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A new animal study has revealed that certain brain regions involved in Parkinson’s disease retain a form of cellular memory following exposure to a pesticide, disrupting the expression of specific genes. Researchers identified region-specific changes in gene activity linked to the immune system and synaptic communication.
Investigating rotenone’s effects on the rat brain
Researchers at the UK Dementia Research Institute at King’s College London, together with collaborators at Imperial College London and the University of Pittsburgh, studied the impact of rotenone exposure on rats. Rotenone is a naturally occurring pesticide, toxic to mammals and invertebrates. It is banned in the UK and European Union, and largely restricted in the United States and Canada. It is still occasionally used in aquatic management to control fish populations.
The pesticide is known to impair mitochondrial function and cause oxidative stress, a process in which reactive oxygen species damage cellular DNA. These are both mechanisms implicated in neurodegeneration and have previously been associated with Parkinson’s pathology.
In the study, rats were exposed daily to rotenone for three weeks. After the exposure period, researchers compared brain tissue from these rats with unexposed controls, focusing on two regions: the substantia nigra and motor cortex. Both regions are involved in movement control and are commonly affected in Parkinson’s disease.
“We have known for some time that pesticide exposure increases risk of Parkinson’s. Our new study digs deeper, revealing the region-specific genes changes following pesticide exposure. This study provides clues as to why dopamine neurons in the substantia nigra are vulnerable in Parkinson’s disease.”
Dr. Emily Rocha.
Brain-region specific gene responses
Changes in the epigenome were examined to understand how environmental exposure might alter gene activity. The epigenome includes chemical modifications that influence how genes are switched on or off without altering the DNA sequence.
In the substantia nigra, a brain region rich in dopamine-producing neurons and central to Parkinson’s pathology, gene expression related to the innate immune response was significantly increased. Analysis pointed to the activation of microglia, the central nervous system’s immune cells, suggesting a neuroinflammatory response.
In contrast, in the motor cortex, gene expression changes were observed in pathways associated with synaptic function. Synapses are the communication points between neurons, and disruptions in their function can interfere with signal transmission across the brain’s motor circuitry.
These findings highlight that the biological response to environmental toxins such as pesticides may vary by brain region, involving different cellular processes and molecular pathways.
Future directions
The study provides evidence that rotenone exposure can lead to long-lasting changes in gene regulation in different parts of the brain, implicating both immune activation and synaptic dysfunction. The researchers plan to further investigate how different cell types contribute to these responses and assess whether other environmental toxicants induce similar changes.
Reference: Tsalenchuk M, Farmer K, Castro S, et al. Unique nigral and cortical pathways implicated by epigenomic and transcriptional analyses in rotenone Parkinson’s model. npj Parkinson’s Dis. 2025;11(1):217. doi: 10.1038/s41531-025-01049-1
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