Environmental Factors in Neurodevelopmental and Neurodegenerative Disorders

428 Pages·2015·10 MB·English

by  Michael Aschner PhD, Lucio G. Costa PhD

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
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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