Pesticides and Parkinson’s: UCLA researchers uncover further proof of a link. Study suggests potential new target in fight against debilitating disease By Mark Wheeler January 03, 2013
For several years, neurologists at UCLA have been building a case that a link exists between pesticides and Parkinson’s disease. To date, paraquat, maneb and ziram — common chemicals sprayed in California’s Central Valley and elsewhere — have been tied to increases in the disease, not only among farmworkers but in individuals who simply lived or worked near fields and likely inhaled drifting particles
The 2009 UCLA epidemiological study didn’t just examine farmers who constantly worked with pesticides, but also people who simply lived near where farm fields were sprayed and who were exposed by “drift.” From 1998 to 2007, the researchers enrolled 362 people with Parkinson’s and 341 controls living in the Central Valley, then obtained historical occupational and residential addresses from all the study participants. Employing their GIS (geographic information system) model, they estimated exposures to fungicides both at work and home, from 1974 to 1999
Suspecting a relationship to Parkinson’s, Jeff Bronstein, a UCLA professor of neurology and co-author of the study, performed a genetic screen to prove that certain fungicides could inhibit the breakdown of proteins used in brain function, which the fungicides DID INHIBIT.
The results reaffirmed what the previous UCLA research had suggested, that the data, “suggests that the critical window of exposure to toxicants may have occurred years before the onset of motor symptoms, when a diagnosis of Parkinson’s is made.“
The UCLA researchers used a Geographic information system–based tool that estimates human exposure to pesticides applied to agricultural crops, according to the distance from fields on which pesticides are sprayed. This GIS tool combined land-use maps and pesticide-use reporting data from the state of California. Each pesticide-use record includes the name of the pesticide’s active ingredient, the amount applied, the crop, the acreage of the field, the application method and the date of application.
The UCLA School of Public Health results appear in the current online edition of the European Journal of Epidemiology. The research was supported by the National Institute of Environmental Health Science, the National Institute of Neurological Disorders and Stroke. Pilot funding was provided by the American Parkinson Disease Association. http://www.eurekalert.org/pub_releases/2013-01/uoc–pap010313.php University of California – Los Angeles
Benomyl a widely used fungicide for several decades has evidence that exposure thereof starts a cascade of cellular events that may lead to Parkinson’s. The pesticide prevents an enzyme called ALDH (aldehyde dehydrogenase) from keeping a lid on DOPAL, a toxin that naturally occurs in the brain. When left unchecked by ALDH, DOPAL accumulates, damages neurons and increases an individual’s risk of developing Parkinson’s.
For several years, neurologists at UCLA have been building a case that a link exists between pesticides and Parkinson’s disease. To date, paraquat, maneb and ziram — common chemicals sprayed in California’s Central Valley and elsewhere — have been tied to increases in the disease, not only among farmworkers but in individuals who simply lived or worked near fields and likely inhaled drifting particles. Now, UCLA researchers have discovered a link between Parkinson’s and another pesticide, benomyl, whose toxicological effects still linger some 10 years after the chemical was banned by the U.S. Environmental Protection Agency.
Even more significantly, the research suggests that the damaging series of events set in motion by benomyl may also occur in people with Parkinson’s disease who were never exposed to the pesticide, according to Jeff Bronstein, senior author of the study and a professor of neurology at UCLA, and his colleagues.
Benomyl exposure, they say, starts a cascade of cellular events that may lead to Parkinson’s. The pesticide prevents an enzyme called ALDH (aldehyde dehydrogenase) from keeping a lid on DOPAL, a toxin that naturally occurs in the brain. When left unchecked by ALDH, DOPAL accumulates, damages neurons and increases an individual’s risk of developing Parkinson’s.
The investigators believe their findings concerning benomyl may be generalized to all Parkinson’s patients. Developing new drugs to protect ALDH activity, they say, may eventually help slow the progression of the disease, whether or not an individual has been exposed to pesticides. The research is published in the current online edition of Proceedings of the National Academy of Sciences.
Parkinson’s disease is a debilitating neurodegenerative disorder that affects millions worldwide. Its symptoms — including tremor, rigidity, and slowed movements and speech — increase with the progressive degeneration of neurons, primarily in a part of the mid-brain called the substantia nigra. This area normally produces dopamine, a neurotransmitter that allows cells to communicate, and damage to the mid-brain has been linked to the disease. Usually, by the time Parkinson’s symptoms manifest themselves, more than half of these neurons, known as dopaminergic neurons, have already been lost.
While researchers have identified certain genetic variations that cause an inherited form of Parkinson’s, only a small fraction of the disease can be blamed on genes, said the study’s first author, Arthur G. Fitzmaurice, a postdoctoral scholar in Bronstein’s laboratory.
“As a result, environmental factors almost certainly play an important role in this disorder,” Fitzmaurice said. “Understanding the relevant mechanisms — particularly what causes the selective loss of dopaminergic neurons — may provide important clues to explain how the disease develops.” Benomyl was widely used in the U.S. for three decades until toxicological evidence revealed it could potentially lead to liver tumors, brain malformations, reproductive effects and carcinogenesis. It was banned in 2001.
The researchers wanted to explore whether there was a relationship between benomyl and Parkinson’s, which would demonstrate the possibility of long-lasting toxicological effects from pesticide use, even a decade after chronic exposure. But because a direct causal relationship between the pesticide and Parkinson’s can’t be established by testing humans, the investigators sought to determine if exposure in experimental models could duplicate some of the pathologic features of the disease. They first tested the effects of benomyl in cell cultures and confirmed that the pesticide damaged or destroyed dopaminergic neurons.
Next, they tested the pesticide in a zebrafish model of the disease. This freshwater fish is commonly used in research because it is easy to manipulate genetically, it develops rapidly and it is transparent, making the observation and measurement of biological processes much easier. By using a fluorescent dye and counting the neurons, the researchers discovered there was significant neuron loss in the fish — but only to the dopaminergic neurons. The other neurons were left unaffected. Until now, evidence had pointed to one particular culprit — a protein called α-synuclein — in the development of Parkinson’s. This protein, common to all Parkinson’s patients, is thought to create a pathway to the disease when it binds together in “clumps” and becomes toxic, killing the brain’s neurons. (See UCLA research using “molecular tweezers” to break up these toxic aggregations.)
The identification of ALDH activity now gives researchers another target to focus on in trying to stop this disease.
“We’ve known that in animal models and cell cultures, agricultural pesticides trigger a neurodegenerative process that leads to Parkinson’s,” said Bronstein, who directs the UCLA Movement Disorders Program. “And epidemiologic studies have consistently shown the disease occurs at high rates among farmers and in rural populations. Our work reinforces the hypothesis that pesticides may be partially responsible, and the discovery of this new pathway may be a new avenue for developing therapeutic drugs.”
Other authors of the study included Lisa Barnhill, Hoa A. Lam, Aaron Lulla, Nigel T. Maidment, Niall P. Murphy, Kelley C. O’Donnell, Shannon L. Rhodes, Beate Ritz, Alvaro Sagastig and Mark C. Stahl, all of UCLA; John E. Casida of UC Berkeley; and Myles Cockburn of the University of Southern California. The authors declare no conflict of interest.
This work was funded in part by National Institute of Environmental Health Sciences grants P01ES016732, R01ES010544, 5R21ES16446-2 and U54ES012078; National Institute of Neurological Disorders and Stroke grant NS038367; the Veterans Affairs Healthcare System (Southwest Parkinson’s Disease Research, Education, and Clinical Center); the Michael J. Fox Foundation; the Levine Foundation; and the Parkinson Alliance.
The UCLA Department of Neurology, with over 100 faculty members, encompasses more than 20 disease-related research programs, along with large clinical and teaching programs. These programs cover brain mapping and neuroimaging, movement disorders, Alzheimer’s disease, multiple sclerosis, neurogenetics, nerve and muscle disorders, epilepsy, neuro-oncology, neurotology, neuropsychology, headaches and migraines, neurorehabilitation, and neurovascular disorders. The department ranks in the top two among its peers nationwide in National Institutes of Health funding.
Low Dose Toxicity and Disease
National Institute of Environmental Health Sciences Strategic Plan called, “Advancing Science, Improving Health: A Plan for Environmental Health Research,”
The entire environmental health science community was engaged in this effort. Here is the link to the NIH Strategic Plan. http://www.niehs.nih.gov/about/strategicplan
As Linda S. Birnbaum * Director, NIEHS and NTP, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, writes : “The NIH focus is on the study of environmental exposures themselves. This approach recognizes that environmentally related health and disease are the result of the totality of a person’s environmental exposures, from all sources and routes, across the life span. This totality of exposure is what is described as the exposome, a concept that has become increasingly salient in the field of environmental health sciences.” She also states that the “NIH is moving beyond the traditional approaches of testing one chemical at a time and are taking on the significant challenge of evaluating mixtures and also is looking at the effects of exposures throughout the life span, expanding research and testing to include prenatal exposures and how they may link to adult disease.” It is clear that there are multiple windows of susceptibility and that exposures early in life may have long-lasting consequences to both health and disease.
The NIH is moving beyond the antiquated idea that the dose makes the poison is overly simplistic. The newest research clearly shows that biology is affected by low doses of chemicals, often within the range of general population exposure, and that these biological changes can be harmful, especially during periods of development. Therefore, low-dose research goes hand in hand with the life-span exposure approach.
* Linda S. Birnbaum, is director of the NIEHS and the NTP, oversees a budget that funds multidisciplinary biomedical research programs and prevention and intervention efforts that encompass training, education, technology transfer, and community outreach. She recently received an honorary Doctor of Science from the University of Rochester, the distinguished alumna award from the University of Illinois, and was elected to the Institute of Medicine. She is the author of > 900 peer-reviewed publications, book chapters, abstracts, and reports. Birnbaum received her M.S. and Ph.D. in microbiology from the University of Illinois, Urbana. A board-certified toxicologist, she has served as a federal scientist for > 32 years, 19 with the U.S. EPA Office of Research and Development, preceded by 10 years at the NIEHS as a senior staff fellow, a principal investigator, a research microbiologist, and a group leader for the institute’s Chemical Disposition Group.