ENVIRONMENTAL FACTORS IN NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS Edited by M a , PhD ichael schner Professor, Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA l G. c , PhD ucio osta Professor, Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA; Professsor, Department of Neuroscience, University of Parma Medical School, Parma, Italy 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 © 2015 Elsevier Inc. All rights reserved. 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Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-12-800228-5 For information on all Academic Press publications visit our website at http://store.elsevier.com/ Publisher: Mica Haley Acquisition Editor: Erin Hill-Parks Editorial Project Manager: Molly McLaughlin Production Project Manager: Lucía Pérez Designer: Greg Harris Typeset by TNQ Books and Journals www.tnq.co.in Preface This book aims to impart new light on the environmental origins of neurodevelopmental and neurodegenerative diseases. Neurological disorders are characterized by degeneration and cell loss, accompanied by a reduction in cell numbers, and a consequence aberrant brain function. Remarkably, even after the enormous investment in recent research, best exempli- fied by the “Decade of the Brain,” most neurodevelopmental and neurodegenerative diseases remain of unknown origin or idiopathic in nature. While genetics clearly plays a role in neurodevelopmental and neurodegenerative diseases, occupational, iatrogenic, medical, and environmental exposures clearly contribute to human morbidity. In most instances exposures are to xenobiotics, but remarkably even essential com- pounds may cause clinical signs secondary to morphological lesions and neurodegeneration, upon exposures to exceedingly high levels or secondary to genetic susceptibility. Neurodegeneration may occur at all life stages. Neurotoxins such as mercury, lead, or alcohol, to name a few, may cause neurodegeneration during brain development or adult- hood. Furthermore, susceptibility may vary, and most often is most pronounced during developmental stages, given the dynamic processes inherent to this life stage (cell division, differentiation, migration). Neurodegeneration at early life stages may also be silent for years if not decades, unmasking itself well into adult life. Thus, there is a clear continuum between neurodevelopmental and neurodegenerative disorders. For the majority of the neurotoxins, support for causality is limited and characterized by lack of confirmation of case diagnoses and inadequate exposure data. Keeping these limits in mind, the book was designed to provide state-of-the-art information on environmental links to neurodevelopmental and neurodegenerative disorders. In the first part, several chapters highlight the vulnerability of the central nervous system (CNS) to neurotoxins, highlight- ing the role of genetics and inflammatory processes in disease etiology. In the second part, focus is directed at neurodegenerative diseases with adult onset. Our primary goals were to provide the reader with information on mechanistic events leading to clinical disease, and facilitate the understanding on mechanisms associated with neurodevelopmental and neuro- degenerative disorders, whether genetically or environmentally linked (or both). We assembled a series of chapters that advance the latest developments and scientific breakthroughs in this fast-paced research area, and provide information that should be of interest to risk assessors, neurobiologists, clinicians, and neurotoxicologists. We are hopeful that the book offers the reader appreciation and renewed sense on contemporary issues in this topic. We are indebted to the authors for their contributions, and hope that as a reader, whether you are novice or a seasoned expert in the topic, the knowledge amassed herein will stimulate and transform your thinking in this contemporary health issue. Michael Aschner and Lucio G. Costa ix Foreword The field of neurotoxicology, the study of the effect of toxic exposures on the ner- vous system, has expanded tremendously in the last decades from a new but descrip- tive science, to one in which highly state of the art, mechanistic research is being done. As a result, it is becoming clearer that neurotoxic exposures have consequences for the nervous system and that the greatest periods of vulnerabilities are the developing ner- vous system and the aging nervous system. While it is still a challenge to find an ideal nonhuman model of exposure to explore this research, the combination of human, mam- malian, and nonmammalian studies have contributed greatly to overcoming the deficits of any one model. And it is this combination of efforts that has contributed to public policy decisions in a meaningful way and to the association of some neuronal dysfunction with exposure. Research has suggested that exposures can affect the quality of life across the lifespan and that a combination of genetic susceptibility and acute and/or chronic exposure can contribute to the problem. Because of the more sophisticated tools now available, we have gleaned an understanding of not only which mutations contribute to one’s vul- nerability, but also to how epigenetic changes to genes due to these exposures can also accomplish this. We also have better evidence for the assumption that early exposure can alter n euronal development that may not be evident until much later in life, that is the long-latency period leading to neurodegeneration. And while the problems have gotten more complex, so are the tools and approaches being used to solve them. We are now more capable of appreciating how exposure to mixtures can be more detrimental to neuronal health either in an additive or synergistic manner and how heavy metals, industrial and agrochemicals, air pollutants either by themselves or combined with life style choices can magnify the challenge of maintaining neuronal health while living in a complex environment. The series of reviews in this book Environmental Factors in Neurodevelopmental and Neurodegenerative Disorders, edited by Lucio Costa and Michael Aschner, is a timely, selec- tive compendium of the state of the field of neurotoxicology on outcomes, some of which were not even associated with neurotoxic exposure until only a decade or two ago. It will provide the state-of-the-science for many of the neuronal outcomes of current con- cern in which the role of exposure had been underappreciated, such as autism, attention deficit-hyperactivity disorder, schizophrenia, Parkinson’s, amyotrophic lateral sclero- sis, Alzheimer’s, and H untington’s disease. It will also comprehensively discuss gene– environment interactions and the potential for long-latency periods in these outcomes, as well as the contribution of alcohol and infection to neuronal development in the fetus. xi xii FOREWORD It will inform us of the role that selective exposures—lead, endocrine disruptors, methyl mercury—have played in establishing the importance of the resulting neuronal disorders contribution to public health. This book is highly recommended to students and research- ers in the field as well as public health advocates and policy makers. Annette Kirshner, PhD Program Director National Institute of Environmental Health Sciences National Institutes of Health Research Triangle Park, North Carolina Contributors Michael Aschner Department of Molecular Shih-Heng Chen Laboratory of Toxicology and Pharmacology, Albert Einstein College of Pharmacology, National Institute of Environ­ Medicine, Bronx, NY, USA mental Health Sciences, National Institutes of Paul Barrett Department of Neurology, Univer­ Health, NC, USA sity of Pittsburgh, Pittsburgh, PA, USA Deborah A. Cory-Slechta Department of Envi­ Eric E. Beier Department of Environmental and ronmental Medicine, University of Rochester School of Medicine, Rochester, NY, USA Occupational Medicine, Rutgers Robert Wood Johnson Medical School and Environmental Lucio G. Costa Department of Environmental and Occupational Health Sciences Institute, and Occupational Health Sciences, University of Piscataway, NJ, USA Washington, Seattle, WA, USA; Department of David C. Bellinger Department of Neurology, Neuroscience, University of Parma Medical Boston Children’s Hospital, Boston, MA, USA; School, Parma, Italy Department of Psychiatry, Boston Children’s Donato A. Di Monte German Center for Hospital, Boston, MA, USA; Department of Neu­ Neurodegenerative Diseases (DZNE), Bonn, rology, Harvard Medical School, Boston, MA, Germany USA; Department of Environmental Health, Pam Factor-Livak Department of Epidemiology, Harvard School of Public Health, Boston, MA, Mailman School of Public Health, Columbia USA University, New York, NY, USA Terry Jo Bichell Vanderbilt Brain Institute, C. Edwin Garner Department of Internal Medi­ Vanderbilt University, Nashville, TN, USA cine, University of New Mexico, Albuquerque, Aaron B. Bowman Department of Neurology, NM, USA School of Medicine, Vanderbilt University, Kimberly S. Grant Department of Environmen­ Nashville, TN, USA tal and Occupational Health Sciences, School Emma Bradley Department of Neurology, of Public Health, University of Washington, Vanderbilt University, Nashville, TN, Seattle, WA, USA; Center on Human Develop­ USA ment and Disability, University of Washington, Thomas M. Burbacher Department of Environ­ Seattle, WA, USA; Washington National Primate mental and Occupational Health Sciences, Research Center, University of Washington, School of Public Health, University of Washing­ Seattle, WA, USA ton, Seattle, WA, USA; Center on Human John T. Greenamyre Department of Neurology, Development and Disability, University of School of Medicine; Pittsburgh Institute for Washington, Seattle, WA, USA; Washington Neurodegenerative Diseases (PIND), University National Primate Research Center, University of of Pittsburgh, Pittsburgh, PA, USA Washington, Seattle, WA, USA; Amgen, Seattle, Marina Guizzetti Department of Behavioral WA, USA Neuroscience, Oregon Health & Science Univer­ Harvey Checkoway Family and Preventive sity, and Research and Development Service Medicine, University of California, San Diego, (R&D39), Department of Veterans Affairs La Jolla, CA, USA Medical Center, Portland, OR, USA xiii xiv CONTRIBUTORS Jau-Shyong Hong Laboratory of Toxicology Tim S. Nawrot Centre for Environmental Sci­ and Pharmacology, National Institute of Envi­ ences, Hasselt University, Belgium; Depart­ ronmental Health Sciences, National Institutes ment of Public Health & Primary Care, Leuven of Health, NC, USA University, Belgium Sarah A. Jewell German Center for Neuro­ Susan Searles Nielsen Department of Environ­ degenerative Diseases (DZNE), Bonn, mental and Occupational Health Sciences, Germany University of Washington, Seattle, WA, USA Lulu Jiang Laboratory of Toxicology and Phar­ Esteban A. Oyarzabal Laboratory of Toxicol­ macology, National Institute of Environmental ogy and Pharmacology, National Institute of Health Sciences, National Institutes of Health, Environmental Health Sciences, National NC, USA Institutes of Health, NC, USA Michal Kicinski Centre for Environmental Valerie S. Palmer Oregon Health & Science Sciences, Hasselt University, Belgium University, Portland, OR, USA Glen E. Kisby Department of Basic Medical Amy M. Palubinsky Neuroscience Graduate Sciences, Western University of Health Sci­ Program, School of Medicine, Vanderbilt ences, Lebanon, OR, USA University, Nashville, TN, USA; Vanderbilt Irene Knuesel University of Zurich, Zurich, Kennedy Center for Research on Human Switzerland Development, Nashville, TN, USA Walter A. Kukull Department of Epidemiology, Rafael Ponce Department of Environmental and University of Washington, Seattle, WA, USA; Occupational Health Sciences, School of Public National Alzheimer Coordinating Center, Health, University of Washington, Seattle, WA, Department of Epidemiology, University of USA; Amgen, Seattle, WA, USA Washington, Seattle, WA, USA Brad A. Racette Department of Neurology, Pamela J. Lein Department of Molecular Biosci­ Washington University, St Louis, MO, USA; ences, School of Veterinary Medicine, Univer­ School of Public Health, Faculty of Health sity of California, Davis, CA, USA Sciences, University of the Witwatersrand, Parktown, South Africa Britney N. Lizama-Manibusan Neuroscience Graduate Program, School of Medicine, Jason R. Richardson Department of Environ­ Vanderbilt University, Nashville, TN, USA; mental and Occupational Medicine, Rutgers Vanderbilt Kennedy Center for Research on Robert Wood Johnson Medical School and Human Development, Nashville, TN, USA Environmental and Occupational Health Sci­ ences Institute, Piscataway, NJ, USA Maitreyi Mazumdar Department of Neurology, Boston Children’s Hospital, Boston, MA, USA; Janine Santos Laboratory of Molecular Carcino­ Department of Neurology, Harvard Medical genesis, National Institute of Environmental School, Boston, MA, USA; Department of Envi­ Health Sciences, National Institutes of Health, ronmental Health, Harvard School of Public NC, USA Health, Boston, MA, USA David S. Sharlin Department of Biological BethAnn McLaughlin Department of Neurol­ Sciences, Minnesota State University, Mankato, ogy, School of Medicine, Vanderbilt University, Mankato, MN, USA Nashville, TN, USA; Department of Pharmacol­ Peter S. Spencer Department of Neurology, ogy, School of Medicine, Vanderbilt University, Center for Research on Occupational & Nashville, TN, USA; Vanderbilt Kennedy Center Environmental Toxicology, and Global Health for Research on Human Development, Nash­ Center; Oregon Health & Science University, ville, TN, USA Portland, OR, USA Dana Miller Department of Biochemistry, Michael Uhouse Department of Neurology, University of Washington, Seattle, WA, Vanderbilt University, Nashville, TN, USA USA Qingshan Wang Laboratory of Toxicology and Ruth E. Musgrove German Center for Neuro­ Pharmacology, National Institute of Environ­ degenerative Diseases (DZNE), Bonn, mental Health Sciences, National Institutes of Germany Health, NC, USA C H A P T E R 1 Overview of the Role of Environmental Factors in Neurodevelopmental Disorders Pamela J. Lein O U T L I N E Introduction 3 Mechanisms by Which Environmental Factors Influence Risk of Evidence Implicating Environmental Neurodevelopmental Disorders 8 Factors 4 Conclusions 14 Environmental Factors Associated with Increased Risk for Neurodevelopmental References 15 Disorders 5 INTRODUCTION Neurodevelopmental disabilities, including autism spectrum disorders (ASD), attention- deficit hyperactivity disorder (ADHD), schizophrenia, learning disabilities, intellectual dis- ability (also known as mental retardation), and sensory impairments, affect 10–15% of all births in the United States [1,2]. ADHD and ASD are among the most common of the neuro- developmental disorders. In 2007, the worldwide prevalence of ADHD was estimated to be 5.3% of children and adolescents [3], and this prevalence is thought to be increasing world- wide [2]. The prevalence of ASD has increased dramatically from an estimated 1:150 children reported by the United States Center for Disease Control (CDC) in 2007 based on 2000 and 2002 data to the current estimate of 1:68 children or 1:42 boys [4]. Subclinical decrements in Environmental Factors in Neurodevelopmental and Neurodegenerative Disorders 3 http://dx.doi.org/10.1016/B978-0-12-800228-5.00001-7 © 2015 Elsevier Inc. All rights reserved. 4 1. OVERVIEW: NEURODEVELOPMENTAL DISORDERS brain function are even more common than either of these neurodevelopmental disorders [5]. When considered in the context of the tremendous costs, which these disorders and disabili- ties exact on the affected individual, their families, and society [6–8], these statistics of their prevalence underscore the urgent need to identify factors that confer risk for neurodevelop- mental disabilities. Until recently, research on the etiology of neurodevelopmental disorders has focused largely on genetic causes [2,9,10]. However, this research has clearly shown that single genetic anomalies can account for only a small proportion of cases [2,11] and that, overall, genetic factors seem to account for at most 30–40% of all cases of neurodevelopmental dis- orders [5]. Credible evidence now exists that many neurodevelopmental disorders are the result of complex gene–environment interactions [11–15]. In contrast to genetic risks, which are currently irreversible, environmental factors are modifiable risk factors. Therefore, iden- tifying specific environmental factors that increase risk for neurodevelopmental disorders may provide rational approaches for the primary prevention of the symptoms associated with these disorders. However, to date, the identities of environmental factors that influ- ence susceptibility to and/or severity of neurodevelopmental disorders and intellectual dis- abilities, and the mechanisms by which environmental factors interact with genetic factors to determine individual risk, remain critical gaps in our understanding. This chapter will provide an overview of the evidence implicating environmental factors in determining risk of neurodevelopmental disorders, using autism and ADHD as prime examples. This chap- ter will also briefly discuss proposed mechanisms by which environmental factors might influence risk, and summarize the challenges and opportunities in this important area of research. EVIDENCE IMPLICATING ENVIRONMENTAL FACTORS The most compelling evidence in support of the hypothesis that environmental factors contribute to risk of neurodevelopmental disorders is the rapid increase in the prevalence of ASD and ADHD over the past several decades [2], which seems unlikely to have been caused entirely by significant shifts in the human genome. Concerns have been raised as to how much of the increased prevalence of these disorders represents true increases in the numbers of affected children. It has been suggested that diagnostic substitution, for example, the labeling of individuals as autistic or ADHD who previously would not have been so labeled, because of broadening of diagnostic criteria, coupled with increased awareness and improved detec- tion of these disorders explain their increased prevalence [16–18]. However, several studies that have investigated these concerns in the context of ASD concluded that the frequency of this disorder has truly increased, with factors other than broadening of diagnostic criteria and increased awareness likely accounting for more than half of all new cases [19–21]. Studies of the genetic causes of neurodevelopmental disorders also support a role for envi- ronmental factors in determining the risk for many neurodevelopmental deficits. Autism is considered to be one of the most heritable complex neurodevelopmental disorders [22,23]; however, genes linked to ASD rarely segregate in a simple Mendelian manner [22]. This wide- spread observation has led many to posit that multiple genetic etiologies, including rare, pri- vate (de novo) single-gene mutations that are highly penetrant, inherited common functional I. NEURODEVELOPMENTAL DISORDERS 5 ENVIRONMENTAL FACTORS ASSOCIATED wITH INCREASED RISk variants of multiple genes with small to moderate effects on ASD, or copy number variation (CNV), occur in combination to determine ASD risk [24–28]. An alternative interpretation of the genetic findings is that environmental factors act as risk modifiers [11,29]. The consistent finding of incomplete monozygotic concordance in twin studies of both autism and ADHD [11,30] as well as data demonstrating that even in genetic syndromes highly associated with ASD, a significant percentage of carriers do not express autistic phenotypes [11,25], are con- sistent with a model in which environmental factors interact with genetic susceptibilities to influence ASD/ADHD risk, clinical phenotype, and/or treatment outcome [11,29]. Given the extensive literature documenting chemical-induced mutagenesis, the identification of de novo gene mutations associated with clinical diagnosis of ASD [11,22,25] is also consis- tent with the idea of environmental risk modifiers for ASD and other neurodevelopmental disorders. More definitive human evidence corroborating a role for environmental factors has recently been reported. In one of the largest twin studies conducted to date, 192 monozygotic- and dizygotic twin pairs were analyzed to quantify the relative contributions of genetic heritability vs. the shared environment. The findings from these analyses suggested that 38% of ASD cases are attributable to genetic causes, whereas 58% are linked to the shared in utero environment [12]. The model used in this study had a number of inherent biases (e.g., it was assumed that gene × environment interactions did not occur, monozygotic and dizygotic twins were assumed to share the environment to the same extent, and questions arise regarding the validity of the values used for the prevalence for autism and ASD). How- ever, similar conclusions were recently reached in an independent study of over 14,000 chil- dren with autism in Sweden that demonstrated a heritability of 50%, supporting an equally strong role for environmental risk factors [31]. Collectively, these studies suggest that envi- ronmental factors can significantly influence susceptibility and the variable expression of traits related to neurodevelopmental disorders, thereby providing a plausible explanation for both the dramatic increase in the prevalence of complex neurodevelopmental disorders and the significant clinical heterogeneity, which is a hallmark of both autism and ADHD [11,32]. ENVIRONMENTAL FACTORS ASSOCIATED WITH INCREASED RISK FOR NEURODEVELOPMENTAL DISORDERS Early indications of an environmental contribution to neurodevelopmental disorders came from observations of a high incidence of autism associated with congenital rubella [33]. Sub- sequent studies linked prenatal infections to increased risk for not only ASD but also other neurodevelopmental disorders, particularly schizophrenia [34–37], and expanded the range of nongenetic risk factors for neurodevelopmental disorders to include other intrauterine stresses [38–42], paternal age [42–45] (but see [46]), maternal nutrition and metabolic status [11,47–49] and hormones, including sex hormones that contribute to the well-documented sex differences in autism susceptibility [50] via gene-specific epigenetic modifications of DNA and histones [51]. Early reports that in utero exposure to valproic acid or thalidomide during critical periods of development was associated with increased expression of autism-related traits in children I. NEURODEVELOPMENTAL DISORDERS