Potential Mechanisms Linking Pesticides and Autism
Background: Autism spectrum disorders (ASDs) have been increasing in many parts of the world and a portion of cases are attributable to environmental exposures. Conclusive replicated findings have yet to appear on any specific exposure; however, mounting evidence suggests gestational pesticides exposures are strong candidates. Because multiple developmental processes are implicated in ASDs during gestation and early life, biological plausibility is more likely if these agents can be shown to affect core pathophysiological features.
Objectives: Our objectives were to examine shared mechanisms between autism pathophysiology and the effects of pesticide exposures, focusing on neuroexcitability, oxidative stress, and immune functions and to outline the biological correlates between pesticide exposure and autism risk.
Methods: We review and discuss previous research related to autism risk, developmental effects of early pesticide exposure, and basic biological mechanisms by which pesticides may induce or exacerbate pathophysiological features of autism.
Discussion: On the basis of experimental and observational research, certain pesticides may be capable of inducing core features of autism, but little is known about the timing or dose, or which of various mechanisms is sufficient to induce this condition.
Conclusions: In animal studies, we encourage more research on gene × environment interactions, as well as experimental exposure to mixtures of compounds. Similarly, epidemiologic studies in humans with exceptionally high exposures can identify which pesticide classes are of greatest concern, and studies focused on gene × environment are needed to determine if there are susceptible subpopulations at greater risk from pesticide exposures.
Causes for the recent rise in autism diagnoses throughout the United States remain largely unknown. In California, a 600% increased incidence in autism was observed among children up to 5 years of age for births from 1990 to 2001, yet only one-third of the rise could be explained by identified factors such as changing diagnostic criteria and a younger age at diagnosis (Hertz-Picciotto and Delwiche 2009). Across the United States, autism spectrum disorders (ASD) are now estimated to affect 1 in 88 eight-year-olds, with much higher prevalence in boys (1 in 54) than girls (1 in 252) (Centers for Disease Control and Prevention 2012). Autism is a heterogeneous, behaviorally defined condition often diagnosed in children prior to age 3 years. Although each individual diagnosis must meet specific criteria related to deficits in social interaction and language and to the presence of repetitive behaviors or restricted interests, autism phenotypes vary widely, even among concordant twins (Le Couteur et al. 1996).
Idiopathic autisms are diagnosed 4–5 times more often in boys than girls and frequently involve a wide range of genes that confer susceptibility as opposed to a singular heritable factor (Geschwind 2011). Genetic contributions to autism risks involve rare mutations, complex gene × gene interactions, and copy number variants (CNVs) including deletions and duplications (Stankiewicz and Lupski 2010). In a recent series of papers, rare de novo point mutations were associated with autism in parent–child trios with sporadic ASD (Neale et al. 2012; O'Roak et al. 2012; Sanders et al. 2012), and those mutations were more frequently derived from fathers, increasing with paternal age (O'Roak et al. 2012). Although twin studies have demonstrated evidence of heritability—a stronger concordance among monozygotic than dizygotic twins (Bailey et al. 1995; Rosenberg et al. 2009; Steffenburg et al. 1989)—in a recent twin study that parsed the contribution from genetics versus the environment, a larger component of the risk of autism was attributable to environmental factors than genetics alone (e.g., Hallmayer et al. 2011). The genetic and twin studies of autism point to variability unexplained by heritable factors and, in recent years, associations between gestational pesticide exposures and ASD or behaviors that are characteristic of pervasive developmental disorders have been reported.
Using exposure estimates from a historical pesticide use database, a study of mothers living in the California Central Valley showed that children born to mothers who had been exposed to organochlorine (OC) insecticides that were agriculturally applied within 500 m of the home between gestational days (GD) 26 and 81 (during neural tube closure) were 7.6 times more likely to be diagnosed with ASD than the children of mothers who lived in the lowest exposure quartile. Associations were also observed for the pyrethroid insecticide bifenthrin and for the organophosphate (OP) chemical class when comparing the cumulative exposure over the course of gestation among the highest versus lowest quartile (Roberts et al. 2007). Although Roberts et al. (2007) present provocative preliminary data and higher odds at closer proximity (a dose–response relationship), unmeasured confounding could have occurred for other exposures such as prenatal vitamin intake or occupational exposures. Additionally, because cases were obtained from the Department of Developmental Services (DDS) and controls from the birth certificate registry, misclassification of cases and controls may have occurred as children who receive an early diagnosis of autism are sometimes reclassified at a later date, and controls may include children who are on the autism spectrum but have not received a DDS diagnosis.
In a prospective cohort study also from the California Central Valley, a 230% increase in maternally reported symptoms of pervasive developmental disorders (PDD) was observed per 10-nM/L increase in prenatal maternal urinary levels of OP metabolites (Eskenazi et al. 2007). PDD is the greater diagnostic umbrella under which ASD falls, also encompassing Rett Syndrome, childhood disintegrative disorder (CDD), and pervasive developmental disorder–not otherwise specified (PDD-NOS). Although the prospective study design has the benefit of accuracy in exposure ascertainment from biospecimens collected during pregnancy, it is generally not feasible to obtain a cohort large enough to observe enough cases of full syndrome autism. Consequently the broader definition of borderline PDD increases the numbers but lacks specificity. Although these studies are by no means conclusive in establishing an autism–pesticide association, they do raise important questions regarding the health effects of these compounds on the developing fetus. In light of these findings and the current theories of autism pathophysiology, we review here potential pathways by which gestational pesticide exposure might contribute to autism, linking what is known about the origins of autism with information on biological effects of pesticides to generate clearer hypotheses that can help guide future research in this area.
Abstract and Introduction
Abstract
Background: Autism spectrum disorders (ASDs) have been increasing in many parts of the world and a portion of cases are attributable to environmental exposures. Conclusive replicated findings have yet to appear on any specific exposure; however, mounting evidence suggests gestational pesticides exposures are strong candidates. Because multiple developmental processes are implicated in ASDs during gestation and early life, biological plausibility is more likely if these agents can be shown to affect core pathophysiological features.
Objectives: Our objectives were to examine shared mechanisms between autism pathophysiology and the effects of pesticide exposures, focusing on neuroexcitability, oxidative stress, and immune functions and to outline the biological correlates between pesticide exposure and autism risk.
Methods: We review and discuss previous research related to autism risk, developmental effects of early pesticide exposure, and basic biological mechanisms by which pesticides may induce or exacerbate pathophysiological features of autism.
Discussion: On the basis of experimental and observational research, certain pesticides may be capable of inducing core features of autism, but little is known about the timing or dose, or which of various mechanisms is sufficient to induce this condition.
Conclusions: In animal studies, we encourage more research on gene × environment interactions, as well as experimental exposure to mixtures of compounds. Similarly, epidemiologic studies in humans with exceptionally high exposures can identify which pesticide classes are of greatest concern, and studies focused on gene × environment are needed to determine if there are susceptible subpopulations at greater risk from pesticide exposures.
Introduction
Causes for the recent rise in autism diagnoses throughout the United States remain largely unknown. In California, a 600% increased incidence in autism was observed among children up to 5 years of age for births from 1990 to 2001, yet only one-third of the rise could be explained by identified factors such as changing diagnostic criteria and a younger age at diagnosis (Hertz-Picciotto and Delwiche 2009). Across the United States, autism spectrum disorders (ASD) are now estimated to affect 1 in 88 eight-year-olds, with much higher prevalence in boys (1 in 54) than girls (1 in 252) (Centers for Disease Control and Prevention 2012). Autism is a heterogeneous, behaviorally defined condition often diagnosed in children prior to age 3 years. Although each individual diagnosis must meet specific criteria related to deficits in social interaction and language and to the presence of repetitive behaviors or restricted interests, autism phenotypes vary widely, even among concordant twins (Le Couteur et al. 1996).
Idiopathic autisms are diagnosed 4–5 times more often in boys than girls and frequently involve a wide range of genes that confer susceptibility as opposed to a singular heritable factor (Geschwind 2011). Genetic contributions to autism risks involve rare mutations, complex gene × gene interactions, and copy number variants (CNVs) including deletions and duplications (Stankiewicz and Lupski 2010). In a recent series of papers, rare de novo point mutations were associated with autism in parent–child trios with sporadic ASD (Neale et al. 2012; O'Roak et al. 2012; Sanders et al. 2012), and those mutations were more frequently derived from fathers, increasing with paternal age (O'Roak et al. 2012). Although twin studies have demonstrated evidence of heritability—a stronger concordance among monozygotic than dizygotic twins (Bailey et al. 1995; Rosenberg et al. 2009; Steffenburg et al. 1989)—in a recent twin study that parsed the contribution from genetics versus the environment, a larger component of the risk of autism was attributable to environmental factors than genetics alone (e.g., Hallmayer et al. 2011). The genetic and twin studies of autism point to variability unexplained by heritable factors and, in recent years, associations between gestational pesticide exposures and ASD or behaviors that are characteristic of pervasive developmental disorders have been reported.
Using exposure estimates from a historical pesticide use database, a study of mothers living in the California Central Valley showed that children born to mothers who had been exposed to organochlorine (OC) insecticides that were agriculturally applied within 500 m of the home between gestational days (GD) 26 and 81 (during neural tube closure) were 7.6 times more likely to be diagnosed with ASD than the children of mothers who lived in the lowest exposure quartile. Associations were also observed for the pyrethroid insecticide bifenthrin and for the organophosphate (OP) chemical class when comparing the cumulative exposure over the course of gestation among the highest versus lowest quartile (Roberts et al. 2007). Although Roberts et al. (2007) present provocative preliminary data and higher odds at closer proximity (a dose–response relationship), unmeasured confounding could have occurred for other exposures such as prenatal vitamin intake or occupational exposures. Additionally, because cases were obtained from the Department of Developmental Services (DDS) and controls from the birth certificate registry, misclassification of cases and controls may have occurred as children who receive an early diagnosis of autism are sometimes reclassified at a later date, and controls may include children who are on the autism spectrum but have not received a DDS diagnosis.
In a prospective cohort study also from the California Central Valley, a 230% increase in maternally reported symptoms of pervasive developmental disorders (PDD) was observed per 10-nM/L increase in prenatal maternal urinary levels of OP metabolites (Eskenazi et al. 2007). PDD is the greater diagnostic umbrella under which ASD falls, also encompassing Rett Syndrome, childhood disintegrative disorder (CDD), and pervasive developmental disorder–not otherwise specified (PDD-NOS). Although the prospective study design has the benefit of accuracy in exposure ascertainment from biospecimens collected during pregnancy, it is generally not feasible to obtain a cohort large enough to observe enough cases of full syndrome autism. Consequently the broader definition of borderline PDD increases the numbers but lacks specificity. Although these studies are by no means conclusive in establishing an autism–pesticide association, they do raise important questions regarding the health effects of these compounds on the developing fetus. In light of these findings and the current theories of autism pathophysiology, we review here potential pathways by which gestational pesticide exposure might contribute to autism, linking what is known about the origins of autism with information on biological effects of pesticides to generate clearer hypotheses that can help guide future research in this area.