Long-term exposure to pesticides linked to Parkinson’s disease, study finds

A new study has identified 53 different pesticides linked to an increased risk of Parkinson’s disease. Tests revealed that 10 of these pesticides are directly toxic to neurons. Mixtures of pesticides, including the herbicide trifluralin, exhibited higher toxicity than any single pesticide. Trifluralin, in particular, kills dopamine-producing neurons by disrupting mitochondrial function, a crucial aspect of cellular operation. The study was published in Nature Communications.

Pesticides are chemical substances or mixtures used to kill pests such as insects, weeds, fungi, rodents, and other organisms that harm crops, humans, livestock, or the environment. They are regularly employed in agriculture, farming, and forestry to prevent damage done by pests, but also to reduce populations of disease-carrying organisms such as mosquitoes.

Pesticides operate by disrupting the normal biological functions of the targeted pests. The mechanisms of action vary among different types. For example, insecticides—a category of pesticides aimed at eradicating insects—may interfere with the insects’ nervous systems or hinder their molting and growth processes. Simply put, pesticides act as poisons for pests. However, substances toxic to pests may also pose risks to human health. Numerous pesticides, once widely used, have been banned upon discovering their harmful effects on humans.

Study author Kimberly C. Paul and her colleagues wanted to explore the possible links between exposure to specific pesticides and the risk of Parkinson’s disease. Parkinson’s disease is a neurodegenerative disorder that impairs the motor functions of the affected individual. The symptoms include tremors, rigidity, slowness of movement, and postural instability. Parkinson’s disease is caused by the progressive loss of neurons that produce the neurotransmitter dopamine in the brain.

Previous research has suggested links between long-term exposure to certain pesticides and an elevated risk of Parkinson’s disease, but these findings were not comprehensive. In this study, the researchers combined epidemiological analysis with direct testing of the effects of specific pesticides on neurons derived from stem cells in a laboratory setting.

The study involved participants from the Parkinson’s Environment and Genes study, a population-based investigation conducted in three agriculturally-rich counties of Central California: Kern, Fresno, and Tulare. California’s status as the largest U.S. agricultural producer, coupled with its extensive use of pesticides, made it an ideal location for this research.

The study included 829 individuals diagnosed with Parkinson’s disease and 824 healthy controls, enrolled between 2000 and 2015. To be eligible, healthy participants needed to be over 35 and have resided in one of the three counties for at least five years prior to enrollment.

The researchers assessed pesticide exposure by correlating participants’ residential and work locations with the agricultural pesticide application data. In California, all pesticide usage must be logged in a database managed by the California Department of Pesticide, providing detailed records. This resulted in 5.9 million usage records of 1,355 different pesticides in the study counties from 1974 to 2017.

By linking this data with the Public Land Survey system and participants’ address histories, researchers could estimate each participant’s exposure to pesticides at their residences for an average of 22 years and at workplaces for 18 years. The study tracked 288 pesticides to which at least 25 participants were exposed.

Additionally, the researchers generated dopamine-producing neurons in the lab using stem cells from a male Parkinson’s patient. These neurons served as models to directly test the effects of pesticides. Since Parkinson’s disease involves the destruction and dysfunction of specific dopamine-producing neurons in the brain, the hypothesis was that pesticides toxic to lab-grown neurons would likely be harmful to brain neurons if exposure occurred.

The results indicated that 53 pesticides were distinctly linked to Parkinson’s disease risk, with 15 others being probable contributors. The five pesticides most strongly associated with increased risk were sodium chlorate, dicofol, prometryn, methomyl, and xylene range aromatic solvent, consistently linked across all study locations.

Testing on lab-grown neurons was conducted with 39 of these pesticides. Exposure to 10 of them at concentrations of 30 µM resulted in significantly higher cell death rates compared to control conditions. The lethal pesticides included propargite, copper sulfate (both basic and pentahydrate forms), dicofol, folpet, naled, endothall, trifluralin, endosulfan, and diquat dibromide. Most of the pesticides are still in use today in the United States.

Since pesticides are often used in combinations, the study also examined the effects of pesticide clusters. Findings revealed that combinations involving trifluralin caused more neural cell deaths than any single pesticide. Notably, trifluralin, a herbicide used in cotton farming, disrupts mitochondrial function, essential for cellular energy production.

“Our comprehensive, pesticide-wide association study has implicated both a variety of individual pesticides in Parkinson’s disease risk and suggested relevant co-exposure profiles,” the researchers wrote. “Coupling this with direct testing in vitro on dopaminergic neurons, we have pinpointed pesticides that were directly toxic to human dopaminergic neurons. Further, real-world co-exposure data has allowed us to develop co-exposure paradigms ‘in the dish’ and establish which combinations of pesticides can indeed lead to greater, synergistic mDA toxicity [toxicity to the dopamine-producing neurons in the midbrain]. Ultimately, we have identified pesticides that are both ostensibly mDA-toxic and pesticides that are not mDA-toxic, but, nonetheless, associated with increased risk of Parkinson’s disease.”

The study makes an important contribution to the scientific understanding of the biological effects of pesticides. However, it should be noted that tests of effects of pesticides were conducted by directly exposing relatively immature neurons developed in the lab. Their effects on neurons located in the brain, protected by the blood-brain barrier and functioning in an environment that also involves other types of cells might not be the same.

The paper, “A pesticide and iPSC dopaminergic neuron screen identifies and classifies Parkinson-relevant pesticides”, was authored by Kimberly C. Paul, Richard C. Krolewski, Edinson Lucumi Moreno, Jack Blank, Kristina M. Holton, Tim Ahfeldt, Melissa Furlong, Yu Yu, Myles Cockburn, Laura K. Thompson, Alexander Kreymerman, Elisabeth M. Ricci-Blair, Yu Jun Li, Heer B. Patel, Richard T. Lee, Jeff Bronstein, Lee L. Rubin, Vikram Khurana, and Beate Ritz.