Background: Chemical exposures are widely suspected to contribute to the rapidly rising rates of autism spectrum disorder (ASD), but direct evidence linking specific chemicals to adverse effects on the social brain is sparse and very little is known about the mechanisms by which the social brain is vulnerable to chemical exposures. A major barrier to elucidating environmental contributions to social disorders is the limited capacity of traditional animal models (including transgenic mice and rats) to model human pro-social traits such as affiliation and pair bonding. To overcome this, we will use the prairie vole (Microtus ochrogaster), a well-established, pro-social animal model for exploring the neurobiology of ASD and other social disorders but generally unfamiliar to toxicologists. We will focus on fire retardants (FRs) because exposure to this chemical class has long been associated with behavioral and cognitive impairments in humans, including heightened risk of ASD, and we have preliminary data linking developmental exposure to emerging FRs with ASD traits and common co-occurrences including neuroinflammation and anxiety.Hypothesis/Objective: Using the prairie vole, which is a uniquely suitable ASD animal model, we will test the hypothesis that developmental FR exposure heightens risk of ASD-related behavioral deficits and neurodevelopment, particularly in males. We further propose that disrupted serotonergic communication between the placenta and developing forebrain as the mechanism of action. Critically, the proposed studies will account for possible sex differences in vulnerability and outcome. These hypotheses are supported by preliminary data showing that developmental exposure to chemical FRs sex-specifically heightens risk of anxiety and hyperactivity, behaviors that frequently co-occur with ASD, and disrupt the placental serotonin (5-HT) biosynthetic pathway, a crucial source of 5-HT for the prenatal brain. Evidence for disruption of placental 5-HT constitutes a potentially key and novel mechanism of neurodevelopmental disruption. 5-HT, arising from the fetal placenta, has profound effects on the developing brain, particularly forebrain and, disrupted 5-HT in the developing brain has been associated with ASD traits.Specific Aims:Aim 1: Establish the long-term impact of developmental FR 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 FRs to alter the placental serotonin biosynthetic pathway in the mid-gestational prairie vole brain with the hypothesis that it results in disrupted fetal 5-HT levels in the developing forebrain.Study Design: For Aim 1, animals will be exposed to three doses of FR through gestation and lactation. Offspring will be distributed to assess a suite of behavioral and neural outcomes associated with ASD including social behavior, oxytocin and vasopressin neuron numbers, 5-HT fiber density in amygdala and prefrontal cortex, 5-HT neuron density in dorsal raphe, and microglial density in cerebellum and cortex. For Aim 2, vole dams will be exposed across the first 2/3 of gestation, when placental 5-HT is most critical, and the fetuses examined for sex specific evidence of 5-HT disruption in placenta and brain, and FR accumulation.Impact: 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 behavior and hyperactivity, disruption of the oxytocin/vasopressin system, and neuroinflammation. Remarkably few studies have specifically sought to establish which of the 85,000+ chemicals in our environment contribute to ASD and other disorders of the social brain, or their mechanisms of action. The resulting data are critically needed to develop methods to screen chemicals for neurodevelopmental effects or mitigate exposures that may be contributing to neurobehavioral disorders.Innovation: Establishing the prairie vole as a new research tool for neuroendocrine toxicology is innovative because it is a more suitable model for probing impacts on social behaviors and the social brain than rats or mice. It also lays the groundwork for future gene by environment type studies aimed at understanding how chemical exposures contribute to ASD-relevant traits. Focusing on the placenta and its relationship with the developing brain is also highly innovative as this ephemeral but critically important coordinator of early brain development is never considered as a target tissue in traditional toxicity tests. Finally, very little is known about the potential toxicological effects of the FRs we have selected to focus on, particularly in a mammalian model, but they have rapidly become some of the most common FRs used in US furniture and baby products and are widely used in other applications including personal care products.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
