Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Parkinson's disease and brain levels of organochlorine pesticides. 751 54

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.
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PMID:Organochlorine compounds in human brain. 883 17

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.
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PMID:Organochlorine insecticides in substantia nigra in Parkinson's disease. 1070 31

We examined the acute toxicity of dieldrin, a possible environmental risk factor of Parkinson's disease, in a dopaminergic cell model, PC12 cells, to determine early cellular events underlying the pesticide-induced degenerative processes. EC(50) for 1 h dieldrin exposure was 143 microM for PC12 cells, whereas EC(50) for non-dopaminergic cells was 292-351 microM, indicating that dieldrin is more toxic to dopaminergic cells. Dieldrin also induced rapid, dose-dependent releases of dopamine and its metabolite, DOPAC, resulting in depletion of intracellular dopamine. Additionally, dieldrin exposure caused depolarization of mitochondrial membrane potential in a dose-dependent manner. Flow cytometric analysis showed generation of reactive oxygen species (ROS) within 5 min of dieldrin treatment, and significant increases in lipid peroxidation were also detected following 1 h exposure. ROS generation was remarkably inhibited in the presence of SOD. Dieldrin-induced apoptosis was significantly attenuated by both SOD and MnTBAP (SOD mimetic), suggesting that dieldrin-induced superoxide radicals serve as important signals in initiation of apoptosis. Furthermore, pretreatment with deprenyl (MAO-inhibitor) or alpha-methyl-L-p-tyrosine (TH-inhibitor) also suppressed dieldrin-induced ROS generation and DNA fragmentation. Taken together, these results suggest that rapid release of dopamine and generation of ROS are early cellular events that may account for dieldrin-induced apoptotic cell death in dopaminergic cells.
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PMID:Dieldrin-induced oxidative stress and neurochemical changes contribute to apoptopic cell death in dopaminergic cells. 1172 20

The purpose of this study was to evaluate the possible association between the risk of developing Parkinson's disease (PD) and exposure to organochlorine pesticides in the mouse model. Animals were treated with a single subcutaneous injection of either dieldrin (40 and 80 mg/kg) or 2,4-dichlorophenoxyacetic acid (100 and 200 mg/kg, 2,4-D) and levels of dopamine (DA) and DA metabolites were measured in the striatum at the 7-day time point. Dieldrin exposure did not affect the striatal concentrations of DA, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Administration of 2,4-D did not produce any changes with the exception of a slight (15%), but statistically significant decrease in DOPAC using the higher dose of the pesticide. No neurochemical signs of dopaminergic injury were found following the combined treatment with either dieldrin or 2,4-D plus diethyldithiocarbamate (DDC), a compound known to potentiate the effects of the dopaminergic toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, neither dieldrin nor 2,4-D caused additional damage in animals previously lesioned with MPTP. Data failed to support the hypothesis that acute exposure to organochlorine compounds or synergistic interactions involving these pesticides may cause significant damage to dopaminergic terminals and therefore contribute to nigrostriatal degeneration in PD.
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PMID:Acute exposure to organochlorine pesticides does not affect striatal dopamine in mice. 1511 Dec 43

We investigated the transcriptional events and signaling pathways involved in the induction of heme oxygenase-1 (HO-1) by dieldrin, an environmental risk factor of Parkinson's disease, in a dopaminergic neuronal cells (SN4741). Dieldrin exposure caused dose-dependent and time-dependent induction of heme oxygenase activity and HO-1 protein expression. Deletional and mutational analyses showed that the 5' distal enhancers, E1 and E2, mediate dieldrin-induced HO-1 gene transcription, and the AP-1 DNA binding sites in the E2 enhancer are critical for E2-mediated HO-1 gene activation. Furthermore, both the p38 and JNK mitogen-activated protein kinase pathways are utilized for HO-1 transcriptional activation by dieldrin. HO-1 inhibitor, ZnPP IX reduced the expression of HO-1 but enhanced the cytotoxicity induced by dieldrin.
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PMID:Heme oxygenase-1 induction by dieldrin in dopaminergic cells. 1577 Jan 61

Exposure to pesticides is implicated in the etiopathogenesis of Parkinson's disease (PD). The organochlorine pesticide dieldrin is one of the environmental chemicals potentially linked to PD. Because recent evidence indicates that abnormal accumulation and aggregation of alpha-synuclein and ubiquitin-proteasome system dysfunction can contribute to the degenerative processes of PD, in the present study we examined whether the environmental pesticide dieldrin impairs proteasomal function and subsequently promotes apoptotic cell death in rat mesencephalic dopaminergic neuronal cells overexpressing human alpha-synuclein. Overexpression of wild-type alpha-synuclein significantly reduced the proteasomal activity. Dieldrin exposure dose-dependently (0-70 microM) decreased proteasomal activity, and 30 microM dieldrin inhibited activity by more than 60% in alpha-synuclein cells. Confocal microscopic analysis of dieldrin-treated alpha-synuclein cells revealed that alpha-synuclein-positive protein aggregates colocalized with ubiquitin protein. Further characterization of the aggregates with the autophagosomal marker mondansyl cadaverine and the lysosomal marker and dot-blot analysis revealed that these protein oligomeric aggregates were distinct from autophagosomes and lysosomes. The dieldrin-induced proteasomal dysfunction in alpha-synuclein cells was also confirmed by significant accumulation of ubiquitin protein conjugates in the detergent-insoluble fraction. We found that proteasomal inhibition preceded cell death after dieldrin treatment and that alpha-synuclein cells were more sensitive than vector cells to the toxicity. Furthermore, measurement of caspase-3 and DNA fragmentation confirmed the enhanced sensitivity of alpha-synuclein cells to dieldrin-induced apoptosis. Together, our results suggest that increased expression of alpha-synuclein predisposes dopaminergic cells to proteasomal dysfunction, which can be further exacerbated by environmental exposure to certain neurotoxic compounds, such as dieldrin.
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PMID:Dieldrin induces ubiquitin-proteasome dysfunction in alpha-synuclein overexpressing dopaminergic neuronal cells and enhances susceptibility to apoptotic cell death. 1598 30

Exposure to pesticides has been speculated to contribute to the development of sporadic Parkinson's disease (PD) characterized by a progressive degeneration of the nigrostriatal dopaminergic pathway. Activation of brain microglia that produce various neurotoxic factors including cytokines and reactive oxygen species (ROS) has been increasingly associated with dopaminergic neurodegeneration induced by various toxicants. Dieldrin, a highly persistent organochlorinated pesticide found enriched in the substantia nigra of some postmortem PD brains, has been shown to be toxic to dopamine neurons. In this study, we set out to determine the effect of dieldrin on the production of ROS and the underlying mechanism of action in murine microglia. Treatment of microglial cells with 0.1 nM to 1 microM dieldrin for 24 h resulted in a concentration-dependent generation of ROS. The dieldrin-induced microglial ROS generation was time-dependent in that significant ROS production was observed in cells 12-24 h, but not 6 h after dieldrin treatment. Furthermore, the dieldrin-induced microglial ROS generation was significantly reduced by inhibitors of NADPH oxidase, gene transcription and protein synthesis. In addition to immortalized microglial cells, dieldrin induced a concentration-dependent ROS generation in primary microglia, but not in primary astroglia. These results demonstrate that nanomolar concentrations of dieldrin can stimulate microglia to produce ROS that may contribute to the degeneration of dopamine neurons known to be vulnerable to oxidative damage. These findings provide important information on the potential role of microglia in dieldrin-induced neurodegeneration in relevance to the development of idiopathic PD.
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PMID:Induction of microglial reactive oxygen species production by the organochlorinated pesticide dieldrin. 1799 24

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.
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PMID:Developmental exposure to organophosphates triggers transcriptional changes in genes associated with Parkinson's disease in vitro and in vivo. 2196 25

Current hypotheses link long-term environmental exposure of humans to persistent organochlorine (OC) insecticides lindane (HCH) and dieldrin (HEOD) to the development of neurodegenerative disorders, such as Parkinson's disease. Primary adverse neurological effects of these insecticides are directed at inhibition of GABA(A) and glycine receptors, although GABA-independent effects have also been reported. In this paper we describe the effect of dieldrin and a binary mixture of dieldrin and lindane on a critical parameter of neuronal function and survival, i.e., intracellular calcium homeostasis. The intracellular calcium concentration ([Ca(2+)](i)) has been monitored using real-time single-cell fluorescence microscopy in dopaminergic PC12 cells loaded with the calcium-sensitive dye Fura-2. The results demonstrate that nanomolar concentrations of dieldrin time- and concentration-dependently inhibit depolarization-evoked influx of Ca(2+). Co-exposure of PC12 cells to a mixture of dieldrin and lindane revealed an additive inhibition of the depolarization-evoked increase in [Ca(2+)](i), whereas the lindane-induced increase in basal [Ca(2+)](i) is inhibited by dieldrin. The combined findings indicate that dieldrin and binary mixtures of organochlorines affect [Ca(2+)](i) already at concentrations below commonly accepted effect concentrations and close to human internal dose levels. Consequently, current findings illustrate the need to take mixtures of OC insecticides into account in human risk assessment.
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PMID:Organochlorine insecticides lindane and dieldrin and their binary mixture disturb calcium homeostasis in dopaminergic PC12 cells. 2219 81


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