Environmental Contaminants and Autism Risk
Abstract
Although scientists and the general public have long suspected that chemical exposures, including air pollution and flame retardants, heighten the risk of autism spectrum disorder (ASD), the available data are surprisingly minimal and highly discordant. There is a critically pressing need for rigorous, reproducible, human-relevant studies examining potential links between chemicals and ASD traits, including commonly coexpressed features such as neuroinflammation. Also lacking is information about potential mechanisms of action, particularly information about why occurrence is higher in boys. We have made the unique finding that flame retardants disproportionally accumulate to a greater degree in male than female placenta. We have further discovered that this sex-specific exposure is accompanied by disruption of the serotonin biosynthetic pathway in placenta, with males more sensitive than females. Serotonin, arising from the fetal placenta, has profound effects on the developing brain, particularly forebrain, and disrupted serotonin in the developing brain has previously been associated with ASD traits. Finally, we have shown that developmental exposure to flame retardants heightens risk of anxiety and other behaviors associated with ASD. Based on these preliminary data, we will use a uniquely suitable animal model to test the hypothesis that developmental exposure to flame retardants contributes to ASD risk, and disruption of placental serotonin is potentially a key and novel mechanism of action, with males more vulnerable. The fire retardants to be tested are rapidly replacing older compounds that are now banned or in the process of being phased out but structurally similar and poised to become the most common FRs used in US furniture and baby products. Some are also used in other applications including personal care products, so human exposure is widespread and rising. This proposal addresses two of the Fiscal Year 2016 Autism Research Program Idea Development Award Areas of Interest: (1) environmental risk factors and (2) mechanisms underlying conditions co-occurring with ASD. Co-occurring conditions to be examined include anxiety and hyperactive behaviors, and neural hallmarks including neuroinflammation. Because ASD is fundamentally a disorder of social behavior, testing how chemical exposures might heighten risk requires a pro-social animal model with human-relevant social traits, particularly those affected by ASD. Rats, mice, and even transgenic ASD mouse models lack some or all of these behaviors or have severe neuropathologies not seen in ASD patients. For example, in the commonly used BTBR mouse, portions of the brain that control memory and fear-related behaviors are missing and it completely lacks the corpus collosum, which is the extensive brain region attaching the left side to the right. Here we will use the prairie vole (Microtus ochrogaster), a species virtually unknown to toxicology but that has successfully been used for decades to elucidate the neurobiology of social disorders and develop therapies for ASD. Prairie voles spontaneously show pro-social human traits including affiliation and pair bonding, traits not shown in rats or mice. Thus, the prairie vole is a uniquely ideal ASD model to address our hypotheses. The resulting data will be foundational for developing methods to screen chemicals for ASD-related effects on the developing brain and more comprehensively identifying which compounds and chemical classes might be contributing to neurobehavioral disorders. Although not commonly known, of the more than 85,000 chemicals in commerce, extremely few (by some estimates, less than 10%) have been tested for any evidence of neurotoxicity at all. Aim 1: Establish the long-term impact of developmental fire retardant exposure on neural and behavioral hallmarks of ASD in prairie voles with the hypothesis that exposure heightens risk, especially in males. Aim 2: Test the capacity of
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710565
Entities
People
- Heather Patisaul
Organizations
- North Carolina State University
- United States Army