methyl-binding domains (MBDs) MBP See Methyl-binding proteins (MBP) 5-mC See 5-methyl cytosine (5-mC) MDD See Major depressive disorder (MDD) 5MeC See 5-methyl cytosine (5-mC) MeCP2, 67 MeCPs See Methyl-CpG binding proteins (MeCPs) Medial preoptic area (MPOA), 67–68 Mediators, 500 MeDIP See Methylated DNA immunoprecipitation (MeDIP) MEF2 See Myocyte enhancer factor (MEF2) MEFs See Mouse embryonic fibroblasts (MEFs) MeHg See Methylmercury (MeHg) MEHP See Mono-ethylhexylphthalate (MEHP) Mental competence, MEs See Metastable epialleles (MEs) Mesenchymal precursors, 279 Mesenchymal stem cell (MSC), 279–280 Mesenchymal-to-epithelial transition (MET), 293 Mesoderm specific transcript (MEST), 277–278 messenger RNA (mRNA), 27, 364–365 MEST See Mesoderm specific transcript (MEST) MET See Mesenchymal-to-epithelial transition (MET) Metabolic disorders, 268 See also Autoimmune disorders; Developmental origins of health and disease (DOHaD); Immune disorders; Inflammatory disorders gestational diabetes in pregnancy, 275–276 effect on offspring, 276–277 epigenetic programming of gene expression exposed to GDM, 277–279 link between diabetes and chromatin remodeling in offspring, 277 IUGR, 268 epigenetic changes at Pdx-1 promoter, 273f induced by maternal dietary protein restriction, 268–270 induced by maternal total calorie restriction, 272–275 rodent models, 275t UPI model, 270–272 obesity in pregnancy and metabolic programming of offspring, 279 adipogenesis, 280–281 epigenetic regulation of adipogenesis, 281–284 experimental systems for studying adipogenesis, 280 linking in utero exposures, 284–285 Metabolic imprinting, 343–344 Metabolic teratogenesis, Metals, 378–379 Metastable epialleles (MEs), 96–97 Methoxychlor (MXC), 156 animal studies, 157–158 epidemiological studies, 157 INDEX MethQTLs See Methylation quantitative trait loci (MethQTLs) 5-methyl cytosine (5-mC), 26, 50–51, 317, 362–363 Methyl donors and precursors, 348 Methyl-binding domains (MBDs), 50–51 Methyl-binding proteins (MBP), 70–71 Methyl-CpG binding proteins (MeCPs), 67 MeCP2, 67, 274, 316–317 Methyl-CpG-binding domain (MBD), 316–317 Methylated DNA immunoprecipitation (MeDIP), 51 Methylated lysine residue of the histone H3 tail (H3K4me), 57 Methylated-DNA binding proteins, 111 Methylation, 203 Methylation quantitative trait loci (MethQTLs), 25–26 Methylene tetrahydrofolate reductase (MTHFR), 326–327 Methylmercury (MeHg), 324–325 Methyltransferases (MTs), 54 Mexican acculturation, 23 MHC See Major histocompatibility complex (MHC) MI See Motivational interviewing (MI) Mi-2/NuRD complex, 57 Michigan State University Extension (MSUE), 493 Microarray analysis, 107 microRNAs (miRNAs), 26–27, 55–56, 71, 115, 134, 181, 317–318, 365, 412 miR-132, 56 miR-29, 56 Microvillus membrane (MVM), 441 MIM See Mothers in Motion (MIM) Mineralocorticoid receptor (MR), 73 miR See microRNAs (miRNAs) miRNAs See microRNAs (miRNAs) Mitogen-activated protein kinase (MAPK), 320–321 Mitotic epigenetic inheritance, 426 Mixed lineage leukemia (MLL), 51–52 MLH1 See mutL homolog (MLH1) MLL See Mixed lineage leukemia (MLL) MNR See Maternal nutrient restriction (MNR) MOF See Multioocyte follicles (MOF) Molecular biology-based techniques, 52 Mono-ethylhexyl-phthalate (MEHP), 75, 152 Mothers criminalization, 476–477 Mothers in Motion (MIM), 482, 486 cohort studies, 482 FIM, 482–483 study design, 495f Motivational interviewing (MI), 493–494 Mouse embryonic fibroblasts (MEFs), 280, 284 Mouse model, 109 MPOA See Medial preoptic area (MPOA) MR See Mineralocorticoid receptor (MR) mRNA See messenger RNA (mRNA) MRP See Multidrug resistance– associated protein (MRP) MS See Multiple sclerosis (MS) MSC See Mesenchymal stem cell (MSC) Msp See Muscle specific protein (Msp) MSUE See Michigan State University Extension (MSUE) MTHFR See Methylene tetrahydrofolate reductase (MTHFR) mTOR signaling, 38 MTs See Methyltransferases (MTs) Multidrug resistance–associated protein (MRP), 442–443 Multioocyte follicles (MOF), 147 Multiple sclerosis (MS), 223 Muscle specific protein (Msp), 321 mutL homolog (MLH1), 323 MVM See Microvillus membrane (MVM) MXC See Methoxychlor (MXC) Myocyte enhancer factor (MEF2), 272–274 MyoD See Myogenic differentiation (MyoD) Myogenic differentiation (MyoD), 272–274 N N-methyl-N-nitosourea (NMU), 321 NADPH See Nicotinamide adenine dinucleotide phosphate (NADPH) 535 Narcolepsy, 228 NAT See Natural antisense transcript (NAT) National Comorbidity Survey Replication study, 236 National Health and Nutrition Examination Survey (NHANES), 21 National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), 490 National Institute of Mental Health (NIMH), 236 National Institutes of Health (NIH), 509 Natural antisense transcript (NAT), 55 Natural killer cells (NK cells), 216 Natural killer-like T cells (NKT cells), 216 NCC See Sodium-chloride cotransporter (NCC) NCDs See Noncommunicable diseases (NCDs) NCOR1 See Nuclear receptor co-repressor proteins (NCOR1) ncRNA See Noncoding RNA (ncRNA) Neonatal Behavioral Assessment Scale, 106 Neonatal cortex, 68 Neonatal maternal deprivation model (NMD model), 346 Nephrogenesis, 293 Nephron endowment, 293–295 renal programming, 295–296 maternal glucocorticoid exposure, 300–301 maternal hypoxia, 299–300 maternal nutrition, 296–299 maternal substance exposure, 301–302 uteroplacental insufficiency, 299–300 Nephron number, 294–295 Nestin (NES), 325–326 Neural development, 239, 249–250 Neuroendocrinology, 510 Neuropsychiatric disorders, 252–253 Nfκb See Nuclear factor kappa B (Nfκb) NGOs See Nongovernmental organizations (NGOs) NGT See Normal glucose tolerance (NGT) 536 NHANES See National Health and Nutrition Examination Survey (NHANES) NHE3 See Sodium-hydrogen exchanger (NHE3) NHPs See Nonhuman primates (NHPs) Nicotinamide adenine dinucleotide phosphate (NADPH), 326 NIDDK See National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) NIH See National Institutes of Health (NIH) NIMH See National Institute of Mental Health (NIMH) Nitrogen dioxide (NO2), 380 NK cells See Natural killer cells (NK cells) NKT cells See Natural killer-like T cells (NKT cells) NMD model See Neonatal maternal deprivation model (NMD model) NMU See N-methyl-N-nitosourea (NMU) NOD mouse See Nonobese diabetic mouse (NOD mouse) Noncoding RNA (ncRNA), 55, 316–318, 412 lncRNAs, 55 miRNAs, 56 sncRNAs, 55–56 Noncommunicable diseases (NCDs), 5, 89–90, 171–172, 212, 215, 218–222, 392–394, 425–426, 434, 507 Nongenetic heritability, 395 Nongenetic transmission process, 391b Nongovernmental organizations (NGOs), 508–509 Nonhuman primates (NHPs), 105 Nonidentity problem, 473–475 Nonobese diabetic mouse (NOD mouse), 227 Normal glucose tolerance (NGT), 277–278 Normal protein diet (NPD), 37 NOS3, 134–135 NP95, 50–51 NPD See Normal protein diet (NPD) NR3C1 promoter methylation, 112 NR4A2 See Nuclear receptor subfamily 4, group A, member (NR4A2) INDEX Nuclear factor kappa B (Nfκb), 319 Nuclear receptor co-repressor proteins (NCOR1), 70–71, 283 Nuclear receptor subfamily 4, group A, member (NR4A2), 325–326 Nucleosome, 110 Nucleosome remodelers, 57 Nucleosome remodeling, 56 BAF complex, 57–58 complexes, 56–57 gene promoters, 57 nucleosome remodelers, 57 Nutrient transport, 440–441, 443, 449, 452 Nutrition, 383–384, 509 nutritional factors, 130–131 O Obesity, 227, 268, 382 See also Cardiovascular disease (CVD); Diabetes models, 39 in pregnancy and metabolic programming of offspring, 279 adipogenesis, 280–281 Olfr151, 115–116 Ongoing mothers, 493–501 Oocyte, 33–34, 39, 145–147 effects, 41 nests, 145–147 breakdown, 147–148 vitrification, 40–41 Oogenesis, 147 Organizational period, 64–65 Organochlorine pesticides DDT animal studies, 156 epidemiological studies, 155–156 and metabolites, 155–156 MXC, 156 animal studies, 157–158 epidemiological studies, 157 Organogenesis, 239 Ovarian development and function, 145 EDC, 149–150 follicular recruitment, selection, and maturation or atresia, 148–149 mice and rats, 145 oocyte nest breakdown, 147–148 ovulation and CL formation, 149 PGC, 145–147 preantral and antral follicle growth, 148–149 primordial follicle formation, 147–148 primordial-to-primary follicular transition, 147–148 reproductive senescence, 150–151 timeline for ovarian developmental events in mice and humans, 146t Overnutrition, 89–91, 298 See also Undernutrition animal models, 92t NCD, 93–94 phenotypic alterations, 93f physiological and molecular alterations, 91 studies of prenatal, 91 transgenerational effect, 91–93 Ovulation, 149 Oxidants, 326 Oxidative phosphorylation (OXPHOS), 274–275 Oxidative stress, 277 OXPHOS See Oxidative phosphorylation (OXPHOS) P P-glycoprotein, 72 P-MIM See Pilot MIM (P-MIM) PAHs See Polycyclic aromatic hydrocarbons (PAHs) Paired box-6 (Pax6), 319–320 PARs See Pseudoautosomal regions (PARs) Particles/air pollution industrial and combustion engine, 380–381 tobacco smoke, 381 Passive demethylation, 58 Paternal aging, 368 Paternal diet, 433 Paternal influence on periconceptional developmental programming, 41–42 Paternally driven environmental effects, 368–370 Pax6 See Paired box-6 (Pax6) PBMC See Peripheral blood mononuclear cells (PBMC) PC programming See Periconceptional programming (PC programming) PCa See Prostate cancer (PCa) PCBs See Polychlorinated biphenyls (PCBs) INDEX PcG See Polycomb group (PcG) PCOS See Polycystic ovary syndrome (PCOS) PCR See Polymerase chain reaction (PCR) pCRH See Placental CRH (pCRH) PCSK5 See Proprotein convertase subtilisin/ketin type (PCSK5) Pde4d4 See Phosphodiesterase type variant (Pde4d4) Pdgfrα See Platelet-derived growth factor alpha (Pdgfrα) Pdx-1 expression, 272 PE See Primitive endoderm (PE) Peer advisory groups, 494 Peer support group teleconference at convenient location, 497 training of moderators, 496–497 Peer support group teleconferences (PSGTs), 487 moderators, 493 PEPCK See Phosphoenolpyruvate carboxykinase (PEPCK) Perfluorooctanoic acid (PFOA), 218–219 Periconceptional period, 34–35, 36f cleavage in mammals, 36–37 ICM, 37 PLCζ, 35–36 Periconceptional programming (PC programming), 34 Peripheral blood mononuclear cells (PBMC), 224 Peroxisome proliferator activated receptor (PPAR), 52–53, 150 PPARγ, 280–281, 318–319 epigenetic regulation, 283 Peroxisome proliferator-activated receptor gamma, coactivator alpha (PPARGC1A), 274–275 Pesticides, 324–325 PFOA See Perfluorooctanoic acid (PFOA) PGC7 See DPP3A PGCs See Primordial germ cells (PGCs) PGR See Progesterone receptor (PGR) Phosphatidylinositol-4, 5-bisphosphate phosphodiesterase beta (Plcβ3), 320–321 Phosphodiesterase type variant (Pde4d4), 320–321 Phosphoenolpyruvate carboxykinase (PEPCK), 269, 408 Phosphoinositide-3-kinase (PI3K), 269–270, 318–319 Phospholipase C-zeta (PLCζ), 35–36, 364–365 Phosphorothioate oligodeoxynucleotides (sODNs), 225 Phthalates, 151 animal studies, 152–155 EDC, 153f–154f epidemiological studies, 151–152 Physical activity, 486–487, 491, 495–496, 500 Physical dissector/fractionator method, 296 PI See Primary investigator (PI) PI3K See Phosphoinositide-3-kinase (PI3K) Pilot MIM (P-MIM), 491 Pilot mothers in motion, 491 method, 491–492 results, 492–493 PIWI interacting RNAs (piRNAs), 55–56, 181, 365 PKC See Protein kinase C (PKC) Placenta, 73, 439–440 See also Placental function epidemiology and, 440–441 epigenetics and, 448–449 environmental influences on, 449–450 on fetal epigenetics, 451–452 on fetus, 450–451 placental epigenome, 449 placental imprinting, 451 extraembryonic tissues epigenetic features and, 402–403 placenta features, 403–404 sex differences, 404 placental phenotype, 452 interventions, 452 structural organization of human, 442f transfer across the ­syncytiotrophoblast, 442f Placental CRH (pCRH), 238 Placental epigenome, 449 Placental function, 440–441 environmental influences on, 444 environmental toxins, 447–448 glucocorticoids, 447 maternal and fetal signals, 444 maternal body composition, 444–445 maternal diet, 445–446 537 maternal exercise, 447 maternal stress, 447 umbilical blood supply, 446 uteroplacental blood supply, 446 placental barrier, 441–442 placental drug transfer, 442–443 placental nutrient transfer, 443–444 Placental growth, 445 Placental hormones, 240–241 Placental imprinting, 451 Placental nutrient metabolism, 443 Placental nutrient transport function, 452 Plasticity allele, 114–115 Platelet-derived growth factor alpha (Pdgfrα), 320–321 Plc-z See Phospholipase C-zeta (PLCζ) Plcβ3, 5-bisphosphate phosphodiesterase beta (Plcβ3) See Phosphatidylinositol-4 PLCζ See Phospholipase C-zeta (PLCζ) Pluripotent stem cells, 282 PMSG See Pregnant mare serum gonadotropin (PMSG) PND See Postnatal day (PND) POA See Preoptic area (POA) Poly vinyl chloride (PVC), 151 Polychlorinated aromatic hydrocarbons, 158 Polychlorinated biphenyls (PCBs), 156, 218, 378–379 Polycomb group (PcG), 55 Polycyclic aromatic hydrocarbons (PAHs), 219–220, 323–324, 379 Polycystic ovary syndrome (PCOS), 156, 425–426 Polymerase chain reaction (PCR), 52 Pomc See Proopiomelanocortin (Pomc) POMC See Proopiomelanocortin (POMC) Population-based epidemiological studies, 245 Postnatal day (PND), 147, 318–319 PND 10, 66 Postnatal weight gain, 202–203 Posttranscriptional regulation of gene expression, 115 Posttranslational histone ­modifications, 53 acetylation of histone lysines, 53–54 changes in histone modification patterns, 54–55 ChIP-seq, 54 histone-modifying enzymes, 54 538 Power of Programming, 509 PPAR See Peroxisome proliferator activated receptor (PPAR) PPARGC1A See Peroxisome proliferatoractivated receptor gamma, coactivator alpha (PPARGC1A) PPT See Propyl-pyrazole triol (PPT) PPTox See Prenatal Programming and Toxicity (PPTox) Preadipocyte, 280 Preantral follicle growth, 148–149 Predictive adaptive response, 6–7 Pregnancy, 127–128 changes in stress system during, 238 gestational diabetes in, 275–276 effect on offspring, 276–277 epigenetic programming of gene expression exposed to GDM, 277–279 link between diabetes and chromatin remodeling in offspring, 277 maternal substance exposure during, 301–302 obesity in pregnancy and metabolic programming of offspring, 279 adipogenesis, 280–281 experimental systems for studying adipogenesis, 280 linking in utero exposures, 284–285 outcomes, 380 Pregnancy-specific anxiety (PSA), 251 Pregnant mare serum gonadotropin (PMSG), 159 Pregnant mothers, DOHaD effects for bad mother criminalization, 467 abortion statute, 468 criminal intent, 469 fetal rights, 467–468 Iowa Legislature, 467 women’s rights, 468 beneficence, nonmaleficence, and future people, 470 duty of beneficence, 471b duty of nonmaleficence, 471b magic doll analogy, 470–472 caring for fetuses vs caring for future persons, 469–470 criminalization of mothers, 476–477 DOHaD effects, 472–473 and nonidentity problem, 473–475 INDEX duty to abortion, 475–476 fetal rights legal recognition, 465 “born alive” rule, 466–467 contingent legal personhood, 466 maternal–fetal conflict, 465 Roe v Wade, 466 Prenatal depression, 108–109 Prenatal environment, 292–293 Prenatal injury, 475 Prenatal programming, 96 Prenatal Programming and Toxicity (PPTox), 507–509 Prenatal stress, 106 exposures, 241–242 and posttranscriptional regulation of gene expression, 115 transgenerational effects, 115–116 Preoptic area (POA), 67 Preprogramming, Preterm birth, 377–378 Primary investigator (PI), 499 Primary outcome, 500 Primitive endoderm (PE), 37 Primordial follicle formation, 147–148 Primordial germ cells (PGCs), 50, 145–147, 174 reprogramming, 59 Primordial-to-primary follicular transition, 147–148 Prior studies, 490 focus group discussions, 490–491 pilot mothers in motion, 490 Process evaluation, 500 Progesterone, 327 Progesterone receptor (PGR), 149 Programming, vulnerable human fetal brain, 247–248 Programming model See Developmental origins of health and disease (DOHaD) Programming neurobehavioral outcomes, 244 birth phenotype, 245–246 intrauterine effects, 246 Swedish population-based cohort, 245f Proinflammatory cytokines, 109 Prolactin, 383 Proopiomelanocortin (Pomc), 74 Proopiomelanocortin (POMC), 370, 430 Proprotein convertase subtilisin/ketin type (PCSK5), 272 Propyl-pyrazole triol (PPT), 68 Prostate cancer (PCa), 317 Prostate cancer, 320–321 Prostate specific antigen (PSA), 325 Protamination, 364 Protamines, 364 Protein kinase C (PKC), 318–319 PKCζ, 269–270 Protein tyrosine phosphate nonreceptor type 12 (PTPN12), 327–328 Proteins, 364–365 PSA See Pregnancy-specific anxiety (PSA); Prostate specific antigen (PSA) Pseudoautosomal regions (PARs), 399 PSGTs See Peer support group teleconferences (PSGTs) Psoriasis, 228 Psychobiological stress, 239, 249–250 PTPN12 See Protein tyrosine phosphate nonreceptor type 12 (PTPN12) PubMed, 510 PVC See Poly vinyl chloride (PVC) R rACC See Rostral anterior cingulate (rACC) Radial neuronal cell migration, 247–248 Randomization, 499–500 retention strategies, 500 RAS See Renin–angiotensin system (RAS) Ras-associated domain family isoform A (RASSF1A), 326–327 Reference dose (RfD), 151 Relative deprivation, 20 Renal dysfunction Brenner hypothesis, 294f CKD, 292 prenatal environment on and, 292–293 kidney development, 293–294 kidney susceptible to programming, 302–303 nephron endowment, 293–295 renal programming of low, 295–302 Renal structure and function, 303 epigenetic and transgenerational regulation, 308–309 long-term alterations in RAS, 306–308 INDEX renal tubules, 304–306 sodium channels, 304–306 pre-and postnatal pathways, 303f renal development, 304 Renal tubules, 304–306 Renin–angiotensin system (RAS), 130, 306–308 maternal perturbations on renal, 307t Reproduction, 394 reproductive senescence, 150–151 Resilience, 18, 395–396 Retinoid X receptor alpha gene (RXRα gene), 96–97 Reversing harmful DOHaD effects community groups, 494 community partners perspectives factors affecting WIC, 489 researchers reflections, 489–490 strategies for, 488–489 WIC perspectives, 487–488 comparison group, 497–498 conceptual model, 494 DPP, 486 DVDs, 487 intervention culturally sensitive DVDs, 494–496 peer support group teleconference, 496–497 limitations, 501–502 measurements, 500 ongoing mothers, 493–501 peer advisory groups, 494 primary aim and hypotheses, 490 randomization, 499–500 retention strategies, 500 sample size, 500–501 setting, participants, and recruitment, 498 recruiter training, 498 recruitment challenges and modification, 498–499 recruitment strategies, 498 sequential screening, 498 statistical methods, 500–501 prior studies, 490 focus group discussions, 490–491 pilot mothers in motion, 490 teleconference environment, 487 weight loss programs, 486 WIC partners, 501 RfD See Reference dose (RfD) Rhox homeobox gene cluster, 181 Rhox5, 181 RNA mechanisms, 135–136 Roadmap protocol, 497 Rodents, maternal protein deficiency in, 37 Emb-LPD, 38 LPD model, 37 maternal serum reductions in insulin and BCAAs, 37–38 Rostral anterior cingulate (rACC), 253 Runt-related transcription factor (Runx3), 319–320 Runx3 See Runt-related transcription factor (Runx3) RXRα gene See Retinoid X receptor alpha gene (RXRα gene) RXRα promoter region, 8–9 S S-adenosylmethionine (SAM), 326–327 sAgs See Superantigens (sAgs) SAM See S-adenosylmethionine (SAM) Scientific meetings, DOHaD–related, 508–509 interdisciplinary meetings, 510 neuroendocrinology, 510 Power of Programming, 509 PPTox, 509 Scientific organizations, DOHaD– related, 506–507 ASA, 508 NCD, 507 Toxicologist and Communiqué, 508 Scopus, 510, 511f SDN See Sexually dimorphic nucleus (SDN) SDN-POA See Sexually dimorphic nucleus of preoptic area (SDN-POA) SE See Staphylococcal enterotoxin (SE) SEATON study, 201 Second-hand smoke (SHS), 198 Secreted frizzled-related protein (Sfrp1), 322 Secreted frizzled-related protein (SFRP2), 322 Selective serotonin reuptake inhibitor (SSRI), 113 Selenium, 323 Serine protease inhibitor Karzal type (SPINK5), 221 539 Sertoli cells, 426 SES See Socioeconomic status (SES) Sex chromosomes, 398 in sex differences, 397–398 Sex differences, 398 and DOHaD model, 253–254 Sex hormones, 398 Sex specificity nongenetic heritability, 395 resilience, 395–396 sex-specific epigenetic marks, 400 sex-specific impact of environmental influences, 400–401 transgenerational responses to programming, 396–397 Sex steroid hormone effects, 65 gonadal sexual differentiation, 65–66 marsupials, 66 sex chromosomes, 66 transsexuality, 66 Sex steroid-induced epigenetic regulation, 67 BNST, 70 chromatin, 69 DNA methylation, 67, 69 Esr1, 68 Esr2, 68–69 estrogen, 70 gonadal sex hormones and sex chromosomes, 71 methyl-CpG binding proteins, 67 miRs, 71 miRs, 71 MPOA, 67–68 MPOA, 70 N-terminal region of histone proteins, 69 NCOR1, 70–71 nonclassical sexually dimorphic brain regions, 68 PPT, 68 sex differences, 69–70 2M females, 68 Sexual dimorphism, 395 complex trajectories due to sex specificity and nongenetic heritability, 395 resilience, 395–396 transgenerational responses to programming, 396–397 environmental factors, 392 epigenetics and gene expression, 399–400 540 sex-specific epigenetic marks, 400 sex-specific impact of environmental influences, 400–401 X/Y pairs of paralogues, 401–402 extraembryonic tissues epigenetic features, 402–404 Jean-Baptiste Lamarck, 391b levels of evidence, 413–414 male/female gametogenesis differences conception for future father and mother, 404–407 life cycle of mammalian gametogenesis and ­embryogenesis, 407f routes for biological transmission of effects of exposure, 405f maternal/paternal genome reprogramming differences, 408–413 nongenomic pathways, 394f placenta, 402–404 sex-dependent gene regulation, 390 sex-specific differences, 394 sex-specific transmission of memory of exposure, 393f unequal expression mechanisms of X-and Y-chromosome-linked genes, 397–399 World Health Organization, 392–394 Sexually dimorphic nucleus (SDN), 66 Sexually dimorphic nucleus of preoptic area (SDN-POA), 66, 68 Sfrp1 See Secreted frizzled-related protein (Sfrp1) SGA See Small for gestational age (SGA) sGC See synthetic glucocorticoid (sGC) Sheep, maternal undernutrition in, 38–39 short interfering (siRNA), 134 short noncoding RNAs (sncRNAs), 55–56 SHR See Spontaneously hypertensive rats (SHR) SHS See Second-hand smoke (SHS) Signal transducer and activator of transcription (STAT6), 221 Single nucleotide polymorphisms (SNPs), 113–114, 268 INDEX siRNA See short interfering (siRNA) SIRT1 See Sirtuin-1 (SIRT1) Sirtuin-1 (SIRT1), 326 SLE See Systemic lupus erythematosus (SLE) Sleep disorders, 228 Small for gestational age (SGA), 156, 240, 249 Small noncoding RNAs (sncRNA), 181–182, 364–365 Smoking, 448 SNAI1 See Snail family zinc finger (SNAI1) Snail family zinc finger (SNAI1), 327–328 sncRNA See Small noncoding RNAs (sncRNA) sncRNAs See short noncoding RNAs (sncRNAs) SNPs See Single nucleotide polymorphisms (SNPs) “Social determinants of health” framework, 22 Social disparities, 21 Social media LSSP, 511–517 reporting DOHaD findings, 511 search terms on social media sites, 518t YouTube videos, 517 Socially toxic environments, 19 Society for Study of Reproduction (SSR), 508 Society of Toxicology (SOT), 508 Socioeconomic status (SES), 19 Sodium channels, 304–306 Sodium-chloride cotransporter (NCC), 305 Sodium-hydrogen exchanger (NHE3), 305 sODNs See Phosphorothioate oligodeoxynucleotides (sODNs) SOT See Society of Toxicology (SOT) Southampton Women’s Study (SWS), 201 SPA See Staphylococcal protein A (SPA) Sperm epigenetics DNA methylation, 362–364 histone modifications, 364 mRNA, 364–365 protamines, 364 proteins, 364–365 sncRNA, 364–365 variants, 364 Spermatogenesis, 35 SPINK5 See Serine protease inhibitor Karzal type (SPINK5) Spontaneously hypertensive rats (SHR), 135 SRC-1 See Steroid hormone receptor coactivator-1 (SRC-1) SSR See Society for Study of Reproduction (SSR) SSRI See Selective serotonin reuptake inhibitor (SSRI) Stability, 111 Stanniocalcin (STC2), 278 Staphylococcal enterotoxin (SE), 225 Staphylococcal protein A (SPA), 225 StAR See Steroidogenic acute regulatory protein (StAR) STAT6 See Signal transducer and activator of transcription (STAT6) Statistical methods, 500–501 STC2 See Stanniocalcin (STC2) STELLA See DPP3A Steroid hormone receptor coactivator-1 (SRC-1), 70 Steroid receptors, 113–114 Steroidogenic acute regulatory protein (StAR), 76 Steroidogenic pathway disruptions, 76 Stress, 104, 345–347, 487, 490–491, 494–495 Subnormal intelligence, Sulfur dioxide (SO2), 380 Superantigens (sAgs), 225 Swedish population-based cohort, 245f Swi/Snf complex, 56–57 SWS See Southampton Women’s Study (SWS) Syncytiotrophoblast, 441–442 synthetic glucocorticoid (sGC), 65 Systemic lupus erythematosus (SLE), 212–213, 223–226 epigenetics, 225–226 female prevalence, 224–225 infectious agents, 225 T T regulatory cells (Tregs), 216, 220 TCDD See Tetrachlorodibenzop-dioxin (TCDD) TDI See Tolerable daily intake (TDI) TDS See Testicular dysgenesis syndrome (TDS) 541 INDEX TE See Trophectoderm epithelium (TE) TEAM See Translational Endocrinology & Metabolism (TEAM) TEBs See Terminal end buds (TEBs) Teleconference environment, 487 Ten-eleven translocation (TET), 52, 111–112, 317 Ten-eleven translocation ­methylcytosine dioxygenase-3 (TET3), 366 Tenascin-C (TnC), 318–319 Terminal end buds (TEBs), 318–319 Testicular dysgenesis syndrome (TDS), 175 Testicular feminized mice (Tfm), 149 Testosterone, 64–65 TET See Ten-eleven translocation (TET) TET3 See Ten-eleven translocation methylcytosine dioxygenase-3 (TET3) Tetrachlorodibenzo-p-dioxin (TCDD), 158, 325, 378–380 Tfm See Testicular feminized mice (Tfm) TGF See Transforming growth factor (TGF) Th1 See Type T-helper cells (Th1) Th2 See Type T-helper lymphocytes (Th2) THBS1 See Thrombospondin (THBS1) Thiazidesensitive cotransporter (TSC), 305–306 “Thrifty phenotype” hypothesis, 5, 18 Thrombospondin (THBS1), 323–324 Time to pregnancy (TTP), 152 TnC See Tenascin-C (TnC) TNFRSF10C See Tumor necrosis factor receptor superfamily membrane 10C (TNFRSF10C) TNFRSF25 See Tumor necrosis factor receptor superfamily membrane 25 (TNFRSF25) Tobacco smoke, 381 Tolerable daily intake (TDI), 151 Toll-like receptor (TLR) activation on innate immune cells, 226–227 gene polymorphisms, 213 Toxicological Sciences (ToxSci), 508 ToxSci See Toxicological Sciences (ToxSci) TP53 See Tumor protein p53 (TP53) Transcription associated protein al (TRα1), 272–274 Transcriptional start site (TSS), 284–285 Transforming growth factor (TGF), 148–149 Transgenerational epigenetic inheritance, 174, 370, 425–426 in animal models behavioral effects, 431 dietary exposures and exercise, 430 exposure to environmental toxicants and drugs, 429–430 fish and invertebrates, 431 initial studies, 428–429 environmental exposures affecting male germline, 433–434 environmentally induced, 427f germline in epigenetic and genetic inheritance, 427–428 in humans, 431–433 mitotic epigenetic inheritance, 426 Transgenerational responses to programming, 396–397 Translational Endocrinology & Metabolism (TEAM), 507–508 Transsexuality, 66 Treg-specific demethylated region (TSDR), 220–221 Tregs See T regulatory cells (Tregs) 1,1,1-trichloro-2,2-bis(4-methoxyphenyl) See Methoxychlor (MXC) 1,1,1-trichloro-2,2-bis[4-chlorophenyl] ethane (DDT), 155–156 animal studies, 156 epidemiological studies, 155–156 and metabolites, 155–156 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), 158 Trimethylation at lysine 27 of histone (H3K27me3), 317 Trimethylation at lysine of histone (H3K4), 226, 323 Trimethylation at lysine of histone (H4K4me3), 326 Trimethylation of lysine of histone H3 (H3K4me3), 51–52 Trophectoderm epithelium (TE), 36–37 TRα1 See Transcription associated protein al (TRα1) TSC See Thiazidesensitive cotransporter (TSC) TSDR See Treg-specific demethylated region (TSDR) TSS See Transcriptional start site (TSS) TTP See Time to pregnancy (TTP) Tubulin beta class III (TUBB3), 325–326 Tumor necrosis factor receptor superfamily membrane 10C (TNFRSF10C), 323–324 Tumor necrosis factor receptor superfamily membrane 25 (TNFRSF25), 327–328 Tumor protein p53 (TP53), 323 Twitter, 506, 511–517 Two male fetuses (2M fetuses), 66 Two-hit hypothesis, 509 Type diabetes, 226–227 Type T-helper cells (Th1), 204 Type diabetes, 268 Type T-helper lymphocytes (Th2), 204 U Ubiquitously transcribed ­tetratricopeptide repeat, X chromosome (UTX), 277 ucp1 See Uncoupling protein (ucp1) UCSC See University of California Santa Cruz (UCSC) UF See Uterine fluid (UF) UHRF1 See NP95 UK See United Kingdom (UK) Ultraviolet filters (UV filters), 320 Umbilical blood supply, 446 Uncoupling protein (ucp1), 282 Undernutrition, 94 See also Overnutrition animal models of maternal prenatal, 94, 95t models of malnutrition, 95–96 paternal, 94 Unequal dosage and compensation mechanisms between males and females, 398–399 United Kingdom (UK), 192, 276 United States (US), 21, 144, 486 University of California Santa Cruz (UCSC), 113 3′untranslated region (UTR), 55–56 UPI See Uteroplacental insufficiency (UPI) Upstream transcription factor (USF-1), 271–272 542 US See United States (US) USF-1 See Upstream transcription factor (USF-1) Uterine fluid (UF), 37–38 Uteroplacental blood supply, 446 Uteroplacental insufficiency (UPI), 270–272, 299–300 UTR See 3′untranslated region (UTR) UTX See Ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX) UV filters See Ultraviolet filters (UV filters) V v-akt murine thymoma viral oncogene homolog (Akt-2), 271 Variably methylated regions (VMRs), 25–26, 114–115 Variants, 364 Vascular epithelial growth factor receptor (VEGFR), 325–326 Vascular smooth muscle cells (VSMCs), 134–135 VEGFR See Vascular epithelial growth factor receptor (VEGFR) Ventromedial hypothalamus (VMH), 67 Very low birth weight (VLBW), 22 Vestigial-like family member (VGLL4), 278–279 Vimentin (VIM), 327–328 Vinclozolin, 176–177, 321, 428–429 INDEX Vitamin D insufficiency, 446 Vitamins, 326–327 VLBW See Very low birth weight (VLBW) VMH See Ventromedial hypothalamus (VMH) VMRs See Variably methylated regions (VMRs) VSMCs See Vascular smooth muscle cells (VSMCs) W Weathering, 18–19, 21–22 Western-style diet, 482 “Westernized” life style, 196 WHO See World Health Organisation (WHO) WIC See Women, Infants, and Children (WIC) Wif1 See Wnt inhibitory factor (Wif1) Wingless type MMTV integration site family, member 5A (WNT5A), 322 Wistar Kyoto rats (WKY rats), 135 Wnt inhibitory factor (Wif1), 322 WNT5A See Wingless type MMTV integration site family, member 5A (WNT5A) Women, Infants, and Children (WIC), 486 World Health Organisation (WHO), 10, 392–394, 510 X X chromosome inactivation (XCI), 398 X-and Y-chromosome-linked genes, unequal expression mechanisms male-specific Y chromosome genes, 399 sex chromosomes in sex differences, 397–398 sex differences, 398 unequal dosage and compensation mechanisms between males and females, 398–399 X-associated protein (XAP2), 159 X/Y pairs of paralogues, 401–402 XAP2 See X-associated protein (XAP2) XCI See X chromosome inactivation (XCI) Xenobiotics, 131–132 Xenoestrogens, 131, 324 Y YouTube videos, 506, 517 Z Zfp423, 284–285 Zygotic epigenetic reprogramming, 365 DNA demethylation, 366–367 methylation, 367–368 male and female pronuclei, 367 paternal epigenetic reprogramming, 366f ... the conceptual paradigm and the research field of developmental origins of health and disease (DOHaD) is that the state of health and risk from disease in later childhood and adult life is significantly... concepts of the biopsychosocial underpinnings of later health and disease It then reviews the development of the current understanding of epigenetics as one of the fundamental biological mechanisms of. .. methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility To the fullest extent of the law, neither the Publisher