Combined Exposure to Environmental Toxics Accelerates Age-Related Development of Parkinson's Disease in Mice

Buck Institute study highlights the role of environmental factors in the most common form of the neurodegenerative disease

June 26, 2007  Scientists at the Buck Institute for Age Research have shown that combining two environmental toxic substances accelerated age-related degeneration in neurons associated with Parkinson’s disease (PD) in mice.  Additionally, the study showed that pre-treating the mice with an antioxidant weakened the impact of the environmental exposures, suggesting the substances damage the neurons via oxidative stress.  The toxics involved include increased neonatal iron intake and exposure to the herbicide paraquat. Results of the study were published in the June 27 issue of The Journal of Neuroscience.

The study highlights the role of environmental factors in the development of PD, a progressive, incurable neurodegenerative disorder that results in tremor, slowness of movement and rigidity. Only five percent of the 160,000 cases of PD diagnosed in the U.S. each year are strictly genetic in nature; most of those afflicted have “sporadic” PD, likely due to a combination of environmental exposures and increased genetic susceptibilities. “Research keeps pointing to Parkinson’s disease as being a very complex disorder,” said Buck Institute faculty member Julie K. Andersen, lead author of the study. “This research looked at environmental risk factors in the context of aging which is essential, given the fact that aging is the single major risk factor for PD in humans.”

Andersen and her team worked with genetically identical mice, which put all the animals on the same footing in regards to genetic susceptibility.  One group was given an excess of iron in infancy, another was given the herbicide paraquat, (both compounds have been shown to increase the risk of PD in earlier studies in mice), a third group was exposed to both substances and a fourth group was not exposed to either of the compounds. Half of each group received treatment with the antioxidant EUK-189, which is known to cross the blood brain barrier. The animals in each group were aged to the human equivalent of young adult, young middle-age (45 – 55 in humans), young-older (65 – 70 and elderly (85+).  Results showed that exposing animals to both toxics accelerated PD-like neurodegeneration in the mice, with symptoms beginning to appear at the human equivalent of middle-age. The mice demonstrated a progression of increased oxidative stress followed by decreased neuronal function and finally neuronal cell loss. In elderly mice, cell loss was roughly equivalent to that observed in the human disorder.  Those mice treated with the antioxidant, which was delivered at the same time as the environmental toxic, had significantly less nerve death in the area of the brain commonly affected by PD.

“The fact that the antioxidant treatment prevented much of the nerve damage in the mice points to the need for an early diagnostic test for Parkinson’s disease,” said Andersen. “Currently, by the time humans are diagnosed with the disease they have already lost 60% of the neurons implicated in PD; treatment with an antioxidant would likely be maximally effective if taken before symptoms appear in order to halt disease progression."

J. Timothy Greenamyre, MD, PhD, Professor of Neurology at the University of Pittsburgh commented on the work, “This study provides further confirmation that ‘innocuous’ early life events or exposures can lead to late life neurodegeneration. Secondly, it adds to the evidence that that abnormalities of iron handling can contribute to the pathogenesis of PD.”  He added, “It also shows that early life exposures can predispose to or exacerbate neurodegeneration caused by subsequent exposures.”

Joining Andersen in the study were Jun Peng, and Fang Feng Stevensen, also of the Buck Institute, along with Li Peng of the Royal Perth Hospital, Perth, Australia; and Susan R. Doctrow of Proteome Systems, Inc., Woburn, MA.  The work was funded by the National Institute of Environmental Health Sciences as part of a large Collaborative Centers for Parkinson’s Disease Environmental Research (CCPDER) U54 grant.

The Buck Institute is an independent non-profit organization dedicated to extending the healthspan, the healthy years of each individual’s life.  The National Institute of Aging designated the Buck a Nathan Shock Center of Excellence in the Biology of Aging, one of just five centers in the country. Buck Institute scientists work in an innovative, interdisciplinary setting to understand the mechanisms of aging and to discover new ways of detecting, preventing and treating age-related diseases such as Alzheimer’s and Parkinson’s disease, cancer, stroke, and arthritis. Collaborative research at the Institute is supported by genomics, proteomics and bioinformatics technology.

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