Study Probes Link Between Pesticides and ALS

Research on ALS, a debilitating condition also known as Lou Gehrig’s disease that leads to muscle weakness and death, has found a link between exposure to pesticides and disease development. A new study led by Assistant Professor of Chemistry, Neuroscience and Behavior, and Integrative Science Alison O’Neil, provides insight into how a specific pesticide damages the nerve cells affected in ALS patients. The finding contributes to understanding of this perplexing disease and potential treatments.

The paper, published in the prestigious multidisciplinary journal PLOS One, is a follow up to another study O’Neil conducted on the pesticide known as cis-chlordane, which is banned but persists in the environment. “The goal of the study was to try to figure out why cis-chlordane is able to kill motor neurons,” which are the nerve cells that die in ALS (amyotrophic lateral sclerosis), she said.

In the earlier study, the research team ruled out a theory that the pesticide was entering the cells through a known mechanism. “Just because you got exposed to pesticides doesn't mean you will get ALS,” she said. “It just increases your risk, but we don't know why.”

To investigate this mystery, O’Neil and her Wesleyan co-authors used adult human stem cells and embryonic stem cells—both cell types that can be turned into other cells—to make motor neurons in the lab. They placed the motor neurons in a petri dish and treated them with cis-chlordane. The research team then used RNA sequencing techniques to learn which genes were active and how they changed under certain conditions. They also used fluorescent dyes to measure molecules that can indicate cell damage.

Further experiments showed the pesticide was causing damage by impacting cell metabolism. “The cells are consuming less oxygen,” said first author Oliver Clackson ’25, who was involved in assessing the metabolism of the motor neurons.

 “It turns out that [the pesticides] are affecting the mitochondria, which are the powerhouse of the cell,” said O’Neil. Without mitochondria, the motor neurons weaken and die. This insight points to potential for more effective treatments for a disease when current therapies extend life by only a few months. “The implications of that finding helps us determine what kind of drugs people need,” said O’Neil.

Those treatments include antioxidant therapies. “We're finding that an antioxidant therapy could be helpful for ALS patients,” she explained. “If we could make a more targeted therapy, so it was [targeted] more towards your motor system so you actually got a better, bigger benefit, then that could be helpful.”  

Since there is clearly an environmental component in most cases of ALS, said Clackson, the research can help pinpoint what is contributing to the disease and potentially change disease trajectory. “If we see these early biomarkers, say pesticides in the blood, then we can perhaps treat them earlier and have a completely different outcome,” he said.

While O’Neil’s research focused on cis-chlordane, there are other pesticides in our environment that have a similar effect on motor neurons. She hopes to develop a screen to test pesticides for nervous system effects before they are approved for use, especially since pesticides also contribute to the risk of other neurodegenerative diseases such as Parkinson’s and Alzheimer’s. “This allows us to say why pesticides are increasing people's risk of getting neurodegenerative diseases,” she said, “and then once we have a really good handle on exactly what the [pesticide] is doing, we can develop better therapeutics for people.”

In a related paper, O’Neil and colleagues investigated a protein, SOD1, that is known to have a toxic effect on the motor neurons in ALS patients. Mutations in this protein cause inherited forms of ALS. The protein can accumulate and aggregate in the nerve cells of the spine (motor neurons). Using stem cells again, her lab identified a SOD1 protein modification that was only present in motor neurons, but not other cell types. Recreating this modification in the lab, her team showed that the modification made the protein aggregate more, just like what is seen in patients. This research further validated a model for studying the disease that O’Neil and her colleagues will use in future studies. “This study lays the groundwork for better understanding how the cellular environment of motor neurons may cause protein modifications that lead to disease,” she said.