Long-term dysregulation of histone acetylation, BDNF expression, and the hippocampal transcriptome in adult rats exhibiting a depressive-like phenotype following repeated chlorpyrifos exposure

Abstract

Epidemiological evidence indicates that occupational exposures to the organophosphate pesticide chlorpyrifos (CPF) in adults are associated with an increased risk for depression. In this study, we use a rat model of occupational-like CPF exposure associated with a chronic depressive phenotype to investigate underlying molecular mechanisms. Adult rats received CPF (5 mg/kg/day) for 21 days. When assessed three months later, blood and brain cholinesterase activity had returned to control levels despite the presence of depressive signs. Hippocampal tissue was collected at this endpoint for molecular analyses. Western blotting analysis showed significant upregulation of histone deacetylase protein levels of HDAC3 and HDAC5, whereas HDAC1 and HDAC2 were unchanged. HDAC5 regulates histone acetylation at the brain-derived neurotrophic factor (Bdnf) gene. We used chromatin immunoprecipitation to assay histone 3 lysine 9 acetylation (H3K9ac) occupancy at the Bdnf promoter IV. H3K9ac levels at the Bdnf promoter IV were significantly reduced in CPF rats, accompanied by a concomitant reduction in BDNF protein expression. Exploratory RNA-sequencing identified 100 significantly differentially expressed genes in CPF-exposed rats at a false discovery rate < 5%, including significant downregulation in genes such as insulin-like growth factor 2 (Igf2), fibroblast growth factor 14 (Fgf14), and slit guidance ligand 2 (Slit2) involved in neuronal growth, synaptic function, and axon guidance. Gene Ontology analysis revealed enrichment in pathways related to neurogenesis, neuronal projections, and myelination. Overall, this study indicates persistent epigenetic and transcriptional dysregulation associated with reduced hippocampal BDNF and alterations in neuronal plasticity-related pathways linked to a long-term depressive-like phenotype following CPF exposure.