dieldrin and Parkinson-Disease

As a prevalent progressive neurodegenerative disorder, Parkinson's disease (PD) is characterized by the neuropathological hallmark of the loss of nigrostriatal dopaminergic (DAergic) innervation and the appearance of Lewy bodies with aggregated α-synuclein. Although several familial forms of PD have been reported to be associated with several gene variants, most cases in nature are sporadic, triggered by a complex interplay of genetic and environmental risk factors. Numerous epidemiological studies during the past two decades have shown positive associations between PD and several environmental factors, including exposure to neurotoxic pesticides/herbicides and heavy metals as well as traumatic brain injury. Other environmental factors that have been implicated as potential risk factors for PD include industrial chemicals, wood pulp mills, farming, well-water consumption, and rural residence. In this review, we summarize the environmental toxicology of PD with the focus on the elaboration of chemical toxicity and the underlying pathogenic mechanisms associated with exposure to several neurotoxic chemicals, specifically 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, paraquat (PQ), dichloro-diphenyl-trichloroethane (DDT), dieldrin, manganese (Mn), and vanadium (V). Our overview of the current findings from cellular, animal, and human studies of PD provides information for possible intervention strategies aimed at halting the initiation and exacerbation of environmentally linked PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; alpha-Synuclein; Animals; DDT; Dieldrin; Herbicides; Humans; Manganese; Mitochondria; Neuroinflammatory Diseases; Neurotoxicity Syndromes; Oxidative Stress; Paraquat; Parkinson Disease; Pesticides; Risk Factors; Rotenone; Trichloroethanes; Vanadium

Parkinson's disease (PD) is frequently reported to be associated with pesticide exposure but the issue has not yet been solved because the data are inconsistent and the studies suffer from several biases and limitations. The aim of this article is to summarise available biochemical and toxicological data on some pesticides, particularly on paraquat, that might help in the evaluation of epidemiological data. The nigrostriatal system appears to be particularly sensitive to oxidative damage caused by different mechanisms and agents, thus supporting the epidemiological evidence that Parkinson's disease is in fact an environmental disease. In available experimental studies, animals have been treated with a high single or a few doses of pesticide, and have been followed up for a few days or weeks after treatment. Moreover, experimental data indicate additive/synergistic effects of different pesticides that act on different targets within the dopaminergic system. In these conditions and to a different extent, pesticides such as paraquat, maneb and other dithiocarbamates, pyrethroids, rotenone, and dieldrin cause neurotoxic effects that may suggest a possible role in the development of a PD-like syndrome in animals. Although, all the characteristics of PD cannot be reproduced by any single chemical, these data can be of help for understanding the role of pesticide exposure in human PD development. On the other hand farmers are exposed for days or weeks during several years to much lower doses than those used in experimental studies. Therefore, a firm conclusion on the role of pesticide exposure on the increased risk of developing PD cannot be drawn. However, it is suggested that close follow up of survivors of acute poisonings by these pesticides, or identification in epidemiological studies of such subjects or of those reporting episodes of accidentally high exposure will certainly provide information useful for the understanding of the relevance of actual human exposure to these pesticides in the development of PD. Also exposure to multiple pesticides, not necessarily at the same time, should be evaluated in epidemiological studies, as suggested by the additive/synergistic effects observed in experimental studies.

Topics: Animals; Brain; Dieldrin; Dose-Response Relationship, Drug; Humans; Maneb; Neurotoxicity Syndromes; Paraquat; Parkinson Disease; Pesticides; Pyrethrins; Risk Assessment; Risk Factors; Rotenone; Time Factors; Toxicity Tests

Exposure to pesticides may be a risk factor for developing Parkinson's disease (PD). To evaluate the evidence regarding this association in the scientific literature, we examined both analytic epidemiologic studies of PD cases in which exposure to pesticides was queried directly and whole-animal studies for PD-like effects after systemic pesticide exposure. Epidemiologic studies were considered according to study quality parameters, and results were found to be mixed and without consistent exposure-response or pesticide-specific patterns. These epidemiologic studies were limited by a lack of detailed and validated pesticide exposure assessment. In animal studies, no pesticide has yet demonstrated the selective set of clinical and pathologic signs that characterize human PD, particularly at levels relevant to human populations. We conclude that the animal and epidemiologic data reviewed do not provide sufficient evidence to support a causal association between pesticide exposure and PD.

Topics: Animals; Case-Control Studies; Dieldrin; Disease Models, Animal; Fungicides, Industrial; Heptachlor; Humans; Maneb; Occupational Diseases; Occupational Exposure; Paraquat; Parkinson Disease; Permethrin; Pesticides; Pyridazines; Risk Factors

Parkinson's disease (PD) is the fastest-growing neurological disease worldwide, with increases outpacing aging and occurring most rapidly in recently industrialized areas, suggesting a role of environmental factors. Epidemiological, post-mortem, and mechanistic studies suggest that persistent organic pollutants, including the organochlorine pesticide dieldrin, increase PD risk. In mice, developmental dieldrin exposure causes male-specific exacerbation of neuronal susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and synucleinopathy. Specifically, in the α-synuclein (α-syn) pre-formed fibril (PFF) model, exposure leads to increased deficits in striatal dopamine (DA) turnover and motor deficits on the challenging beam. Here, we hypothesized that alterations in DA handling contribute to the observed changes and assessed vesicular monoamine transporter 2 (VMAT2) function and DA release in this dieldrin/PFF 2-hit model. Female C57BL/6 mice were exposed to 0.3 mg/kg dieldrin or vehicle every 3 days by feeding, starting at 8 weeks of age and continuing throughout breeding, gestation, and lactation. Male offspring from independent litters underwent unilateral, intrastriatal injections of α-syn PFFs at 12 weeks of age, and vesicular 3H-DA uptake assays and fast-scan cyclic voltammetry were performed 4 months post-PFF injection. Dieldrin-induced an increase in DA release in striatal slices in PFF-injected animals, but no change in VMAT2 activity. These results suggest that developmental dieldrin exposure increases a compensatory response to synucleinopathy-triggered striatal DA loss. These findings are consistent with silent neurotoxicity, where developmental exposure to dieldrin primes the nigrostriatal striatal system to have an exacerbated response to synucleinopathy in the absence of observable changes in typical markers of nigrostriatal dysfunction and degeneration.

Topics: alpha-Synuclein; Animals; Dieldrin; Dopamine; Female; Male; Mice; Mice, Inbred C57BL; Parkinson Disease; Pesticides; Substantia Nigra; Synaptic Transmission; Synucleinopathies; Vesicular Monoamine Transport Proteins

There is evidence that environmental factors contribute to the onset and progression of Parkinson's disease (PD). Pesticides are a class of environmental toxins that are linked to increased risk of developing PD. However, few studies have investigated the association between specific pesticides and PD, especially in China, which was one of the first countries to adopt the use of pesticides.. In this study, serum levels of 19 pesticides were measured in 90 patients with PD and 90 healthy spouse controls. We also analyzed the interaction between specific pesticides and PD. In addition, the association between pesticides and clinical features of PD was also investigated. Finally, we investigated the underlying mechanism of the association between pesticides and PD.. Serum levels of organochlorine pesticides, which included α-hexachlorocyclohexane (HCH), β-HCH, γ-HCH, δ-HCH, propanil, heptachlor, dieldrin, hexachlorobenzene, p,p'-dichlorodiphenyltrichloroethane and o,p'-dichloro-diphenyl-trichloroethane were higher in PD patients than controls. Moreover, α-HCH and propanil levels were associated with PD. Serum levels of dieldrin were associated with Hamilton Depression Scale and Montreal Cognitive Assessment scores in PD patients. In SH-SY5Y cells, α-HCH and propanil increased level of reactive oxygen species and decreased mitochondrial membrane potential. Furthermore, propanil, but not α-HCH, induced the aggregation of α-synuclein.. This study revealed that elevated serum levels of α-HCH and propanil were associated with PD. Serum levels of dieldrin were associated with depression and cognitive function in PD patients. Moreover, propanil, but not α-HCH, induced the aggregation of α-synuclein. Further research is needed to fully elucidate the effects of pesticides on PD.

Topics: Aged; Blotting, Western; Case-Control Studies; Cell Line, Tumor; Cognition; Cognition Disorders; Depression; Dieldrin; Female; Hexachlorocyclohexane; Humans; Hydrocarbons, Chlorinated; Male; Membrane Potential, Mitochondrial; Middle Aged; Parkinson Disease; Pesticides; Propanil; Reactive Oxygen Species; Risk Factors

Human and animal studies have shown that exposure to the organochlorine pesticide dieldrin is associated with increased risk of Parkinson's disease (PD). Despite previous work showing a link between developmental dieldrin exposure and increased neuronal susceptibility to MPTP toxicity in male C57BL/6 mice, the mechanism mediating this effect has not been identified. Here, we tested the hypothesis that developmental exposure to dieldrin increases neuronal susceptibility via genome-wide changes in DNA methylation. Starting at 8 weeks of age and prior to mating, female C57BL/6 mice were exposed to 0.3 mg/kg dieldrin by feeding (every 3 days) throughout breeding, gestation, and lactation. At 12 weeks of age, pups were sacrificed and ventral mesencephalon, containing primarily substantia nigra, was microdissected. DNA was isolated and dieldrin-related changes in DNA methylation were assessed via reduced representation bisulfite sequencing. We identified significant, sex-specific differentially methylated CpGs (DMCs) and regions (DMRs) by developmental dieldrin exposure (false discovery rate < 0.05), including DMCs at the Nr4a2 and Lmx1b genes, which are involved in dopaminergic neuron development and maintenance. Developmental dieldrin exposure had distinct effects on the male and female epigenome. Together, our data suggest that developmental dieldrin exposure establishes sex-specific poised epigenetic states early in life. These poised epigenomes may mediate sensitivity to subsequent toxic stimuli and contribute to the development of late-life neurodegenerative disease, including PD.

Topics: Animals; Dieldrin; DNA Methylation; Dopaminergic Neurons; Female; Fetus; GRB10 Adaptor Protein; Male; Mesencephalon; Mice, Inbred C57BL; Parkinson Disease; Sex Characteristics

Epidemiologic studies support a connection between organophosphate pesticide exposures and subsequent risk of Parkinson's disease (PD). We used differentiating, neuronotypic PC12 cells to compare organophosphates (chlorpyrifos, diazinon), an organochlorine (dieldrin) and a metal (Ni(2+)) for their effects on the transcription of PD-related genes. Both of the organophosphates elicited significant changes in gene expression but with differing patterns: chlorpyrifos evoked both up- and downregulation whereas diazinon elicited overall reductions in expression. Dieldrin was without effect but Ni(2+) produced a pattern resembling that of diazinon. We then exposed neonatal rats to chlorpyrifos or diazinon for the first 4 days after birth and examined the expression of PD-related genes in the brainstem and forebrain. Chlorpyrifos had no significant effect whereas diazinon produced significant increases and decreases in expression of the same PD genes that were targeted in vitro. Our results provide some of the first evidence for a mechanistic relationship between developmental organophosphate exposure and the genes known to confer PD risk in humans; but they also point to disparities between different organophosphates that reinforce the concept that their neurotoxic actions do not rest solely on their shared property as cholinesterase inhibitors. The parallel effects of diazinon and Ni(2+) also show how otherwise unrelated developmental neurotoxicants can nevertheless produce similar outcomes by converging on common molecular pathways, further suggesting a need to examine metals such as Ni(2+) as potential contributors to PD risk.

Topics: Animals; Animals, Newborn; Brain; Chlorpyrifos; Cholinesterase Inhibitors; Diazinon; Dieldrin; Gene Expression; Gene Expression Profiling; Humans; Microarray Analysis; Nickel; Organophosphates; Parkinson Disease; PC12 Cells; Rats; Transcription, Genetic

Pesticides have been implicated as likely environmental risk factors for Parkinson disease (PD), but assessment of past exposure to pesticides can be difficult. No prior studies of pesticide exposure and PD used biomarkers of exposure collected before the onset of PD. Our investigation examined the association between prospective serum biomarkers of organochlorine pesticides and PD.. We conducted a nested case-control study within the Finnish Mobile Clinic Health Examination Survey, with serum samples collected during 1968-1972, and analyzed in 2005-2007 for organochlorine pesticides. Incident PD cases were identified through the Social Insurance Institution's nationwide registry and were confirmed by review of medical records (n = 101). Controls (n = 349) were matched for age, sex, municipality, and vital status. Adjusted odds ratios (ORs) of PD were estimated using logistic regression.. Little association emerged with a summary score of the 5 organochlorine pesticides found at high levels, and only increasing dieldrin concentrations trended toward a higher risk of PD (OR per interquartile range [IQR] 1.28, 95% confidence interval [CI] 0.97-1.69, p = 0.08). Because of possible strong confounding by cigarette smoking among smokers, we ran additional analyses restricted to never smokers (n = 68 cases, 183 controls). In these analyses, increasing dieldrin concentrations were associated with increased odds of PD (OR per IQR 1.95, 95% CI 1.26-3.02, p = 0.003). None of the other organochlorine pesticides were associated with PD in these analyses.. These results provide some support for an increased risk of Parkinson disease with exposure to dieldrin, but chance or exposure correlation with other less persistent pesticides could contribute to our findings.

Topics: Adult; Aged; Case-Control Studies; Dieldrin; Environmental Exposure; Female; Finland; Humans; Hydrocarbons, Chlorinated; Logistic Models; Male; Middle Aged; Odds Ratio; Parkinson Disease; Pesticides; Registries; Risk Factors; Smoking; Young Adult

In previous work, we investigated dieldrin cytotoxicity and signaling cell death mechanisms in dopaminergic PC12 cells. Dieldrin has been reported to be one of the environmental factors correlated with Parkinson's disease and may selectively destroy dopaminergic neurons.. Here we further investigated dieldrin toxicity in a dopaminergic neuronal cell model of Parkinson's disease, namely N27 cells, using biochemical, immunochemical, and flow cytometric analyses.. In this study, dieldrin-treated N27 cells underwent a rapid and significant increase in reactive oxygen species followed by cytochrome c release into cytosol. The cytosolic cytochrome c activated caspase-dependent apoptotic pathway and the increased caspase-3 activity was observed following a 3 hr dieldrin exposure in a dose-dependent manner. Furthermore, dieldrin caused the caspase-dependent proteolytic cleavage of protein kinase C delta (PKCδ) into 41 kDa catalytic and 38 kDa regulatory subunits in N27 cells as well as in brain slices. PKCδ plays a critical role in executing the apoptotic process in dieldrin-treated dopaminergic neuronal cells because pretreatment with the PKCδ inhibitor rottlerin, or transfection and over-expression of catalytically inactive PKCδ(K)³⁷⁶(R), significantly attenuates dieldrin-induced DNA fragmentation and chromatin condensation.. Together, we conclude that caspase-3-dependent proteolytic activation of PKCδ is a critical event in dieldrin-induced apoptotic cell death in dopaminergic neuronal cells.

Topics: Animals; Apoptosis; Biocatalysis; Brain; Caspase 3; Caspase Inhibitors; Cell Nucleus; Cytochromes c; Dieldrin; DNA Fragmentation; Environmental Pollutants; Enzyme Activation; Male; Mitochondria; Mutant Proteins; Nerve Degeneration; Neurotoxins; Parkinson Disease; Protein Kinase C-delta; Protein Processing, Post-Translational; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species

We previously demonstrated that the organochlorine pesticide dieldrin, a potential chemical risk factor for development of Parkinson's disease (PD), impairs mitochondrial function and promotes apoptosis in dopaminergic PC12 cells. We further demonstrated that caspase-3-dependent proteolytic activation of a member of the novel PKC family, protein kinase Cdelta (PKCdelta), contributes to apoptotic cell death in dopaminergic cells. In the present study, we report that the proapoptotic function of PKCdelta can be regulated by overexpression of the mitochondrial anti-apoptotic protein Bcl2 in dieldrin-treated dopaminergic cells. Exposure to dieldrin (30 or 100 micro M) for 3 h produced a dose-dependent increase in caspase-3 activation and DNA fragmentation in vector-transfected PC12 cells. Overexpression of human Bcl-2 in PC12 cells completely suppressed dieldrin-induced caspase-3 activation and DNA fragmentation. Furthermore, dieldrin-induced proteolytic activation of PKCdelta was also remarkably reduced in Bcl-2-overexpressed cells. Together, these results suggest that the proapoptotic function of PKCdelta can be regulated by mitochondrial redox modulators during neurodegenerative processes.

Topics: Animals; Apoptosis; Dieldrin; Endopeptidases; Enzyme Activation; Genetic Vectors; Humans; Oxidative Stress; Parkinson Disease; PC12 Cells; Protein Kinase C; Proto-Oncogene Proteins c-bcl-2; Rats; Transfection

Parkinson's disease involves intracellular deposits of alpha-synuclein in the form of Lewy bodies and Lewy neurites. The etiology of the disease is unknown, however, several epidemiological studies have implicated environmental factors, especially pesticides. Here we show that several pesticides, including rotenone, dieldrin and paraquat, induce a conformational change in alpha-synuclein and significantly accelerate the rate of formation of alpha-synuclein fibrils in vitro. We propose that the relatively hydrophobic pesticides preferentially bind to a partially folded intermediate conformation of alpha-synuclein, accounting for the observed conformational changes, and leading to association and subsequent fibrillation. These observations suggest one possible underlying molecular basis for Parkinson's disease.

Topics: alpha-Synuclein; Circular Dichroism; Dieldrin; Ditiocarb; Nerve Tissue Proteins; Paraquat; Parkinson Disease; Pesticides; Protein Binding; Protein Conformation; Protein Folding; Rotenone; Spectrometry, Fluorescence; Spectroscopy, Fourier Transform Infrared; Synucleins

The concentrations of organochlorine (OC) compounds in the substantia nigra (SN) were compared in Parkinson's disease (PD) with concentrations in brain from cortical Lewy body dementia (CLBD), Alzheimer's disease (AD), and nondemented nonparkinsonian controls (CON). The levels of the gamma isomer of hexachlorocyclohexane (gammaHCH, lindane) were significantly higher in PD tissues (mean +/- SD: 0.56 +/- 0.434 microg/g lipid) than in the other three groups (CLBD 0.052 +/- 0.101 microg/g lipid; AD none detected; CON 0.125 +/- 0.195; all differences from PD significant at p < .05, Mann-Whitney U-test). Dieldrin (HEOD) was higher in PD brain than in AD or control brain, while 1,1'-(2,2-dichloroethenyl diene)-bis(4-chlorobenzene) (p,p-DDE) and total Aroclor-matched polychlorinated biphenyls (matched PCBs) were only higher in PD substantia nigra when these concentrations were compared with those of CLBD. These findings are not inconsistent with the hypothesis derived from epidemiological work and animal studies that organochlorine insecticides produce a direct toxic action on the dopaminergic tracts of the substantia nigra and may contribute to the development of PD in those rendered susceptible by virtue of cytochrome P-450 polymorphism, excessive exposure, or other factors.

Topics: Alzheimer Disease; Case-Control Studies; Chromatography, Gas; Dichlorodiphenyl Dichloroethylene; Dieldrin; Environmental Pollutants; Hexachlorocyclohexane; Humans; Insecticides; Lewy Body Disease; Parkinson Disease; Polychlorinated Biphenyls; Substantia Nigra

Having observed polychlorinated biphenyls (PCBs) in brain tissue obtained post mortem from two men we have carried out a study of organochlorine compounds in frontal cortex from patients with Parkinson's disease (PD) and from controls. No PCBs were found in any of those samples. There was no difference in the concentration of the DDT metabolite pp'-DDE in the PD brain samples. Dieldrin (HEOD) was significantly decreased in PD brain when analysed by lipid weight. While these findings would not support the hypothesis that PCBs may contribute to the development of Parkinson's disease in humans it remains possible that they may cause damage to the basal ganglia before being displaced from brain tissue.

Topics: Aged; Aged, 80 and over; Brain Chemistry; Cerebral Cortex; DDT; Dieldrin; Female; Humans; Male; Parkinson Disease; Polychlorinated Biphenyls

Epidemiological studies have suggested an etiologic relationship between pesticide exposure and Parkinson's disease (PD). Organochlorine pesticides were assayed in postmortem brain samples from 20 PD, 7 Alzheimer's disease (AD), and 14 nonneurological control cases. The three groups were similar in age at death, sex, and demographic variables. Only two of 16 pesticide residues screened were detected. A long-lasting residue of DDT (pp-DDE) was found in the majority of cases of PD and AD, as well as in all the control cases; pp-DDT was significantly more likely to be found in AD controls than the PD cases (Fisher's exact two-tailed, p = 0.04). Dieldrin was detected in 6 of 20 PD brains, 1 of 7 AD, and in none of 14 control samples. Despite the relatively small number of brains assayed, the association between Dieldrin and the diagnosis of PD was highly significant (p = 0.03). Dieldrin, a lipid-soluble, long-lasting mitochondrial poison, should be investigated as a potential etiological agent of Parkinsonism.

Topics: Age Factors; Aged; Alzheimer Disease; Brain Chemistry; Cross-Sectional Studies; DDT; Dieldrin; Female; Hexachlorocyclohexane; Humans; Male; Middle Aged; Occupational Exposure; Parkinson Disease; Pesticide Residues; Pesticides; Sex Factors