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Calls to Action

NAAR: Grants on Environmental Factors (1997-2005)

Total Funding Commitment: $2,164,888

A. Some examples where toxicants and other environmental factors were directly examined (direct part of the research question) include:

Lipkin (1997)

Bornavirus Infection and Autism Pathogeneses ($30,000)

This study was the first by Dr. Lipkin's group which developed an animal model for autism based on early exposure to an infectious agent which triggered an immune response. Update: This project was expanded into a new animal model for the etiology of autism spectrum disorders. Dr. Lipkin has published these findings in the Proceedings of the National Academy of Sciences, Molecular Psychiatry and Trends in Microbiology.

Factor-Litvac (1998)

Autism and Hazardous Waste Sites: an Ecological Study in NJ ($51,596)

This study examined the rates of autism with respect to living proximity to EPA designated hazardous waste sites. Dr. Factor-Litvac did not show an increased association but is continuing this study as part of an ongoing epidemiological investigation with the EPA and Columbia University.

Holson (1999)

Gestational Retinoic Acid Exposure: An Animal Model of Autism ($29,480)

Retinoic acid (high dose vitamin A) is a known cause of birth defects, this study examined whether administration during pregnancy to rats mimicked neuropathology of autism.

Cohen (2000)

Epidemiology of Autism on Staten Island ($79,504)

Goals were to examine Autism prevalence on Staten Island (environmental toxins high) as a comparison to national rates. Autism prevalence was not firmly established in this population.

Paul Thorson (2001 and 2002)

Risk Factors for Neurodevelopmental Disorders: MMR Vaccine and Childhood Autism ($105,300)

Used medical records in a group of children in Denmark to determine the change in rates of autism as a function of MMR vaccination. No association was found, and these results were published in a 2003 issue of the Journal of the American Medical Association.

Keller (2002)

Reelin as a target of interaction between genotype and environment in autistic disorder ($103,800)

Examined sensitivity of heterozygous reeler mice (reduced levels of reelin) to organophosphate pesticides on brain structure. Dr. Keller and his colleagues reported complex gene x environment interactions, where prenatal exposure to chlorpyrifos reversed some of the detrimental behavioral effects of reelin mutation in mice. Other cholinergic behaviors were only influenced in the presence of both genetic mutations and the environmental exposure.

A colleage of Dr. Keller, Dr. Antonio Persico, also published a study on a receptor for Reelin, called APOe, and its relationship to autism. Dr. Keller was also an author on this study. He did not find a significant association between APOe gene variants and autism, but attributed a low sample size and heterogeneous clinical presentation to the lack of findings. Cure Autism Now (CAN) funded a "sister" study which looked at another gene variant, paraxonase, which is an enzyme which regulates the body's response to certain pesticides.

Adams (Mentor-based fellowship, 2005)

Early Markers of Autism and Social-Cognitive Processing in Infants Exposed to Valproic Acid During Prenatal Development ($54,000)

The use of drugs to control epilepsy (such as valproic acid) during pregnancy has been suggested to increase the risk for autism spectrum disorders in offspring. Thus far, data on autism risk has been based primarily on case reports, retrospective sample studies, and suggestions from animal research. This study will assess the developmental outcomes in a group of infants prenatally exposed to VPA, as well as a comparison group of infants matched by age, maternal age and demographic characteristics. It will also examine the effects of prenatal VPA exposure on motor, mental, and social-emotional development, as well as social-cognitive processing.

What this means for people with autism: This study will help clarify if there is indeed an increased risk of autism in children exposed to valproic acid in utero . Determination of environmental or pharmaceutical contributions to autism will contribute to development of better animal models and intervention strategies to prevent VPA associated cases of autism.

Freedman (Pilot Award, 2004)

Double Hit Hypothesis of Autism: Genetic Susceptibility and Environmental Exposure to Metals. ($120,000)

(Received extension 2005 due to change in investigator to Ed Levin)

High level exposure to the heavy metals mercury and copper can lead to neuropsychological impairments in adults. Of concern, children are more susceptible to these cognitive impairments. While the levels at which exposure has led to dysfunction in motor and memory functions is considerably high, there are conditions under which an individual can not properly metabolize/detoxify metals, leading to a high bioburden compared to exposure level. Drs. Freedman and Levin will test whether a defect in metal metabolism (genetic) combined with exposure to copper or mercury (environmental) are causative factors in the development of autism like behaviors using an animal model. They will test the hypothesis that a disruption in normal metal metabolism and concomitant metal intoxication during development contributes to persistent cognitive and social impairment. Changes in cognitive and social behavior in response to exposure to copper or inorganic mercury will be examined in wild type mice and a transgenic strain in which a central component in metal metabolism, metallothionein, has been inactivated. The enzyme metallothionein is essential for removing heavy metals from the body, therefore this genetic manipulation may serve as a susceptibility factor to the deleterious effects of heavy metals such as mercury and copper.

What this means for people with autism: The information and improved mechanistic understanding obtained from the proposed studies will help define the roles of metal toxicants in the etiology of neurodevelopmental and neurobehavioral disorders. This information may be applied to the clinical intervention and possible prevention of metal-induced neurological disorders.

Keller (Interdisciplinary Award, 2005)

Comparative Analysis of Cerebellar Neuropathology in Human Autistic Patients and in Cerebellar Mouse Mutants ($292,024)

Neuroanatomical and neuroimaging studies in autism conducted by several research groups show faulty development of neural structures, particularly in a structure at the base of the brain called the cerebellum. The cerebellum is a particularly interesting research target because its structure and function has remained consistent throughout evolution. In addition, the development of the cerebellum takes place during late pregnancy and early postnatal life, which is a period that is believed to be critical for autism. Specifically, the size of the cerebellum is reported to be smaller in individuals with autism and the number of cells which direct messages to other brain areas, Purkinje cells, are shown to be reduced in number.

While the mechanism that affects Purkinje cell number and cerebellar size is not yet well described, preliminary data suggests that reelin, an autism candidate gene, interacts with gonadal sex hormones during cerebellar development. An interaction of abnormal reelin expression coupled with exposure to differing levels of testosterone during brain development may contribute to the reduced number of Purkinje cells in individuals with autism. This study will look for alterations of enzymes and receptors involved in gonadal steroid signaling in human brain tissue to determine the interaction between testosterone levels, reelin expression, and Purkinje cell development. The results of human brain tissue research will be followed by examining the effects of estrogen in a genetic strain of mouse named Reeler mice. Reeler mice lack the reelin protein which leads to a malformed cerebellum with disorganized Purkinje cells. By using this approach, the effects changes in gestational environment, including testosterone levels with genetic mutations on human pathology can be investigated in a multifaceted way.

What this means for people with autism: This study will investigate the interaction between genetic vulnerability and gonadal steroid hormones on Purkinje cell survival, migration, and/or differentiation, which would account for the biased sex ratio of autism. This hypothesis has not yet been tested and these researchers will examine the role of reelin, a candidate gene for autism, and 17beta-Estradiol, on mouse Purkinje cells. Dr. Keller's group will be linking animal models with human pathological studies in an interdisciplinary fashion and studying the possible protective role of estrogen on genetic susceptibility to autism spectrum disorders.

McCaffrey (Pilot Award, 2005)

Disruption of Organization of the Cerebral Cortex by Retinoic Acid ($119,200)

Dysfunction of the cerebral cortex is likely to be a significant contributor to the pathogenesis of autism. One mechanism by which changes in cortical function may occur is by too much activity, leading to “overexcitation.” This may be caused by a dysregulation in systems that normally turn off neurons. In this study, Dr. McCaffery and associates will investigate the influence of retinoic acid, which inhibits the migration of specific neurons to the cortex and so would reduce the number of neurons that regulate brain activity. Retinoic acid has been suggested as one possible candidate of an environmental input that, in excess, may result in some features of autistic pathology. Fetal exposure to retinoic acid can occur through the use of a number of drugs that can influence the levels or potency of retinoic acid, including Accutane, alcohol, or valproate.

What this means for people with autism: Studying the effects of pharmaceutical agents and teratogens on brain development will help illustrate the mechanisms by which environmental factors may contribute to the neuropathology of autism.

Newschaffer (Pilot Award, 2005)

Autism, Autoimmunity and the Environment ($120,000)

There is some evidence regarding an association between autism and autoimmunity, but the nature of this connection is still unclear. At the same time, given apparent upsurges in autism prevalence, interest into environmental risk factors continues to build. Because autism pathology likely begins early in development, the prenatal period is a critical time window for exposures to environmental risk factors. This study will look at two potentially related factors contributing to the fetal environment: maternal antibody levels and chemical exposures during pregnancy. The results of this research will add to the understanding of immunologic and environmental risk factors in autism.

What this means for people with autism: A reliable biomarker to enhance diagnosis of autism has not yet been well characterized or established. This study will explore autoantibodies as potential biomarkers of autism risk and will link biomarker data with ecologic data on environmental exposures.

Newschaffer (Pilot Award, 2005)

Autism risk and Exposures/Biomarkers Measured During the pre-, peri-, and neonatal periods: a Baby Sibs Pilot Investigation ($120,000)

Given the strong evidence supporting the early origins of ASD, exposure and biomarker data collected during the pre-, peri- and neonatal time periods could be more strongly associated with ASD risk because they are measured during an etiologically more significant time period than those collected later in life. Also, although it is possible to collect interview data on pre-, peri- and neonatal exposures retrospectively, prospective collection offers substantive advantages in reducing error and limiting recall bias.
Collection of biomarker and exposure data in a high-risk cohort offers some distinct advantages over collecting these data in a population-based cohort. Most obvious is that, in a high-risk cohort, informative analyses can be completed with a relatively smaller sample size because clinical events are more common and there is greater variation in subclinical (continuously measured) endpoints. A second advantage of a high-risk cohort is compliance. Motivation to sustain study participation in the high-risk cohort would likely be higher on average then in a population-based cohort (although compliance and sample collection logistics are still a major challenge in this study design). Finally, studying a genetically susceptible population may allow for observation of associations between biomarkers and/or risk factors and ASD that would be more difficult to detect in a population-based sample.

What this means for people with autism: This investigation will demonstrate the feasibility of assembling and retaining a study population to determine if a larger study is possible. The pilot effort will also focus on data collection areas anticipated to present particular challenges – for example: the collection of biosamples during the labor and delivery, post-partum, and early neonatal periods. Finally, the pilot investigation will provide some data on the distribution of exposure and biomarker values observed during the pre-natal period, critical for brain development.

Schmitz (Pilot Award, 2005)

Cytoarchitectural Alterations in the Cerebral Cortex in Autism($120,000)

Dr. Schmitz's lab has been studying the neuropathological characteristics of autism for many years. His group has reported abnormalities in size, number, and organization of neurons in the cerebral cortex. This current study will utilize novel tools to view the organization of cells in the cortex in three dimensions, specifically examining the connectivity of neurons between different areas of the cortex. Furthermore, his lab will compare these changes with those of a current animal model of autism: in utero maternal influenza virus exposure.

What this means for people with autism: The results of the proposed project will contribute to a better understanding of the neuropathology of autism using software which will be made available to the research community. In addition, this study will investigate the validity of an animal model of autism where environmental factors play a key role.

Wagner (Pilot Award, 2005)

Animal Model of Autism Using Engrailed2 Knockout Mice. ($98,880)

Autism is a neurobiological disorder with primary symptoms include impaired communication and social interaction with restricted or repetitive motor movements. Dr. Wagner and his colleagues have developed a model that examines the neurobehavioral development of mice in three core areas: motor, cognitive, and social. As the EN2 gene has been shown to be associated with autism, Dr. Wagner's lab will examine behavioral development in a mouse model where this gene is not expressed. Furthermore, the effects of two environmental toxicants, VPA and DEHP will be examined to determine if this gene confers susceptibility to environmental exposures. He predicts that disruption of the En2 gene will alter the developmental path of the brain and lead to widespread behavioral changes that may be made worse in the presence of these toxicants.

What this means for people with autism: These studies may help clarify the genetic, neurobiological and environmental influences in autism. Finding genes involved in autism susceptibility and learning how they contribute to disease development will provide information that could lead to more effective treatments and interventions.

B. Other studies which indirectly examine toxicant exposure/immune function:

Croen (2004)

Biologic Markers of Maternal Infection and Immune Function in Autism ($119,680)

Building on Dr. Ian Lipkin's work on the role of the immune function during gestation, Dr. Croen has used biobanking infrastructure through Kaiser Permanente Health Foundation to identify potential immune markers in blood of pregnant women who later have children affected with autism. At the time, this was only possible through blood spot analysis on stored biomaterial through the Kaiser health care system. While the biological aspect of this study is still ongoing, Dr. Croen published a study earlier this year in Pediatrics that reported that while overall, children with autism did not present with infections any more often than non-affected children during their first 2 years of life, they may be at higher risk for certain types of infections.

Belichenko (1999)

The Role of Brain-Directed Autoimmune Reaction in the Pathogenesis of Infantile Autism in Children and Young Adults ($30,000)

Dr. Belichenko has not published on the findings of his study and he reports that his results were inconclusive. However, since 1999, other researchers (including those in Japan and California) have reported differences in BDNF levels in children and adults affected with autism, both looking at BDNF and the targets of BDNF in the brain.

Ponzio (2002)

Contribution of Immunological Mechanisms to Autism Spectrum Disorders ($118,000)

Dr. Ponzio published a study in 2007 in the Annals of the NY Academy of Medicine which reported neurobehavioral differences in offspring exposed to a maternal immune disruptor (IL-2) compared to non-exposed pups.

Singer (Pilot Award, 2005)

Autoimmune Abnormalities in Autism: a Family Study ($120,000)

Several theories have been proposed based on the presence of antineurononal antibodies (ANAb) in individuals with autism. One study suggests that autism may be caused by the placental transfer of antibodies that, in turn, interfere with the development of the fetal brain. A second hypothesis suggests that identifying antibodies against specific central nervous system (CNS) proteins is essential in providing clues about the underlying pathophysiology. In order to further investigate the possibility of placental transfer of antibodies as a cause for autism, Dr. Singer's research will compare antibody levels in mothers of children with autism to those of unaffected children. He will also study both adult and fetal postmortem brain tissue to look at differentiation based on developmental factors.

What this means for people with autism: The identification of autoimmune abnormalities can aid in the definition of the autism phenotype, and provide new insight for physiological mechanisms behind the cause of autism as well as potential preventative therapy.

Vogt (Pilot Award, 2005)

Immune Biomarkers in Serum and Newborn Dried Blood Spots ($118,880)

At present, there are no biological tests that can be performed to diagnose autism. This study will help develop methods and establish reference ranges for measuring immune biomarkers in infants, children, and mothers that could aid in early recognition and diagnosis of autism. The researchers will investigate if autism may be caused by immune and inflammatory reactions that influence neural development during gestation and infancy. They will use the microbead suspension array (MSA), which is a flexible, highly sensitive assay system that can be used to measure multiple biomarkers simultaneously from a very small sample, such as a drop of blood. Dr. Vogt and his colleagues hope to develop a panel of reliable, transferable laboratory methods for measuring selected biological markers of the immune system in serum and dried blood spots (DBS).

What this means for people with autism: This study will help establish tests and reference ranges that are readily transferable to other laboratories, so that all research and public health investigators can make use of them. Ideally, these population- based research activities will implicate specific environmental triggers of autism and help lead to preventive measures.

Zalcman (2001)

Cytokines, Monoamines and Sterotypical Motor Activity ($96,170)

C. Studies which investigated other environmental factors:

Thorsen (2003)

Exposure to pharmaceuticals in pregnancy and development of autistic disorder ($118,454)

Retrospective analysis of medical records to determine prenatal factors such as exposure to different pharmaceuticals and relationship to autism. While no reports have been published that links different pharmaceuticals to autism, Dr. Thorsen was able to report that different prenatal environmental events, including breech presentation, low APGAR score and gestational age at birth were associated with elevated risk of autism. Other factors, including season of birth, and number of antenatal visits did not elevate risk of autism. Dr. Thorsen is a participant in the Autism Epidemiology Network.