Impacts of phthalate exposure on the development of social behavior circuits - Summary: Our modern environment contains many industrially produced chemicals that can impact human health, including molecules classified as endocrine disrupting compounds (EDCs). One type of EDC with potentially profound implications for neurodevelopment is the environmentally ubiquitous family of phthalates. Phthalates serve as stabilizers in plastics and are found in vinyl flooring, children’s toys, personal care products, and medical devices. Pregnant women are exposed to phthalates throughout pregnancy and metabolite concentrations of phthalates is greatest in children 6-11 years old. Recent studies suggest that individuals exposed gestationally to phthalate metabolites show higher scores of autistic traits including increased social anxiety and impaired communication. Despite these important developments, very little is known about how phthalate exposure alters the nervous system to contribute to changes in social behavior or communication. Our preliminary data indicate that exposure to phthalates during development leads to reduced social investigation and social communication in mice, which coincides with large-scale changes in anatomical and functional connectivity in the brain. It also results in changes in dopaminergic gene expression in limbic regions important for processing social stimuli. This is important as atypical social behavior and reduced communication are key diagnostic criteria for autism spectrum disorders (ASD). Therefore, the goal of this proposal is to test the novel hypothesis that exposure to phthalates during development leads to alterations in whole-brain connectivity, gene expression profiles, and physiological signaling across limbic regions important for the processing of social reward. Specifically, we will test: (1) whether phthalate exposure results in reduced anatomical and functional connectivity of frontal, sensory, and limbic regions essential for motivated social engagement; (2) whether phthalate exposure results in decreased social investigation and reduced dopamine signaling in pathways essential for processing of social reward; (3) whether phthalate exposure alters the molecular profile of hormone, dopaminergic, and cellular signaling markers across limbic regions in juvenile and adult animals. Explicit tests of these hypotheses will be accomplished by using whole brain magnetic resonance imaging, projection specific fiberphotometry during behavior, and multi-region high-density transcriptomics. The proposed research plan integrates the diverse technical skills and scientific knowledge of a MPI team and a strong cast of supporting toxicology, imaging, and bioinformatics collaborators, to generate an innovative and comprehensive approach for linking clinically-relevant features of autistic behaviors to phthalate exposure during development. This will be the first study to examine the effects of phthalate exposure on changes in social behavior, while innovatively and quantitatively assessing alterations across the entirety of limbic structures essential for contextual modulation of behavior. As such, it will launch a novel direction of research and is critical for determining the risks of environmental phthalates on atypical neural development in regions that regulate social behavior.
