Objective/Rationale:
Although the causes of sporadic Parkinson’s disease are still unknown, recent evidence suggests that exposure to pesticides increases the risk for PD. However, most of these studies have not identified specific pesticides that may contribute to the disease. We have recently found that levels of the organochlorine pesticide beta-hexachlorcyclohexane (B-HCH) are 9-fold higher in serum of current PD patients when compared to patients with no neurological disease or patients with Alzheimer’s disease. Although suggestive of a role for organochlorine pesticides in PD, low levels of B-HCH are sometimes found in patients with no neurological disease, although generally at lower levels than those found in PD patients. This suggests that other factors may interact with pesticide exposure to increase the risk of PD. In this project, we propose to expand our study of elevated serum B-HCH levels in PD patients and determine whether genetic polymorphisms of one or more enzymes involved in the metabolism of B-HCH may be responsible for the elevated B-HCH found in PD patients.
Project Description:
This project will entail measuring B-HCH levels in the serum of PD patients and patients with no neurological disease. Serum B-HCH levels will be determined by gas chromatography/mass spectrometry using a method we have developed to be sensitive enough to determine accurate concentrations in small samples of serum. We will also determine whether genetic polymorphisms in two key enzymes involved in the metabolism of B-HCH, glutathione-S-transferase and N-acetyltransferase 2, contribute to the elevated levels of B-HCH in PD patients. We predict that the low activity variants of these enzymes do not efficiently metabolize B-HCH, which leads to a prolonged period of elevated levels of B-HCH and subsequent damage to the dopamine system in the brain.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
If we continue to find elevated serum levels of B-HCH in PD patients, this would suggest that measurement of B-HCH may be a useful clinical measure to identify people at risk for PD. This is particularly important because by the time PD patients are diagnosed, neurodegeneration has often progressed to a point where neuroprotective strategies are largely ineffective. Thus, determination of those who may be at risk for PD based on pesticide exposure and/or genetic polymorphisms may allow for early detection and more efficacious treatments aimed at slowing or preventing further damage to the dopamine system.
Anticipated Outcome:
These experiments will provide critical information on the potential role of pesticides as a causative factor in idiopathic PD. Our preliminary results suggest that elevated levels of the pesticide B-HCH is associated with the diagnosis of PD, and we expect that this finding will be supported by the analysis of additional samples. Furthermore, we anticipate that the elevated levels of B-HCH may be related to genetic polymorphisms in enzymes that metabolize B-HCH. Ultimately, we hope that these studies may provide potential biomarkers to identify people at risk for PD.
Final Outcome
Our studies proceeded in two parts. In the first part, we used existing serum samples taken before 2000 and found that beta-hexachlorocyclohexane (beta-HCH) was more often detectable in patients with PD compared with controls and patients with Alzheimer's disease. Additionally, the median level of beta-HCH was higher in patients with PD compared with controls and patients with Alzheimer's. There were no marked differences in detection between controls and patients with PD concerning any of the other 15 organochlorine pesticides. Finally, we observed a significant odds ratio for the presence of beta-HCH in serum to predict a diagnosis of PD vs control and PD vs Alzheimer's, providing further evidence for the apparent association between serum beta-HCH and PD. These findings were published in the journal Archives of Neurology.
In the second part of the study, we sought to confirm our initial findings and to determine whether genetic polymorphisms of enzymes involved in the metabolism of beta-HCH were related to the elevated levels of beta-HCH using serum samples from patients with PD compared to spousal controls. These samples were collected in 2008. In this cohort, serum beta-HCH was not more often detectable in patients with PD compared with spousal controls, but there was a higher incidence among the PD patients of a polymorphism known as NAT-481.
Taken in concert, these data suggest that beta-HCH levels were associated with a diagnosis of PD in samples taken before 2000, but not in those taken in 2008. This finding may be the result of declining environmental levels of beta-HCH. To test this hypothesis, we compared levels of beta-HCH in PD patients examined before and after the year 2002 and found that levels were significantly higher in the PD patients studied before 2002. This would suggest that beta-HCH may no longer be a risk factor for PD, owing to its decreasing levels in the environment.
We are currently collecting more samples taken prior to 2002 and in 2008 to increase our statistical power to further test our hypothesis that beta-HCH levels are higher and associated with PD in the older samples, but not the most current.
Results from this study have been published: Richardson JR, et al. beta-Hexachlorocyclohexane levels in serum and risk of Parkinson’s disease. Neurotoxicology (2011), doi:10.1016/j.neuro.2011.04.002.