Developmental pyrethroid exposure disrupts molecular pathways for circadian rhythms and synaptic plasticity in mouse brain.

ABSTRACT: Neurodevelopmental disorders (NDD) are a category of pervasive disorders of the developing nervous system with few or no recognized biomarkers. A significant portion of the risk for NDD, including ADHD, is contributed by the environment, and exposure to pyrethroid pesticides during pregnancy has been identified as a potential risk factor for NDD in the unborn child. We recently showed that low-dose developmental exposure to the pyrethroid pesticide deltamethrin (DPE) in mice causes male-biased changes to ADHD- and NDD-relevant behaviors as well as the striatal dopamine system. Here, we used a multiomics approach to determine the broadest possible set of pharmacologically relevant changes in mouse brain resulting from DPE. Using a litter-based, split-sample design, we deltamethrin 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. The male offspring were raised to adulthood, euthanized, and whole brain samples pulverized and divided for split-sample transcriptomics, kinomics and multiomics integration. The transcriptome revealed alterations to multiple canonical clock genes. The kinome revealed changes in the activity of multiple kinases involved in synaptic plasticity, and broadly in the AGC kinase family. Multiomics integration revealed a dysregulated protein-protein interaction network containing primary clusters for MAP kinase cascade, synaptic function, and regulation of apoptosis. These results demonstrate that DPE causes a multi-modal biophenotype in the brain relevant to ADHD and identifies new potential avenues for therapeutics.

ORGANISM(S): Mus musculus

PROVIDER: GSE241185 | GEO | 2023/08/28

REPOSITORIES: GEO