Unique nigral and cortical pathways implicated by epigenomic and transcriptional analyses in a rotenone rat model of Parkinson's disease [ChIP-Seq]

Pesticide exposure is increasingly recognised as a potential environmental factor contributing to the onset of idiopathic Parkinson's disease, yet the molecular mechanisms underlying this connection remain unclear. This study aims to explore how pesticide exposure disrupts key brain regions involved in Parkinson's disease pathology by reshaping gene expression and epigenetic landscapes. Using the well established rotenone rat model of the disease, we used H3K27ac ChIP-sequencing and RNA-sequencing to profile active regulatory elements and transcriptional activity in the substantia nigra and cortex. We identified widespread transcriptomic and epigenetic differences which are consistent across the assays. Our results indicate there is a strong immune response to rotenone localised to the substantia nigra and highlight an enrichment of immune-related motifs in this brain region, suggesting that the immune response is at least partially driven by gene regulatory mechanisms. We also noted an increase in C1q complement pathway activity in the substantia nigra. In contrast, we identified widespread dysregulation of synaptic function at the gene regulatory level in the cortex of these same rats. Our results highlight a role for gene regulatory mechanisms potentially mediating the effects of pesticide exposure, driving region-specific functional responses in the brain that may contribute to the pathology of Parkinson's disease. Overall design: To profile gene regulatory variation in the SN and cortex of rats exposed to rotenone compared to vehicle controls, we used RNA sequencing (RNA-seq) and H3K27ac chromatin immunoprecipitation (ChIP)-seq