A new study, partially funded by APDA, has found that exposure to a common pesticide can leave long-term changes in the brain’s genetic landscape, possibly increasing the risk of Parkinson’s disease (PD). The research, published in Nature’s npj Parkinson’s Disease journal in July 2025, shows that the pesticide rotenone triggers lasting alterations in brain gene activity and epigenetic markers (chemical tags that turn genes on or off).
The changes were especially pronounced in the substantia nigra which is the region of the brain most affected in PD, where genes related to inflammation and immune activation were turned on and others were shut down. Even weeks after exposure stopped, this molecular memory persisted, suggesting that environmental toxins may prime the brain for disease, years down the road.
What this Means and Why it Matters
The risks associated with developing PD remain poorly understood. Researchers have increasingly turned their attention to environmental exposures, especially pesticides such as paraquat, organochlorine and organophosphate pesticides, and chemicals like TCE, among others. Studies have shown that people who live near farms, golf courses, or work with agricultural chemicals are at a higher risk for developing PD along with other diseases. You can learn more about other pesticides and pollutants and their connection to PD here and here.
“We have known for some time that pesticide exposure increases risk of Parkinson’s,” explained Emily Rocha, MD, PhD, Assistant Professor of Neurology at the University of Pittsburgh and the co-senior author of this study. “Understanding more about the underlying mechanisms through which pesticide exposure impacts disease development will help us to better understand Parkinson’s overall.” Dr. Rocha is an APDA-funded researcher and University of Pittsburgh Medical Center houses one of APDA’s nine Centers for Advanced Research (CAR). The Director of the University of Pittsburgh CAR is Dr. Tim Greenamyre, a pioneer in the understanding of the environmental contributors to PD risk, and is also an author on the paper.
Rotenone, in particular, is a pesticide that has been shown to interfere with the mitochondria (energy producing organelle in cells) and has been used in past research to mimic Parkinson’s-like damage in animals. One key question that has still yet to be answered is how does a pesticide exposure leave a long-term effect on the brain?
What the Study Found
Researchers from Imperial College London in collaboration with the University of Pittsburgh exposed rats to small daily doses of rotenone over a three-week period. These doses were meant to simulate a low-level environmental exposure similar to what humans might be subjected to. Afterward, they examined two key brain regions that are affected in PD: the substantia nigra and motor cortex.
Rather than looking for physical damage to these areas, they studied how the activity of the genes expressed in these areas had changed and whether there were any significant epigenetic modifications. These refer to alterations, not in the DNA sequence itself, but to structural changes around the DNA that changes gene expression. One of the key mechanisms of epigenetic modification in histone acetylation. Histones are the proteins around which DNA is wrapped and acetylation of this protein increases DNA accessibility and gene expression.
In the substantia nigra alone, there were hundreds of genes that were altered, many of them related to inflammation and microglial activation, effectively turning on the immune system of the brain. Meanwhile, in the motor cortex, the picture was a little different. The genes affected in this region of the brain were more typically involved in the function of the synapse, or the space between two neurons through which communication using neurotransmitters such as dopamine, occurs.
Long-term Consequences
The most concerning discovery within the study was that these changes did not go away after the exposure ended. The gene activity and epigenetic remodeling persisted which pointed to a potential long-term reprogramming of brain cells, which could set the stage for disease development later down the road.
“Through this work, we have advanced vital understanding of how pesticide exposure might lead someone to develop Parkinson’s and the mechanisms involved,” added Sarah Marzi, PhD, group leader at the UK Dementia Research Institute at Imperial College London and co-senior author of the study. “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.”
Epigenetics is increasingly recognized as a contributor to the development of many different diseases. Changes surrounding DNA, as opposed to changes in the DNA sequence itself, could be caused not just by toxins, but by multiple other environmental factors such as diet and stress, with effects that could last for years.
Outcomes from this Research
This study further strengthens the case that environmental factors play a crucial role in PD and some exposures may act as initiators for disease development later in life. Even a brief period of pesticide exposure might prime the brain for reprogramming gene activity in ways that are only detectable years later. This study also adds urgency to the call for regulating neurotoxic pesticides more strictly, and APDA is working collaboratively with other PD organizations to push for lawmakers to step up and ban unsafe chemicals. Pesticides such as rotenone and similarly-acting paraquat (mitochondrial inhibitors) are still used in agriculture in the United States and in other countries around the world.
These findings however, may also pave the way for new therapy options. Drugs that repair the epigenetic changes caused by environmental factors could reverse the processes that lead to disease development.
How to Build Upon this Research
Further studies will focus on examining the specific cell types in the brain that are most affected by these changes (neurons, immune cells, etc.). It is also important to assess the translatability of this work from rats to humans.
APDA is proud to fund the work of Drs. Rocha and Greenamyre, contributing to our crucial understanding of the environmental risk factors that contribute to PD. You can learn more about APDA-funded research on our website.