Unique nigral and cortical pathways implicated by epigenomic and transcriptional analyses in rotenone Parkinson’s model

Pesticide exposure is increasingly recognized as a potential environmental factor in idiopathic Parkinson’s disease, though the molecular mechanisms remain unclear. This study explores how pesticide exposure alters gene regulation in key brain regions using the rotenone rat model. We performed H3K27ac ChIP-sequencing to profile active regulatory elements in the substantia nigra and motor cortex. Despite uniform complex I inhibition across regions, we observed region-specific epigenomic changes associated with rotenone exposure. RNA-sequencing confirmed transcriptomic alterations. We identified a strong, rotenone-induced immune response in the substantia nigra, including increased activity in the C1q complement pathway, suggesting immune involvement driven by regulatory mechanisms. In contrast, the cortex showed dysregulation of synaptic function at the gene regulatory level. 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 and selective vulnerability that characterise Parkinson’s disease.