Research led by Dr Sarah Marzi (UK DRI at King’s) with collaborators at Imperial College London and the University of Pittsburgh, reveals cells in key brain regions involved in Parkinson’s retain a ‘memory’ of pesticide exposure that disrupts gene expression.
The study found significant changes in the substantia nigra and motor cortex – two areas of the brain known to be affected in Parkinson’s – of rats, following exposure to the pesticide rotenone.
Rotenone is a naturally occurring pesticide known to be toxic to invertebrates and mammals, and is banned in the UK and European Union. In the US and Canada, rotenone is banned for the most part but is still used to control fish populations in lakes and reservoirs. The pesticide is known to cause dysfunction in mitochondria, the cell’s powerhouses, as well as oxidative stress – when molecules are produced that damage the DNA in cells – which the researchers observed across both the brain regions investigated in the study. There is strong epidemiological evidence linking pesticides and Parkinson’s, particularly in the case of farm workers exposed to agricultural pesticides over long periods of time.
In the study, rats were exposed daily to rotenone for a period of 3 weeks, and their brains were analysed after the exposure period. These were compared to rats which had not been exposed to rotenone. The researchers looked for changes in the epigenome of the rats. The epigenome is a collection of chemical markers that act like switches and levers on our DNA, dialling the output of genes up and down in response to our environment.
In the exposed animals, they found that the expression of genes associated with the innate immune system were strongly increased in the substantia nigra, the area of the brain typically associated with Parkinson’s. Investigating further, the team were able to pinpoint that microglia, the brain’s resident immune cells, were activated in the substantia nigra.
What we have found is that responses to this environmental pesticide exposure were strikingly different in the two different brain regions we looked at. Our study provides compelling evidence that rotenone causes changes in gene expression, related to the immune system in the substantia nigra, and synapse dysfunction in the motor cortex.
Group Leader
In the motor cortex, genes related to the function of synapses – the connection points between brain cells – were markedly different in the rats which had been exposed to the pesticide. This supports a role for disrupted communication between cells driving Parkinson’s following pesticide exposure.
Published in the journal npj Parkinson’s, and funded by the Edmond J. Safra Foundation and the UK DRI, the new study unlocks key understanding of the mechanisms underlying the role of pesticide exposure in Parkinson’s – for which there is well documented epidemiological evidence.
Next, the team plan to study how different cells contribute to these responses and test further environmental toxicants to understand whether they cause similar changes.
Co-senior author Dr Sarah Marzi, Group Leader at the UK Dementia Research Institute at King’s College London, said:
“We were interested in understanding how cells retain a memory of long-term, low-grade exposure to pesticides, and how that predisposes someone to developing Parkinson’s.
What we have found is that responses to this environmental pesticide exposure were strikingly different in the two different brain regions we looked at. Our study provides compelling evidence that rotenone causes changes in gene expression, related to the immune system in the substantia nigra, and synapse dysfunction in the motor cortex.
Through this work we have advanced vital understanding of how pesticide exposure might lead someone to develop Parkinson’s, and the mechanisms involved.”
Co-senior author Dr Emily Rocha, Assistant Professor of Neurology at the University of Pittsburgh, said:
“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.
Understanding more about the underlying mechanisms through which pesticide exposure impacts disease development will help us to better understand Parkinson’s overall. With deeper insight into the role of gene regulation in disease progression, we hope to be able to harness the therapeutic potential of some of these pathways.”
Reference: ‘Unique nigral and cortical pathways implicated by epigenomic and transcriptional analyses in a rotenone rat model of Parkinson’s disease’ by M Tsalenchuk, K Farmer, S Castro et al is published in npj Parkinsons’s. DOI: 10.1038/s41531-025-01049-1, available at https://www.nature.com/articles/s41531-025-01049-1
Banner image: Immune cells are upregulated in the substantia nigra of rats exposed to the pesticide rotenone. Microglia (white), the immune cells of the brain, are activated (red) in the vicinity of dopaminergic neurons (green), which degenerate in Parkinson’s disease. Credit: Emily Rocha
