Developmental pyrethroid exposure in the prairie vole as a model of environmental risk for autism - Project Summary The prevalence of autism and other neurodevelopmental disorders (NDDs) is at an all-time high, with 17% of children diagnosed with a developmental disability and 1 in 44 diagnosed with autism. Many of these disorders have few or no established biomarkers, few or no medical treatments, and can only be diagnosed behaviorally, emphasizing the need for research into causes and treatments. One risk factor for autism and NDDs is exposure during pregnancy to pyrethroid pesticides, which are present in 70-80% of blood samples from the general public and are implicated in risk for autism and developmental delay. There is a critical knowledge gap regarding the maximum safe exposure to pyrethroids during development. To address this knowledge gap, I propose to use to explore the maximum safe developmental dose relative to behavioral and molecular outcomes using developmental deltamethrin exposure (DPE) in the prairie vole. Prairie voles are hamster-sized rodents indigenous to the Midwest that are studied in behavioral neuroscience for their unique complex social behaviors, including monogamous bonding, biparental care, and empathy- based consoling. Prairie voles have other species-specific advantages, such as diurnal cycles, circadian and ultradian rhythms, and the fact that they share an environment with humans and are co-exposed to pesticides. These factors make the prairie vole the ideal model for exploring environmental effects of pesticide exposure. Our central hypothesis is that DPE causes dose-dependent changes in NDD-relevant outcomes in prairie vole, including disrupted circadian/ultradian movement, hyperactivity, repetitive behaviors, decreased vocalizations, learning deficits, natural wild behaviors. We also hypothesize that developmentally exposed prairie voles will show dose-dependent, multi-modal changes in molecular function of the suprachiasmatic nucleus (SCN), the master control region for biological rhythms in the brain. To test these hypotheses, we will expose prairie vole mothers to deltamethrin at four doses (0, 0.03, 0.3, 3 mg/kg) during pregnancy and lactation, and look for developmental effects in the subsequent offspring. Aim 1 will assess dose-dependent effects in controlled laboratory assays to look for task-specific dose-response curves and the maximum dose at which no adverse effects are observed. In Aim 2, we will release DPE prairie voles into natural outdoor enclosures with advanced tracking technology and measure dose-dependent changes to natural social and survival behaviors. In Aim 3, we will use a split-sample multiomics approach to look for dose-dependent multimodal molecular changes in the SCN and striatum, focusing on bulk and cell type-specific gene transcription, kinome array profiling, and multiomics integration analyses. Successful completion of these Aims will provide the broadest possible view of dose-dependent changes in brain and behavior, including the doses relevant to each behavioral outcome and task, and the full range of exposure-induced changes in the SCN.
