Pesticide exposure linked to brain gene changes in Parkinson’s
Rat study shows exposure triggered activation changes in two brain regions
Researchers have uncovered how exposure to a common environmental pesticide may disrupt brain function in ways that contribute to Parkinson’s disease.
Exposing rats to rotenone, a pesticide mostly banned in the U.S. and Canada, but still used in lake management, triggered changes in the activation of certain genes in two key brain regions — the substantia nigra, where changes were linked to immune activation, and the motor cortex, where it caused a disruption in how nerve cells communicate.
“Through this work, we have advanced vital understanding of how pesticide exposure might lead someone to develop Parkinson’s and the mechanisms involved,” Sarah Marzi, PhD, group leader at the UK Dementia Research Institute at King’s College London and co-senior author of the study, said in a news story from the institute.
The study, “Unique nigral and cortical pathways implicated by epigenomic and transcriptional analyses in rotenone Parkinson’s model,” was published in npj Parkinson’s Disease. It was led by Marzi in collaboration with researchers at Imperial College London and the University of Pittsburgh.
Parkinson’s is marked by the gradual loss of certain brain cells in the substantia nigra, a region involved in controlling movement. While this area is a well-known site of damage, other parts of the brain, like the motor cortex — which helps plan and coordinate movement — are also affected, especially as the disease progresses.
While the exact causes of Parkinson’s are still unclear, a combination of genetic and environmental factors is thought to play a role in its development and progression. Among environmental contributors, pesticide exposure has been increasingly recognized as a potential risk factor. The molecular mechanisms by which these agents drive the disease remain poorly understood, however.
“We have known for some time that pesticide exposure increases risk of Parkinson’s,” said Emily Rocha, MD, PhD, assistant professor of neurology at the University of Pittsburgh and co-senior author of the study. “Understanding more about the underlying mechanisms through which pesticide exposure impacts disease development will help us to better understand Parkinson’s overall.”
Gene changes with pesticide exposure
Here, researchers examined how genes are regulated following pesticide exposure in certain brain regions affected by Parkinson’s. They exposed rats to rotenone, a pesticide widely used in research to induce Parkinson’s-like symptoms because it disrupts the function of nerve cells’ mitochondria, which are referred to as cells’ powerhouses or energy generators. Once used in agriculture, rotenone has been banned in the U.K. and European Union and is largely banned in the U.S. and Canada due to health and environmental concerns. It’s still occasionally used to manage invasive fish populations in lakes and rivers, however.
The rats received daily injections into their abdominal cavity over three weeks. A separate group of control animals received a neutral solution. After confirming the disease had been induced, brain tissue from both regions was analyzed.
The researchers examined which genes were turned on or off, called gene expression, and how those genes were controlled through chemical modifications to DNA-associated proteins. One such modification, called histone acetylation, makes genes more accessible and easier to activate, without altering the genetic code itself.
Exposure to rotenone exposure led to widespread changes in both gene activity and regulation in the substantia nigra and motor cortex, but the nature of these changes differed between the two.
Immune and inflammatory responses, synaptic dysfunction
In the substantia nigra, rotenone exposure led to the activation of immune and inflammatory responses, particularly through increased expression of genes encoding components of the complement system — a key part of the body’s first line of defense that helps tag and clear damaged cells. Genes like C1QA, C1QB, and C1QC  were not only switched on, but also marked by increased histone acetylation. This pattern suggests “an enhanced inflammatory response in this region,” the researchers wrote.
These molecular findings were supported by increased activation of microglia, the brain’s resident immune cells, in the substantia nigra of rats treated with rotenone compared with controls.
The main alterations seen in the motor cortex involved the function of synapses, the points where brain cells connect and communicate. Specifically, regions near genes involved in synapse organization and signaling, such as HOMER1, GRIN2B, and SHANK1, showed increased histone acetylation. The genes’ altered regulation may contribute to the synaptic dysfunction seen in this brain region as the disease progresses.
Both brain regions showed signs of oxidative stress — a type of cellular stress caused by the buildup of harmful molecules — and dysfunction in mitochondria. However, changes in genes involved in these pathways were more pronounced in the substantia nigra, showing it to be a more vulnerable region in Parkinson’s disease, according to researchers.
“What we have found is that responses to this environmental pesticide exposure were strikingly different in the two different brain regions we looked at,” Marzi said. “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.”
“With deeper insight into the role of gene regulation in [Parkinson’s] disease progression, we hope to be able to harness the therapeutic potential of some of these pathways,” Rocha said.
About the Author
