Pesticides and Parkinson's disease: Attributable Risk of Occupational Exposure and Neurochemical Analysis of Sub-Chronic Environmental Exposure Open Access

Abstract

Background: The causes of Parkinson's disease (PD) are not well understood. In the past 30 years, epidemiological studies have emerged associating occupational and environmental pesticide exposure with PD. However, exposure misclassification and a lack of understanding the underlying biological mechanisms in pesticide exposure, particularly lipophilic pesticides that are potential toxins to the developing nervous system, obscure a reliable association with PD.

Objective: This study is designed to assess the epidemiologic factors in determining the attributable risk percent of PD from occupational exposure to pesticides as well as to determine the neurochemical mechanism underlying developmental exposure to the recently banned insecticide, endosulfan. Methods: Using US Census data from 1990 and 2011 as well as a Job Exposure Matrix, occupational exposure to pesticides was generated. Risk-ratios from two meta-analyses were then used to calculate a range of attributable risk percentages (AR) for PD. Next, endosulfan toxicity was assessed in the SK-N-SH dopaminergic cell line and in primary culture neurons from the ventral mesencephalon. Finally, the impact of endosulfan was evaluated using mice developmentally exposed to endosulfan during gestation and lactation. Animals were challenged with MPTP to evaluate toxicity on the dopaminergic system in the striatum. Immunoblotting was performed to determine the effect of endosulfan on various neuronal proteins. Results: Using never vs. ever occupationally exposed to pesticides, we found that the AF ranged from 6.3 - 13.41% depending on the mRR and Census data used. High vs. low occupational exposure yielded an AF of 3%. Endosulfan was toxic to SK-N-SH cells and primary cultured neurons elicited markers of oxidative stress. Developmental exposure to endosulfan did not cause significant modulation of dopaminergic proteins in the striatum. However, several cortical proteins were significantly altered following endosulfan exposure. Discussion: While the range of the attributable risk fraction for PD varies, it underscores the uncertainty in assessing occupational exposure to pesticides. Furthermore, assessment of developmental exposure to endosulfan indicates that environmental exposure disrupts processes integral to the neural transmission in the cortex. Future studies should continue to research the effects induced by endosulfan on the brain and their association with neurological diseases such as schizophrenia.

Table of Contents

INTRODUCTION...1

Parkinson's disease: background, pathology and general risk factors...1 Parkinson's disease and pesticides: epidemiology ...5 Pesticides and PD: organochlorine toxicology...11 Endosulfan and PD...13 Hypothesis for current research...15 METHODS...16 Occupational survey data...16 Data sets, job exposure matrix, and job codes...17 Proportion ever exposed to pesticides...19 Proportion of "high" exposure compared to "low" exposure occupations...19 Meta-analysis estimate and attributable risk fraction...20 Chemicals and reagents for neurochemical assessment of endosulfan...21 In vitro analysis of endosulfan and metabolites on SK-N-SH cells...22 In vitro analysis of endosulfan as an oxidative stressor...23 In vitro analysis of endosulfan and metabolites on ventral mesencephalon cells...23 In vivo analysis of developmental exposure to endosulfan...24 MPTP administration...25 Neurochemical analysis of developmental exposure to endosulfan...26 Wet-lab statistical analysis...26 RESULTS...27 Risk attributable to pesticide exposure in ever exposed vs. never exposed...27 Risk attributable to pesticide exposure using levels of exposure (high and low)...27 Neurochemical results of endosulfan exposure...28 In vitro 24hr endosulfan exposure is cytotoxic to SK-N-SH cells...28 In vitro 72hr endosulfan and metabolite exposure is cytotoxic to SK-N-SH cells...29 In vitro endosulfan exposure modulates GSH and GSSG levels in SK-N-SH cells...29 In vitro 24hr endosulfan exposure is cytotoxic to ventral mesencephalon neurons...30 In vivo endosulfan exposure reduces striatal DAT and TH levels in mothers...30 In vivo developmental endosulfan exposure modulates striatal dopaminergic proteins in offspring...31 In vivo developmental endosulfan exposure does not significantly exacerbate toxicity to MPTP in striatum...32 In vivo developmental endosulfan exposure significantly reduces cortical levels of DAT and TH in offspring...32 In vivo developmental endosulfan exposure significantly modulates cortical concentrations of GABAergic proteins in male mice...32 In vivo developmental endosulfan exposure significantly modulates cortical concentrations of glutamatergic proteins in male mice...33 DISCUSSION...34 Epidemiological assessment of attributable risk calculations...34 Toxicological investigation of developmental exposure to endosulfan...38 CONCLUSION...47 REFERENCES...49 TABLES...62 FIGURES...64 TABLES Table 1. Job Exposure Matrix of Occupational Exposure to Pesticides.................................62 Table 2. Attributable Risk of Pesticide Exposure in Ever vs. Never Exposure......................62 Table 3. Percentage of Exposure by Level..............................................................................63 Table 4. Total AFp of High/Low Pesticide Exposure..............................................................63 FIGURES Figure 1. 24hr cytotoxicity assay: endosulfan toxicity in SK-N-SH cells..............................64 Figure 2. 72hr cytotoxicity assay: endosulfan toxicity in SK-N-SH cells..............................65 Figure 3. Oxidative stress and DCF-DA assay: endosulfan effect in SK-N-SH cells............66 Figure 4. Primary culture: endosulfan toxicity in ventral mesencephalic neurons.................67 Figure 5. Western blot analysis of striatal dopaminergic markers in mothers........................68 Figure 6. Western blot analysis of striatal dopaminergic markers in pups.............................69 Figure 7. Western blot analysis of MPTP administration in pups..........................................70 Figure 8. Western blot analysis of cortical dopaminergic markers in male pups ..................71 Figure 9. Western blot analysis of cortical GABAergic markers in male pups......................72 Figure 10. Western blot analysis of cortical glutamatergic markers in male pups.................73

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School	Rollins School of Public Health
Department	Environmental Health
Degree	MSPH
Submission	Master's Thesis
Language	English
Research Field	Biology, Neuroscience Health Sciences, Toxicology Health Sciences, Epidemiology
Keyword	Developmental Toxicology Pesticides Occupational Exposure Parkinson's disease Attributable Risk Schizophrenia Endosulfan
Committee Chair / Thesis Advisor	Caudle, William Michael, Emory University Steenland, Kyle, Emory University
Committee Members	Tolbert, Paige, Emory University
Partnering Agencies	Emory University schools, faculty or affiliated programs US (Federal) agency other than CDC

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