Chapter 1

Pamela J. Lein

Evidence implicates environmental factors in the pathogenesis of diverse complex neurodevelopmental disorders. However, the identity of specific environmental chemicals that confer risk for these disorders, and the mechanisms by which environmental chemicals interact with genetic susceptibilities to influence adverse neurodevelopmental outcomes remain significant gaps in our understanding of the etiology of most neurodevelopmental disorders. It is likely that many environmental chemicals contribute to the etiology of neurodevelopmental disorders but their influence depends on the genetic substrate of the individual. Research into the pathophysiology and genetics of neurodevelopmental disorders may inform the identification of environmental susceptibility factors that promote adverse outcomes in brain development. Conversely, understanding how low-level chemical exposures influence molecular, cellular, and behavioral outcomes relevant to neurodevelopmental disorders will provide insight regarding gene–environment interactions and possibly yield novel intervention strategies.

Introduction 3

Evidence Implicating Environmental Factors 4

Environmental Factors Associated with Increased Risk for Neurodevelopmental Disorders 5

Mechanisms by Which Environmental Factors Influence Risk of Neurodevelopmental Disorders 8

Conclusions 14

References 15

Neurodevelopmental disabilities, including autism spectrum disorders (ASD), attention-deficit hyperactivity disorder (ADHD), schizophrenia, learning disabilities, intellectual disability (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 neurodevelopmental 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 worldwide [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 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 disabilities 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 neurodevelopmental 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 disorders [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, identifying 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 influence susceptibility to and/or severity of neurodevelopmental disorders and intellectual disabilities, 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 chapter 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.

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 detection 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 environmental 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 widespread observation has led many to posit that multiple genetic etiologies, including rare, private (de novo) single-gene mutations that are highly penetrant, inherited common functional 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 consistent 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 consistent 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). However, similar conclusions were recently reached in an independent study of over 14,000 children 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 environmental 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].

Early indications of an environmental contribution to neurodevelopmental disorders came from observations of a high incidence of autism associated with congenital rubella [33]. Subsequent 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...