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bioRxiv · 10.1101/2023.10.13.562226

Developmental pyrethroid exposure disrupts folate metabolism in mouse brain

Curtis, M. A.·Saferin, N.·Nguyen, J. H.·Imami, A. S.·Neifer, K. L.·Miller, G. W.·Burkett, J. P.
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Abstract

Environmental and genetic risk factors, and their interactions, contribute significantly to the etiology of neurodevelopmental disorders (NDDs). Recent epidemiology studies have implicated pyrethroid pesticides as an environmental risk factor for autism and developmental delay. Our previous research showed that low-dose developmental exposure to the pyrethroid pesticide deltamethrin in mice caused male-biased changes in the brain and in NDD-relevant behaviors in adulthood. Here, we used a metabolomics approach to determine the broadest possible set of metabolic changes in the adult male mouse brain caused by low-dose pyrethroid exposure during development. Using a litter-based design, we exposed mouse dams during pregnancy and lactation to deltamethrin (3 mg/kg or vehicle every 3 days) at a concentration well below the EPA-determined benchmark dose used for regulatory guidance. We raised male offspring to adulthood and collected whole brain samples for untargeted high-resolution metabolomics analysis. Developmentally exposed mice had disruptions in 116 metabolites which clustered into pathways for folate biosynthesis, retinol metabolism, and tryptophan metabolism. As a cross-validation, we integrated metabolomics and transcriptomics data from the same samples, which confirmed previous findings of altered dopamine signaling. These results suggest that pyrethroid exposure during development leads to disruptions in metabolism in the adult brain, which may inform both prevention and therapeutic strategies. HighlightsO_LIDevelopmental pyrethroid exposure disrupts brain metabolism in adulthood C_LIO_LIExposure disrupts metabolic pathways for folate, retinol, and tryptophan C_LIO_LIExposure disrupts genetic and metabolic pathways for dopamine signaling C_LI

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Curtis, M. A., Saferin, N., Nguyen, J. H., Imami, A. S., Neifer, K. L., Miller, G. W., Burkett, J. P.. 2023-10-17. Developmental pyrethroid exposure disrupts folate metabolism in mouse brain. https://doi.org/10.1101/2023.10.13.562226

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