Pesticides are biocidal, principally neurotoxic chemicals commonly used in the USA and throughout the world for agriculture, landscaping, household use, and insect-born disease control. Because many pesticides have been linked to risk for various neurological disorders, the proper determination of safe exposure levels for each pesticide is critical to public health. Recent epidemiological studies in our lab and others have linked perinatal exposure to pyrethroid pesticides with increased risk for autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD) in children. Our lab has also demonstrated that mice exposed to pyrethroid concentrations below the EPA ?no observable adverse effect? level have alterations in dopamine (DA) release, storage, and trafficking, as well as an ADHD-related behavioral phenotype. Critically, no existing animal study has evaluated the impact of pyrethroid exposure on social behaviors relevant to psychiatric disorders like ASD. There is a critical knowledge gap regarding the full extent of the behavioral and neurophysiological phenotypes caused by low-dose exposure to pyrethroids and relevant to ADHD and ASD risk. To address this knowledge gap, we will take advantage of the extraordinary expertise of the Miller lab in neurotoxicology, as well as my expertise in complex social behavior and the prairie vole, an animal model with unique social behaviors considered translationally relevant to ASD. We propose to study the effects of developmental pyrethroid exposure on neurophysiology and behavior in translational animal models relevant to human psychiatric disorders.
In Aim 1, we will determine the behavioral phenotype of pyrethroid-exposed mice by testing for a broad range of behavioral deficits relevant to ASD, including social interaction, communication, repetitive behaviors, and the new generation of empathy-based behavioral tests.
In Aim 2, we will use a wide range of morphological, neurochemical and electrophysiological techniques to determine the neurophysiological changes in DA storage and release in pyrethroid-exposed mice.
In Aim 3, I will carry these same techniques into my independent research program, where I will use them to determine the critical disruptions in DAT in pyrethroid-exposed mice.
In Aim 4, I will more fully develop my independent research program by determining the behavioral and neurophysiological phenotype of pyrethroid exposed prairie voles, focusing on alterations in unique social behaviors shared between human and vole, including social bonding, spontaneous parental care, and empathy-based consoling behavior. This project is designed to develop a successful long-term research program focused on the contribution of environmental toxins to risk for psychiatric disease. This will involve a substantial training and career development program led by primary mentor Dr. Gary Miller, an expert in neurotoxicology; and involving a mentoring team consisting of Dr. Shannon Gourley, an expert on animal models of psychopathy and psychiatric disease; Dr. Donald Rainnie, an expert on neurodevelopment and electrophysiology; and Dr. Michael Caudle, a toxicologist and expert on mouse models of developmental toxic exposure. In addition to their expert guidance and mentorship, Dr. Gourley will contribute her significant expertise on spine density morphometry and analysis, and Dr. Rainnie will contribute his significant expertise on whole cell patch clamp. Completion of these Aims, along with the extensive training and career development plan outlined in this proposal, will help to build an innovative, productive, and long-term research program focused on the contribution of environmental toxicants to risk for psychiatric and neurological disorders, which may inform treatments, preventive measures and regulations.
Although pyrethroid pesticides have been approved by the EPA for widespread use, recent epidemiological studies have linked residential pyrethroid exposure during pregnancy to increased risk for autism spectrum disorders and ADHD. The purpose of this proposal is to determine the effects of developmental exposure to pyrethroid pesticides below the current EPA ?no observable adverse effect? level, using translational rodent models with predictive validity for human psychiatric disorders. This proposal will provide support for research, training, and career development intended to build a productive, long-term research program focused on the contribution of environmental toxicants toward risk for psychiatric and neurological disorders, including autism.
| Cliburn, Rachel A; Dunn, Amy R; Stout, Kristen A et al. (2017) Immunochemical localization of vesicular monoamine transporter 2 (VMAT2) in mouse brain. J Chem Neuroanat 83-84:82-90 |
