maneb and Parkinson-Disease

Parkinson's disease (PD) is a neurodegenerative disorder which mainly targets motor symptoms such as tremor, rigidity, bradykinesia and postural instability. The physiological changes occur due to dopamine depletion in basal ganglia region of the brain. PD aetiology is not yet elucidated clearly but genetic and environmental factors play a prominent role in disease occurrence. Despite of various environmental factors, pesticides exposure has been convicted as major candidate in PD pathogenesis. Among various pesticides 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been widely investigated in PD following with paraquat (PQ), maneb (MB), organochlorines (OC) and rotenone. Effect of these pesticides has been suggested to be involved in oxidative stress, alterations in dopamine transporters, mitochondrial dysfunction, α-synuclein (αSyn) fibrillation, and neuroinflammation in PD. The present review discusses the influence of pesticides in neurodegeneration and its related epidemiological studies conducted in PD. Furthermore, we have deliberated the common pesticides involved in PD and its associated genetic alterations and the probable mechanism of them behind PD pathogenesis. Hence, we conclude that pesticides play a prominent role in PD pathogenesis and advance research is needed to investigate the alterations in genetic and mechanistic aspects of PD.

Topics: Dopamine; Humans; Maneb; Neurotoxicity Syndromes; Paraquat; Parkinson Disease; Pesticides

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

Nonhuman primate models of Parkinson's disease (PD) have been invaluable to our understanding of the human disease and in the advancement of novel therapies for its treatment. In this review, we attempt to give a brief overview of the animal models of PD currently used, with a more comprehensive focus on the advantages and disadvantages presented by their use in the nonhuman primate. In particular, discussion addresses the 6-hydroxydopamine (6-OHDA), 1-methyl-1,2,3,6-tetrahydopyridine (MPTP), rotenone, paraquat, and maneb parkinsonian models. Additionally, the role of primate PD models in the development of novel therapies, such as trophic factor delivery, grafting, and deep brain stimulation, are described. Finally, the contribution of primate PD models to our understanding of the etiology and pathology of human PD is discussed.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Cell Transplantation; Deep Brain Stimulation; Disease Models, Animal; Fungicides, Industrial; Glial Cell Line-Derived Neurotrophic Factor; Herbicides; Humans; Maneb; Nerve Degeneration; Oxidopamine; Paraquat; Parkinson Disease; Pesticides; Primates; Rotenone

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

The etiologic basis of Parkinson's disease (PD), the second most common age-related neurodegenerative disorder, is unknown. Recent epidemiological and experimental studies indicate that exposure to environmental agents, including a number of agricultural chemicals, may contribute to the pathogenesis of this disorder. Animal models are important tools in experimental medical science for studying the pathogenesis and therapeutic intervention strategies of human diseases. Since many human disorders do not arise spontaneously in animals, characteristic functional changes have to be mimicked by neurotoxic agents. Recently, agricultural chemicals, when administrated systemically, have been shown to reproduce specific features of PD in rodents, thus opening new routes for the development of animal models for this disorder. In addition to a brief historical overview of the toxin-induced PD models, this study provides a detailed description of exiting models in which Parkinsonism is initiated via the exposure of animals to such agricultural chemicals as rotenone, paraquat, and maneb. Suggested neurotoxicity mechanisms of these chemicals are considered, and the major lessons learned from the analysis of pesticide-induced PD models are discussed.

Topics: Animals; Disease Models, Animal; Fungicides, Industrial; Herbicides; Maneb; Nerve Degeneration; Neurotoxins; Paraquat; Parkinson Disease; Rotenone; Uncoupling Agents

Maneb, a widely-used dithiocarbamate fungicide, remains in the environment and exerts adverse health effects. Epidemiological evidence shows that maneb exposure is associated with a higher risk of Parkinson's disease (PD), one of the most common neurodegenerative diseases. However, the molecular mechanisms underlying maneb-induced neurotoxicity remain unclear. Here we investigated the toxic effects and the underlying mechanisms of maneb on the degeneration of dopaminergic cells and α-synuclein in A53T transgenic mice. In SH-SY5Y cells, exposure to maneb reduces cell viability, triggers neuronal apoptosis, induces mitochondrial dysfunction, and generates reactive oxidative species (ROS) in a dose-dependent manner. Furthermore, Western blot analysis found that the mitochondrial apoptosis pathway (Bcl-2, Bax, cytochrome c, activated caspase-3) and the PKA/CREB signaling pathway (PKA, PDE10A, CREB, p-CREB) were changed by maneb both in vitro and in vivo. In addition, the activation of the mitochondrial apoptosis pathway induced by maneb was attenuated by activating PKA. Therefore, these results suggest that the PKA/CREB signaling pathway is involved in maneb-induced apoptosis. This study provides novel insights into maneb-induced neurotoxicity and the underlying mechanisms, which may serve as a guide for further toxicological assessment and standard application of maneb.

Topics: Animals; Apoptosis; Fungicides, Industrial; Humans; Maneb; Mice; Neuroblastoma; Parkinson Disease; Phosphoric Diester Hydrolases

The mechanisms of cognitive impairments in Parkinson's disease (PD) remain unknown. Accumulating evidence revealed that brain neuroinflammatory response mediated by microglial cells contributes to cognitive deficits in neuropathological conditions and macrophage antigen complex-1 (Mac1) is a key factor in controlling microglial activation.. To explore whether Mac1-mediated microglial activation participates in cognitive dysfunction in PD using paraquat and maneb-generated mouse PD model.. Cognitive performance was measured in wild type and Mac1. Genetic deletion of Mac1 significantly ameliorated learning and memory impairments, neuronal damage, synaptic loss and α-synuclein phosphorylation (Ser129) caused by paraquat and maneb in mice. Subsequently, blocking Mac1 activation was found to mitigate paraquat and maneb-elicited microglial NLRP3 inflammasome activation in both in vivo and in vitro. Interestingly, stimulating activation of NOX by phorbol myristate acetate abolished the inhibitory effects of Mac1 blocking peptide RGD on paraquat and maneb-provoked NLRP3 inflammasome activation, indicating a key role of NOX in Mac1-mediated NLRP3 inflammasome activation. Furthermore, NOX1 and NOX2, two members of NOX family, and downstream PAK1 and MAPK pathways were recognized to be essential for NOX to regulate NLRP3 inflammasome activation. Finally, a NLRP3 inflammasome inhibitor glybenclamide abrogated microglial M1 activation, neurodegeneration and phosphorylation (Ser129) of α-synuclein elicited by paraquat and maneb, which were accompanied by improved cognitive capacity in mice.. Mac1 was involved in cognitive dysfunction in a mouse PD model through NOX-NLRP3 inflammasome axis-dependent microglial activation, providing a novel mechanistic basis of cognitive decline in PD.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Dopaminergic Neurons; Inflammasomes; Integrins; Macrophage-1 Antigen; Macrophages; Maneb; Memory Disorders; Mice; Microglia; NADPH Oxidases; NLR Family, Pyrin Domain-Containing 3 Protein; Paraquat; Parkinson Disease

Maneb is a typical dithiocarbamate fungicide that has been extensively used worldwide. Epidemiological evidence shows that exposure to maneb is an environmental risk factor for Parkinson's disease (PD). However, the mechanisms underlying maneb-induced neurotoxicity have yet to be elucidated. In this study, we exposed SH-SY5Y cells to maneb at environmentally relevant concentrations (0, 0.1, 5, 10 mg/L) and found that maneb dose-dependently decreased the cell viability. Furthermore, maneb (60 mg/kg) induced PD-like motor impairment in α-synuclein A53T transgenic mice. The results of tandem mass tag (TMT) proteomics and metabolomics studies of mouse brain and serum revealed significant changes in proteins and metabolites in the pathways involved in the neurotransmitter system. The omics results were verified by targeted metabolomics and Western blot analysis, which demonstrated that maneb induced disturbance of the PD-related pathways, including the phenylalanine and tryptophan metabolism pathways, dopaminergic synapse, synaptic vesicle cycle, mitochondrial dysfunction, and oxidative stress. In addition, the PD-like phenotype induced by maneb was attenuated by the asparagine endopeptidase (AEP) inhibitor compound #11 (CP11) (10 mg/kg), indicating that AEP may play a role in maneb-induced neurotoxicity. To the best of our knowledge, this is the first study to investigate the molecular mechanisms underlying maneb-induced PD-like phenotypes using multiomics analysis, which identified novel therapeutic targets for PD associated with pesticides and other environmental pollutants.

Topics: alpha-Synuclein; Animals; Environmental Pollutants; Fungicides, Industrial; Humans; Maneb; Metabolomics; Mice; Neuroblastoma; Neurotoxicity Syndromes; Paraquat; Parkinson Disease; Pesticides; Phenylalanine; Proteomics; Tryptophan

The dithiocarbamate fungicide maneb (MB) has attracted interest due to increasing concern of the negative health effects of pesticides, as well as its association with Parkinson's disease (PD). Our laboratory has previously reported distinct phenotypic changes of neuroblastoma cells exposed to acute, sub-toxic levels of MB, including decreased mitochondrial respiration, altered lactate dynamics, and metabolic stress. In this study, we aimed to further define the specific molecular mechanisms of MB toxicity through the comparison of several thiol-containing compounds and their effects on cellular energy metabolism and thiol redox nodes. Extracellular flux analyses and stable isotope labeled tracer metabolomics were employed to evaluate alterations in energy metabolism of SK-N-AS human neuroblastoma cells after acute exposure of an array of compounds, including dithiocarbamates (maneb, nabam, zineb) and other thiol-containing small molecules (glutathione, N-acetylcysteine). These studies revealed MB and its methylated form (MeDTC) as unique toxicants with significant alterations to mitochondrial respiration, proliferation, and glycolysis. We observed MB to significantly impact cellular thiol redox status by oxidizing cellular glutathione and altering the thiol redox status of peroxiredoxin 3 (Prx3, mitochondrial) after acute exposure. Redox Western blotting revealed a MB-specific modification of cellular Prx3, strengthening the argument that MB can preferentially target mitochondrial enzymes containing reactive cysteine thiols. Further, stable isotope tracer metabolomics confirmed our energetics assessments, and demonstrated that MB exposure results in acute derangement of central carbon metabolism. Specifically, we observed shunting of cellular glucose into the pentose-phosphate pathway and reduction of TCA intermediates derived from glucose and glutamine. Also, we report novel lactate utilization for TCA enrichment and glutathione synthesis after MB exposure. In summary, our results further confirm that MB exerts its toxic effects via thiol modification, and significantly transforms central carbon metabolism.

Topics: Carbon; Humans; Maneb; Oxidation-Reduction; Parkinson Disease; Sulfhydryl Compounds

Topics: Animals; Cognition; Disease Models, Animal; Dopaminergic Neurons; Hippocampus; Learning; Maneb; Memory; Mice, Inbred C57BL; Microglia; Parkinson Disease

To investigate three expression-altering NFE2L2 SNPs and four PPARGC1α previously implicated SNPs and pesticides on Parkinson's disease (PD) risk and symptom progression.. In 472 PD patients and 532 population-based controls, we examined variants and their interactions with maneb and paraquat (MB/PQ) pesticide exposure on PD onset (logistic regression) and progression of motor symptoms and cognitive decline (n = 192; linear repeated measures).. NFE2L2 rs6721961 T allele was associated with a reduced risk of PD (OR = 0.70, 95% CI = 0.53, 0.94) and slower cognitive decline (β = 0.095; p = 0.0004). None of the PPARGC1α SNPs were marginally associated with PD risk. We estimate statistical interactions between MB/PQ and PPARGC1α rs6821591 (interaction p = 0.009) and rs8192678 (interaction p = 0.05), such that those with high exposure and the variant allele were at an increased risk of PD (OR ≥ 1.30, p ≤ 0.05). PPARGC1α rs6821591 was also associated with faster motor symptom progression as measured with the UPDRS-III (β = 0.234; p = 0.001).. Our study provides support for the involvement of both NFE2L2 and PPARGC1α in PD susceptibility and progression, marginally and through pathways involving MB/PQ exposure.

Topics: Aged; Aged, 80 and over; Environmental Exposure; Female; Follow-Up Studies; Genetic Predisposition to Disease; Humans; Male; Maneb; Middle Aged; NF-E2-Related Factor 2; Paraquat; Parkinson Disease; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Pesticides; Polymorphism, Single Nucleotide; Risk Factors

How genetic variations in the dopamine transporter (DAT) combined with exposure to environmental toxins modulate the risk of Parkinson's disease remains unclear. Using unbiased stereology in DAT knock-down mice (DAT-KD) and wild-type (WT) littermates, we found that decreased DAT caused a loss of tyrosine hydroxylase-positive (dopaminergic) neurons in subregions of the substantia nigra pars compacta at 3-4 days, 5 weeks, and 18 months of age. Both genotypes lost dopaminergic neurons with age and remaining neurons at 11 months were resilient to paraquat/maneb. In 5-week-old mice, the toxins decreased substantia nigra pars compacta dopaminergic neurons in both genotypes but less in DAT-KD. Regional analysis revealed striking differences in the subsets of neurons affected by low DAT, paraquat/maneb, and aging. In particular, we show that a potentially protective effect of low DAT against toxin exposure is not sufficient to reduce death of all nigrostriatal dopaminergic neurons. Thus, different regional vulnerability of nigrostriatal dopaminergic neurons may contribute to an increased risk of developing Parkinson's disease when multiple factors are combined.

Topics: Aging; Animals; Disease Models, Animal; Dopamine Plasma Membrane Transport Proteins; Dopaminergic Neurons; Genetic Variation; Male; Maneb; Mice, Knockout; Mice, Mutant Strains; Paraquat; Parkinson Disease; Pars Compacta; Risk

Topics: Acetophenones; Adrenergic Neurons; Animals; Disease Models, Animal; Enzyme Inhibitors; Locus Coeruleus; Male; Maneb; Mice; Mice, Inbred C57BL; Microglia; NADPH Oxidases; Nerve Degeneration; Neurotoxicity Syndromes; NF-kappa B; Paraquat; Parkinson Disease; Risk Factors

Parkinson's disease (PD) is a debilitating, progressive, neurodegenerative disorder characterized by progressive loss of dopaminergic neurons and motor deficits. Alpha-synuclein-containing aggregates represent a feature of a variety of neurodegenerative disorders, including PD; however, the mechanism that initiates and promotes intraneuronal alpha-synuclein aggregation remains unknown. We hypothesized protein radical formation as an initiating mechanism for alpha-synuclein aggregation. Therefore, we used the highly sensitive immuno-spin trapping technique to investigate protein radical formation as a possible mechanism of alpha-synuclein aggregation as well as to investigate the source of protein radical formation in the midbrains of Maneb- and paraquat-coexposed mice. Coexposure to Maneb and paraquat for 6 weeks resulted in active microgliosis, NADPH oxidase activation, and inducible nitric oxide synthase (iNOS) induction, which culminated in protein radical formation in the midbrains of mice. Results obtained with immuno-spin trapping and immunoprecipitation experiments confirmed formation of alpha-synuclein radicals in dopaminergic neurons of exposed mice. Free radical formation requires NADPH oxidase and iNOS, as indicated by decreased protein radical formation in knockout mice (P47phox(-/-) and iNOS(-/-)) and in mice treated with inhibitors such as FeTPPS (a peroxynitrite decomposition catalyst), 1400 W (an iNOS inhibitor), or apocynin (a NADPH oxidase inhibitor). Concurrence of protein radical formation with dopaminergic neuronal death indicated a link between protein radicals and disease progression. Taken together, these results show for the first time the formation and detection of the alpha-synuclein radical and suggest that NADPH oxidase and iNOS play roles in peroxynitrite-mediated protein radical formation and subsequent neuronal death in the midbrains of Maneb- and paraquat-coexposed mice.

Topics: alpha-Synuclein; Animals; Cyclic N-Oxides; Disease Models, Animal; Dopaminergic Neurons; Injections, Intraperitoneal; Male; Maneb; Mesencephalon; Mice, Inbred C57BL; Microglia; Models, Biological; NADPH Oxidases; Nitric Oxide Synthase Type II; Paraquat; Parkinson Disease; Peroxynitrous Acid; Spin Labels; Substantia Nigra; Tyrosine 3-Monooxygenase

Current evidence suggests suceptibility of both the substantia nigra and striatum to exposure to components of air pollution. Further, air pollution has been associated with increased risk of PD diagnsosis in humans or PD-like pathology in animals. This study examined whether exposure of mice to concentrated ambient ultrafine particles (CAPS; <100nm diameter) during the first two weeks of life would alter susceptibility to induction of the Parkinson's disease phenyotype (PDP) in a pesticide-based paraquat and maneb (PQ+MB) model during adulthood utilizing i.p. injections of 10mg/kg PQ and 30mg/kg MB 2× per week for 6 weeks. Evidence of CAPS-induced enhancement of the PQ+MB PDP was limited primarily to delayed recovery of locomotor activity 24 post-injection of PQ+MB that could be related to alterations in striatal GABA inhibitory function. Absence of more extensive interactions might also reflect the finding that CAPS and PQ+MB appeared to differentially target the nigrostriatal dopamine and amino acid systems, with CAPS impacting striatum and PQ+MB impacting dopamine-glutamate function in midbrain; both CAPS and PQ+MB elevated glutamate levels in these specific regions, consistent with potential excitotoxicity. These findings demonstrate the ability of postnatal CAPS to produce locomotor dysfunction and dopaminergic and glutamateric changes, independent of PQ+MB, in brain regions involved in the PDP.

Topics: Air Pollutants; Animals; Animals, Newborn; Cell Count; Corpus Striatum; Disease Models, Animal; Drug Combinations; Female; Fungicides, Industrial; Herbicides; Male; Maneb; Mice; Mice, Inbred C57BL; Motor Activity; Nanoparticles; Paraquat; Parkinson Disease; Particulate Matter; Silicones; Substantia Nigra; Tyrosine 3-Monooxygenase

Robust epidemiological data link higher levels of the antioxidant urate to a reduced risk of developing Parkinson׳s disease (PD) and to a slower rate of its progression. Allopurinol, an inhibitor of xanthine oxidoreductase (XOR), blocks the oxidation of xanthine to urate. The present study sought to determine whether lowering levels of urate using allopurinol results in exacerbated neurotoxicity in a dual pesticide mouse model of PD. Although oral allopurinol reduced serum and striatal urate levels 4-fold and 1.3-fold, respectively, it did not alter the multiple motor deficits induced by chronic (7 week) intermittent (biweekly) exposure to intraperitoneal Paraquat (PQ) plus Maneb (MB). However, striatal dopamine content, which was unaffected after either allopurinol or chronic pesticide exposure alone, was significantly reduced by 22% in mice exposed to the combination. Stereological assessment showed that the numbers of dopaminergic nigral neurons were significantly reduced by 29% and the tyrosine hydroxylase (TH) negative neurons unaffected after PQ+MB treatments. This reduction in TH-positive neurons was not affected by allopurinol treatment. Of note, despite the expectation of exacerbated oxidative damage due to the reduction in urate, protein carbonyl levels, a marker of oxidative damage, were actually reduced in the presence of allopurinol. Overall, allopurinol lowered urate levels but did not exacerbate dopaminergic neuron degeneration, findings suggesting that basal levels of urate in mice do not appreciably protect against oxidative damage and neurotoxicity in the PQ+MB model of PD, and/or that allopurinol produces an antioxidant benefit offsetting its detrimental urate-lowering effect.

Topics: Allopurinol; Animals; Corpus Striatum; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Enzyme Inhibitors; Male; Maneb; Mice; Mice, Inbred C57BL; Motor Activity; Paraquat; Parkinson Disease; Pesticides; Uric Acid

Epidemiological studies indicate a role of genetic and environmental factors in Parkinson's disease involving alterations of the neuronal α-synuclein (α-syn) protein. In particular, a relationship between Parkinson's disease and occupational exposure to pesticides has been repeatedly suggested. Our objective was to precisely assess changes in α-syn levels in human neuroblastoma (SH-SY5Y) and melanoma (SK-MEL-2) cell lines following acute exposure to pesticides (rotenone, paraquat, maneb, and glyphosate) using Western blot and flow cytometry. These human cell lines express α-syn endogenously, and overexpression of α-syn (wild type or mutated A53T) can be obtained following recombinant adenoviral transduction. We found that endogenous α-syn levels in the SH-SY5Y neuroblastoma cell line were markedly increased by paraquat, and to a lesser extent by rotenone and maneb, but not by glyphosate. Rotenone also clearly increased endogenous α-syn levels in the SK-MEL-2 melanoma cell line. In the SH-SY5Y cell line, similar differences were observed in the α-syn adenovirus-transduced cells, with a higher increase of the A53T mutated protein. Paraquat markedly increased α-syn in the SK-MEL-2 adenovirus-transduced cell line, similarly for the wild-type or A53T proteins. The observed differences in the propensities of pesticides to increase α-syn levels are in agreement with numerous reports that indicate a potential role of exposure to certain pesticides in the development of Parkinson's disease. Our data support the hypothesis that pesticides can trigger some molecular events involved in this disease and also in malignant melanoma that consistently shows a significant but still unexplained association with Parkinson's disease.

Topics: alpha-Synuclein; Cell Death; Cell Line, Tumor; Cell Survival; Glycine; Glyphosate; Humans; Insecticides; Maneb; Melanoma; Neuroblastoma; Paraquat; Parkinson Disease; Rotenone; Transduction, Genetic

Humans are exposed to various chemical mixtures daily. The toxic response to a mixture of chemicals could be potentiated or suppressed. This study demonstrates that non-toxic doses of pesticides can induce cellular changes that increase cell sensitivity to other toxins or stress. Pesticide exposure is an environmental risk factor for Parkinson's disease. Manganese (Mn) is essential but high dose exposure may results in neurological dysfunction. Mn-containing dithiocarbamates, maneb (MB) and mancozeb (MZ), are primarily used as pesticides. Studies have shown that MB can augment dopaminergic damage triggered by sub-toxic doses of Parkinsonian mimetic MPTP. However, the mechanism underlying this effect is not clear. Activation of nuclear factor kappa B (NF-κB) has been implicated in MPTP toxicity. Mn stimulates the activation of NF-κB and subsequently induces neuronal injury via an NF-κB dependent mechanism. We speculate that MB and MZ enhance MPTP active metabolite (methyl-4-phenylpyridine ion, MPP(+)) toxicity by activating NF-κB. The activation of NF-κB was observed using Western blot analysis and NF-κB response element driven Luciferase reporter assay. Western blot data demonstrated the nuclear translocation of NF-κB p65 and the degradation of IkBα after MB and MZ 4-h treatments. Results of NF-κB response element luciferase reporter assay confirmed that MB and MZ activated NF-κB. The NF-κB inhibitor (SN50) was also shown to alleviate cytotoxicity induced by co-treatment of MB or MZ and MPP(+). This study demonstrates that activation of NF-κB is responsible for the potentiated toxic effect of MB and MZ on MPP(+) induced cytotoxicity.

Topics: 1-Methyl-4-phenylpyridinium; Animals; Cell Death; Cell Survival; Ditiocarb; Luciferases; Maneb; Manganese; NF-kappa B; Parkinson Disease; PC12 Cells; Peptides; Rats; Response Elements; Signal Transduction; Zineb

Parkinson's disease (PD) is a neurodegenerative disease in which the etiology of 90 percent of the patients is unknown. Pesticide exposure is a major risk factor for PD, and paraquat (PQ), pyridaben (PY) and maneb (MN) are amongst the most widely used pesticides. We studied mRNA expression using transcriptome sequencing (RNA-Seq) in the ventral midbrain (VMB) and striatum (STR) of PQ, PY and paraquat+maneb (MNPQ) treated mice, followed by pathway analysis. We found concordance of signaling pathways between the three pesticide models in both the VMB and STR as well as concordance in these two brain areas. The concordant signaling pathways with relevance to PD pathogenesis were e.g. axonal guidance signaling, Wnt/β-catenin signaling, as well as pathways not previously linked to PD, e.g. basal cell carcinoma, human embryonic stem cell pluripotency and role of macrophages, fibroblasts and endothelial cells in rheumatoid arthritis. Human PD pathways previously identified by expression analysis, concordant with VMB pathways identified in our study were axonal guidance signaling, Wnt/β-catenin signaling, IL-6 signaling, ephrin receptor signaling, TGF-β signaling, PPAR signaling and G-protein coupled receptor signaling. Human PD pathways concordant with the STR pathways in our study were Wnt/β-catenin signaling, axonal guidance signaling and G-protein coupled receptor signaling. Peroxisome proliferator activated receptor delta (Ppard) and G-Protein Coupled Receptors (GPCRs) were common genes in VMB and STR identified by network analysis. In conclusion, the pesticides PQ, PY and MNPQ elicit common signaling pathways in the VMB and STR in mice, which are concordant with known signaling pathways identified in human PD, suggesting that these pathways contribute to the pathogenesis of idiopathic PD. The analysis of these networks and pathways may therefore lead to improved understanding of disease pathogenesis, and potential novel therapeutic targets.

Topics: Animals; Corpus Striatum; Gene Expression Profiling; Gene Regulatory Networks; Humans; Male; Maneb; Mesencephalon; Mice; Mice, Inbred C57BL; Oligonucleotide Array Sequence Analysis; Paraquat; Parkinson Disease; Parkinson Disease, Secondary; Pesticides; Pyridazines; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Transcriptome

Parkinson's disease (PD) is a multifactorial disease where environmental factors act on genetically predisposed individuals. Although only 5% of PD manifestations are associated with specific mutations, majority of PD cases are of idiopathic origin, where environment plays a prominent role. Concurrent exposure to Paraquat (PQ) and Maneb (MB) in rural workers increases the risk for PD and exposure of adult mice to MB/PQ results in dopamine fiber loss and decreased locomotor activity. While PD is characterized by neuronal loss in the substantia nigra, we previously showed that accumulation of α-synuclein in the limbic system contributes to neurodegeneration by interfering with adult neurogenesis.. We investigated the effect of pesticides on adult hippocampal neurogenesis in two transgenic models: Line 61, expressing the human wild type SNCA gene and Line LRRK2(G2019S), expressing the human LRRK2 gene with the mutation G2019S. Combined exposure to MB/PQ resulted in significant reduction of neuronal precursors and proliferating cells in non-transgenic animals, and this effect was increased in transgenic mice, in particular for Line 61, suggesting that α-synuclein accumulation and environmental toxins have a synergistic effect. We further investigated the transcription of 84 genes with direct function on neurogenesis. Overexpresion of α-synuclein resulted in the downregulation of 12% of target genes, most of which were functionally related to cell differentiation, while LRRK2 mutation had a minor impact on gene expression. MB/PQ also affected transcription in non-transgenic backgrounds, but when transgenic mice were exposed to the pesticides, profound alterations in gene expression affecting 27% of the studied targets were observed in both transgenic lines. Gene enrichment analysis showed that 1:3 of those genes were under the regulation of FoxF2 and FoxO3A, suggesting a primary role of these proteins in the response to genetic and environmental cues.. We report that adult neurogenesis is highly susceptible to multiple "risk factors" for PD, including α-synuclein accumulation, LRRK2 G2019 mutation and exposure to environmental toxins. We identified specific groups of genes that are responsive to each stressor, while uncovering a novel function for Fox transcription factors in PD.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Gene Expression Regulation; Gene-Environment Interaction; Hippocampus; Humans; Immunohistochemistry; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Maneb; Mice; Mice, Transgenic; Neurogenesis; Paraquat; Parkinson Disease; Pesticides; Protein Serine-Threonine Kinases; Real-Time Polymerase Chain Reaction; Transcription, Genetic

Oxidative stress is reported as one of the most widely accepted mechanisms of maneb (MB)- and paraquat (PQ)-induced nigrostriatal dopaminergic neurodegeneration leading to the Parkinson's disease (PD) phenotype. The study investigated the effects of silymarin, an antioxidant of plant origin, and melatonin, an indoleamine produced in all species, in MB- and PQ-induced mouse model of PD. The mice were treated intraperitoneally daily with silymarin (40mg/kg) or melatonin (30mg/kg) along with respective controls for 9wk. Subsets of these animals were also treated with MB (30mg/kg) and PQ (10mg/kg), twice a week, for 9wk, 2hr after silymarin/melatonin treatment. Locomotor activities along with striatal dopamine content, tyrosine hydroxylase (TH) immunoreactivity, number of degenerating neurons, lipid peroxidation and nitrite content were estimated. Additionally, mRNA expression of vesicular monoamine transporter, cytochrome P-450 2E1 (CYP2E1), and glutathione-S-transferase A4-4 (GSTA4-4), catalytic activities of CYP2E1 and GSTA4-4 and protein expressions of unphosphorylated and phosphorylated p53 (p53 and P-p53), Bax and caspase 9 were measured in control and MB- and PQ-treated mice with either silymarin or melatonin treatments. Silymarin/melatonin significantly offset MB- and PQ-mediated reductions in locomotor activities, dopamine content, TH immunoreactivity, VMAT 2 mRNA expression and the expression of p53 protein. Silymarin/melatonin attenuated the increases in lipid peroxidation, number of degenerating neurons, nitrite content, mRNA expressions of cytochrome P-450 2E1 (CYP2E1) and GSTA4-4, catalytic activities of CYP2E1 and GST and P-p53, Bax and caspase 9 protein expressions. The results demonstrate that silymarin and melatonin offer nigrostriatal dopaminergic neuroprotection against MB- and PQ-induced PD by the modulation of oxidative stress and apoptotic machinery.

Topics: Animals; Blotting, Western; Cytochrome P-450 CYP2E1; Dopamine; Lipid Peroxidation; Male; Maneb; Melatonin; Mice; Paraquat; Parkinson Disease; Polymerase Chain Reaction; Silymarin; Tyrosine 3-Monooxygenase; Vesicular Monoamine Transport Proteins

Epidemiological and in vivo studies have demonstrated that exposure to the pesticides paraquat (PQ) and maneb (MB) increase the risk of developing Parkinson's disease (PD) and cause dopaminergic cell loss, respectively. PQ is a well-recognized cause of oxidative toxicity; therefore, the purpose of this study was to determine if MB potentiates oxidative stress caused by PQ, thus providing a mechanism for enhanced neurotoxicity by the combination. The results show that PQ alone at a moderately toxic dose (20-30% cell death in 24 h) caused increased reactive oxygen species (ROS) generation, oxidation of mitochondrial thioredoxin-2 and peroxiredoxin-3, lesser oxidation of cytoplasmic thioredoxin-1 and peroxiredoxin-1, and no oxidation of cellular GSH/GSSG. In contrast, MB alone at a similar toxic dose resulted in no ROS generation, no oxidation of thioredoxin and peroxiredoxin, and an increase in cellular GSH after 24 h. Together, MB increased GSH and inhibited ROS production and thioredoxin/peroxiredoxin oxidation observed with PQ alone, yet resulted in more extensive (> 50%) cell death. MB treatment resulted in increased abundance of nuclear Nrf2 and mRNA for phase II enzymes under the control of Nrf2, indicating activation of cell protective responses. The results show that MB potentiation of PQ neurotoxicity does not occur by enhancing oxidative stress and suggests that increased toxicity occurs by a combination of divergent mechanisms, perhaps involving alkylation by MB and oxidation by PQ.

Topics: Cell Line; Dopamine; Glutathione; Humans; Maneb; Neurons; Neurotoxicity Syndromes; Neurotoxins; NF-E2-Related Factor 2; Oxidation-Reduction; Oxidative Stress; Paraquat; Parkinson Disease; Peroxiredoxins; Pesticides; Reactive Oxygen Species; Thioredoxins; Transcription Factors

α-Synuclein (α-Syn) plays a crucial role in the pathophysiology of Parkinson's disease (PD). α-Syn has been extensively studied in many neuronal cell-based PD models but has yielded mixed results. The objective of this study was to re-evaluate the dual cytotoxic/protective roles of α-Syn in dopaminergic SH-SY5Y cells. Stable SH-SY5Y cells overexpressing wild type or familial α-Syn mutants (A30P, E46K and A53T) were subjected to acute and chronic rotenone and maneb treatment. Compared with untransfected SH-SY5Y cells, wild type α-Syn attenuated rotenone and maneb-induced cell death along with an attenuation of toxin-induced mitochondrial membrane potential changes and Reactive Oxygen Species level, whereas the mutant α-Syn constructs exacerbated environmental toxins-induced cytotoxicity. After chronic treatment, wild type α-Syn but not the mutant variants was found to rescue cells from subsequent acute hydrogen peroxide insult. These results suggest that the fundamental property of wild type α-Syn may be protective, and such property may be lost by its familial PD mutations.

Topics: alpha-Synuclein; Cell Death; Cell Line, Tumor; Cytoprotection; Dopamine; Dose-Response Relationship, Drug; Humans; Hydrogen Peroxide; Maneb; Membrane Potential, Mitochondrial; Mutagenesis, Site-Directed; Mutation; Neurons; Oxidative Stress; Parkinson Disease; Reactive Oxygen Species; Rotenone; Transfection

A liposomal preparation of glutathione (GSH) was investigated for its ability to replenish intracellular GSH and provide neuroprotection in an in vitro model of Parkinson's disease using paraquat plus maneb (PQMB) in rat mesencephalic cultures. In mixed neuronal/glial cultures depleted of intracellular GSH, repletion to control levels occurred over 4 h with liposomal-GSH or non-liposomal-GSH however, liposomal-GSH was 100-fold more potent; EC(50s) 4.75 μM and 533 μM for liposomal and non-liposomal-GSH, respectively. Liposomal-GSH utilization was also observed in neuronal cultures, but with a higher EC(50) (76.5 μM), suggesting that glia facilitate utilization. Blocking γ-glutamylcysteine synthetase with buthionine sulfoxamine prevented replenishment with liposomal-GSH demonstrating the requirement for catabolism and resynthesis. Repletion was significantly attenuated with endosomal inhibition implicating the endosomal system in utilization. Liposomal-GSH provided dose-dependent protection against PQMB with an EC(50) similar to that found for repletion. PQMB depleted intracellular GSH by 50%. Liposomal-GSH spared endogenous GSH during PQMB exposure, but did not require GSH biosynthesis for protection. No toxicity was observed with the liposomal preparation at 200-fold the EC(50) for repletion. These findings indicate that glutathione supplied in a liposomal formulation holds promise as a potential therapeutic for neuronal maintenance.

Topics: Animals; Antioxidants; Cell Survival; Cells, Cultured; Glutathione; Glycerol; Intracellular Space; Lecithins; Liposomes; Maneb; Mesencephalon; Neurons; Neuroprotective Agents; Paraquat; Parkinson Disease; Pesticides; Rats; Rats, Sprague-Dawley

Although of great interest and suggested in prior reports, possible α-synuclein (SNCA) gene-environment interactions have not been well investigated in humans.. We used a population-based approach to examine whether the risk of Parkinson's disease (PD) depended on the combined presence of SNCA variations and two important environmental factors, pesticide exposures and smoking.. Similar to recent meta- and pooled analyses, our data suggest a lower PD risk in subjects who were either homozygous or heterozygous for the SNCA REP1 259 genotype, and a higher risk in subjects who were either homozygous or heterozygous for the REP1 263 genotype, especially among subjects with an age of onset ≤68 years. More importantly, while analyses of interactions were limited by small cell sizes, risk due to SNCA variations seemed to vary with pesticide exposure and smoking, especially in younger onset cases, suggesting an age-of-onset effect.

Topics: Age of Onset; Aged; alpha-Synuclein; California; Causality; Comorbidity; Educational Status; Environmental Exposure; Female; Fungicides, Industrial; Herbicides; Humans; Male; Maneb; Paraquat; Parkinson Disease; Risk Assessment; Rural Health; Smoking

Evidence from animal and cell models suggests that pesticides cause a neurodegenerative process leading to Parkinson's disease (PD). Human data are insufficient to support this claim for any specific pesticide, largely because of challenges in exposure assessment. The authors developed and validated an exposure assessment tool based on geographic information systems that integrated information from California Pesticide Use Reports and land-use maps to estimate historical exposure to agricultural pesticides in the residential environment. In 1998-2007, the authors enrolled 368 incident PD cases and 341 population controls from the Central Valley of California in a case-control study. They generated estimates for maneb and paraquat exposures incurred between 1974 and 1999. Exposure to both pesticides within 500 m of the home increased PD risk by 75% (95% confidence interval (CI): 1.13, 2.73). Persons aged < or =60 years at the time of diagnosis were at much higher risk when exposed to either maneb or paraquat alone (odds ratio = 2.27, 95% CI: 0.91, 5.70) or to both pesticides in combination (odds ratio = 4.17, 95% CI: 1.15, 15.16) in 1974-1989. This study provides evidence that exposure to a combination of maneb and paraquat increases PD risk, particularly in younger subjects and/or when exposure occurs at younger ages.

Topics: Adult; Aged; Aged, 80 and over; Agriculture; California; Case-Control Studies; Comorbidity; Environmental Exposure; Environmental Monitoring; Epidemiological Monitoring; Female; Humans; Male; Maneb; Middle Aged; Odds Ratio; Paraquat; Parkinson Disease; Pesticides; Population Surveillance; Smoking

Research suggests that independent and joint effects of genetic variability in the dopamine transporter (DAT) locus and pesticides may influence Parkinson's disease (PD) risk.. In 324 incident PD patients and 334 population controls from our rural California case-control study, we genotyped rs2652510, rs2550956 (for the DAT 5' clades), and the 3' variable number of tandem repeats (VNTR). Using geographic information system methods, we determined residential exposure to agricultural maneb and paraquat applications. We also collected occupational pesticide use data. Employing logistic regression, we calculated odds ratios (ORs) for clade diplotypes, VNTR genotype, and number of susceptibility (A clade and 9-repeat) alleles and assessed susceptibility allele-pesticide interactions.. PD risk was increased separately in DAT A clade diplotype carriers [AA vs. BB: OR = 1.66; 95% confidence interval (CI), 1.08-2.57] and 3' VNTR 9/9 carriers (9/9 vs. 10/10: OR = 1.8; 95% CI, 0.96-3.57), and our data suggest a gene dosing effect. Importantly, high exposure to paraquat and maneb in carriers of one susceptibility allele increased PD risk 3-fold (OR = 2.99; 95% CI, 0.88-10.2), and in carriers of two or more alleles more than 4-fold (OR = 4.53; 95% CI, 1.70-12.1). We obtained similar results for occupational pesticide measures.. Using two independent pesticide measures, we a) replicated previously reported gene-environment interactions between DAT genetic variants and occupational pesticide exposure in men and b) overcame previous limitations of nonspecific pesticide measures and potential recall bias by employing state records and computer models to estimate residential pesticide exposure.. Our results suggest that DAT genetic variability and pesticide exposure interact to increase PD risk.

Topics: Case-Control Studies; Dopamine Plasma Membrane Transport Proteins; Environmental Exposure; Environmental Pollutants; Female; Genetic Variation; Genotype; Humans; Male; Maneb; Middle Aged; Paraquat; Parkinson Disease; Pesticides; Polymorphism, Single Nucleotide; Risk Factors

The factors initiating or contributing to the pathogenesis of Parkinson's disease and related neurodegenerative synucleinopathies are still largely unclear, but environmental factors such as pesticides have been implicated. In this study, A53T mutant human alpha-synuclein transgenic mice (M83), which develop alpha-synuclein neuropathology, were treated with the pesticides paraquat and maneb (either singly or together), and their effects were analyzed. Immunohistochemical and biochemical analyses showed that chronic treatment of M83 transgenic mice with both pesticides (but not with either pesticide alone) drastically increased neuronal alpha-synuclein pathology throughout the central nervous system including the hippocampus, cerebellum, and sensory and auditory cortices. alpha-Synuclein-associated mitochondrial degeneration was observed in M83 but not in wild-type alpha-synuclein transgenic mice. Because alpha-synuclein inclusions accumulated in pesticide-exposed M83 transgenic mice without a motor phenotype, we conclude that alpha-synuclein aggregate formation precedes disease onset. These studies support the notion that environmental factors causing nitrative damage are closely linked to mechanisms underlying the formation of alpha-synuclein pathologies and the onset of Parkinson's-like neurodegeneration.

Topics: alpha-Synuclein; Animals; Brain; Drug Synergism; Environmental Exposure; Fungicides, Industrial; Humans; Inclusion Bodies; Maneb; Mice; Mice, Transgenic; Mitochondria; Mutation, Missense; Paraquat; Parkinson Disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder contributed by the combination of age, genetic and environmental factors. Several studies have clearly shown increase in the incidences of PD in the rural environments and hypothesized the involvement of pesticides such as paraquat and maneb in neurodegeneration. These studies have prompted researchers to develop paraquat and maneb models to study the effect of co-treatment of maneb and paraquat on neuronal toxicity; however, the mechanism underlying maneb and paraquat co-treatment induced neuronal toxicity has not yet been clearly understood. The involvement of cytochrome P4502E1 and glutathione S-transferases A4-4 enzymes in the detoxification of several pesticides such as atrazine, fenamirol, organophosphorous insecticide parathion, methoxychlor, diethyl dithiocarbamate and paraquat has been known. The contribution of CYP2E1 and GSTA4-4 in neuronal toxicity has also been reported. The present study was therefore undertaken to investigate the mechanism of maneb- and paraquat-induced neurodegeneration by estimating the level of antioxidant defense enzymes in the striatum and measuring the differential expressions of CYP2E1 and GSTA4-4 genes. Animals were treated with and without maneb (30 mg/kg, i.p.) or paraquat (10 mg/kg, i.p.) either alone or in combination in exposure time-dependent manner. A significant increase in catalase, glutathione S-transferase and lipid peroxidation in the striatum was found following 3, 6 and 9 weeks of co-treatment as compared with individual treatment or controls. Individual treatment of maneb or paraquat did not exhibit any significant alteration in CYP2E1 and GSTA4-4 expression up to 6 weeks; however, an augmentation in CYP2E1 and GSTA4-4 expression was observed in the animals exposed to maneb or paraquat for 9 weeks. Augmentation in the expression of CYP2E1 and GSTA4-4 was more pronounced in the animals treated with maneb and paraquat in combination for nine weeks. A significant reduction in the augmented lipid peroxidation in the striatum was observed when the striatum was pre-administered with CYP2E1 inhibitors; however, glutathione pre-administration induced lipid peroxidation. Results obtained from the present investigation suggest the involvement of CYP2E1 and GSTA4-4 in the augmentation of the lipid peroxidation thereby enhancing neurodegeneration.

Topics: Analysis of Variance; Animals; Catalase; Corpus Striatum; Cytochrome P-450 CYP2E1; Disease Models, Animal; Gene Expression; Glutathione Transferase; Herbicides; Lipid Peroxidation; Male; Maneb; Mice; Paraquat; Parkinson Disease; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Superoxide Dismutase; Time Factors

Oxidative stress has been implicated in the pathogenesis of Parkinson disease based on its role in the cascade of biochemical changes that lead to dopaminergic neuronal death. This study analyzed the role of oxidative stress as a mechanism of the dopaminergic neurotoxicity produced by the combined paraquat and maneb model of the Parkinson disease phenotype. Transgenic mice overexpressing either Cu,Zn superoxide dismutase or intracellular glutathione peroxidase and non-transgenic mice were exposed to saline, paraquat, or the combination of paraquat + maneb twice a week for 9 weeks. Non-transgenic mice chronically exposed to paraquat + maneb exhibited significant reductions in locomotor activity, levels of striatal dopamine and metabolites, and dopaminergic neurons in the substantia nigra pars compacta. In contrast, no corresponding effects were observed in either Cu,Zn superoxide dismutase or glutathione peroxidase transgenic mice. Similarly, the increase in levels of lipid hydroperoxides in the midbrain and striatum of paraquat + maneb-treated non-transgenic mice was not detected in either Cu,Zn superoxide dismutase or glutathione peroxidase transgenic mice. To begin to determine critical pathways of paraquat + maneb neurotoxicity, the functions of cell death-inducing and protective mechanisms were analyzed. Even a single injection of paraquat + maneb in the non-transgenic treated group modulated several key pro- and anti-apoptotic proteins, including Bax, Bad, Bcl-xL, and upstream stress-induced cascade. Collectively, these findings support the assertion that protective mechanisms against paraquat + maneb-induced neurodegeneration could involve modulation of the level of reactive oxygen species and alterations of the functions of specific signaling cascades.

Topics: Animals; Apoptosis; bcl-X Protein; Blotting, Western; Body Weight; Cerebral Cortex; Corpus Striatum; Dopamine; Fungicides, Industrial; Glutathione Peroxidase; Herbicides; Hydrogen Peroxide; Immunohistochemistry; Lipid Metabolism; Lipid Peroxidation; Maneb; Mesencephalon; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Neurodegenerative Diseases; Neurons; Oxidative Stress; Paraquat; Parkinson Disease; Proto-Oncogene Proteins c-bcl-2; Serotonin; Signal Transduction; Substantia Nigra; Superoxide Dismutase; Tyrosine 3-Monooxygenase

It has been hypothesized that developmental insults could contribute to Parkinson disease (PD), a neurodegenerative disorder resulting from the loss of the dopamine neurons of the nigrostriatal pathway. Two models of developmental pesticide exposures in mice are presented here that yield PD phenotypes consistent with this possibility. Combined exposures to the herbicide paraquat (PQ) and the fungicide maneb (MB), both of which adversely affect dopamine systems, administered from postnatal days 5-19, produced selective losses of dopamine and metabolites and reduced numbers of dopamine neurons in the substantia nigra. Effects were greater than those produced by adult-only exposures. Moreover, developmental PQ + MB exposures enhanced vulnerability to this pesticide regimen when administered subsequently in adulthood. In a second model, exposure to MB from gestational days 10-17 markedly increased vulnerability to PQ exposures during adulthood, with reductions in dopamine and metabolites and numbers of dopamine neurons in the substantia nigra. Females evidenced protection in both models. Collectively, these models demonstrate that developmental exposures can produce progressive, permanent, and cumulative neurotoxicity of the nigrostriatal dopamine system and enhance vulnerability to subsequent environmental insults. Finally, effects of PQ + MB were greater than those of either pesticide alone in the postnatal model. This is consistent with a multiple-hit hypothesis predicting that multiple concurrent insults occurring at different target sites within a system (here nigrostriatal dopamine) may constrict the range and flexibility of compensatory mechanisms, thereby compromising the integrity and viability of the system. As such, this hypothesis presents a biologic strategy for identifying potentially significant neurotoxic mixtures for hazard identification in future studies.

Topics: Age Factors; Animals; Animals, Newborn; Dopamine; Drug Synergism; Female; Fungicides, Industrial; Herbicides; Male; Maneb; Mice; Mice, Inbred C57BL; Models, Biological; Motor Activity; Paraquat; Parkinson Disease; Phenotype; Pregnancy; Prenatal Exposure Delayed Effects; Substantia Nigra

Idiopathic Parkinson's disease (PD) is associated with advanced age, but it is still unclear whether dopaminergic neuronal death results from events initiated during development, adulthood, or represents a cumulative effect across the span of life. This study hypothesized that paraquat (PQ) and maneb (MB) exposure during critical periods of development could permanently change the nigrostriatal dopamine (DA) system and enhance its vulnerability to subsequent neurotoxicant challenges. C57BL/6 mice were treated daily with saline, 0.3 mg/kg PQ, 1 mg/kg MB or PQ + MB from post-natal (PN) days 5 to 19. At 6 weeks, a 20% decrease in activity was evident only in the PQ + MB group, with a further decline (40%) observed at 6 months. A subset of mice were re-challenged as adults with saline, 10 mg/kg PQ, 30 mg/kg MB, or PQ + MB 2 x a week for 3 weeks. Mice exposed developmentally to PQ + MB and rechallenged as adults were the most affected, showing a 70% reduction in motor activity 2 weeks following the last rechallenge dose. Striatal DA levels were reduced by 37% following developmental exposure to PQ + MB only, butfollowing adult re-challenge levels were reduced by 62%. A similar pattern of nigral dopaminergic cell loss was observed, with the PQ + MB treated group exhibiting the greatest reduction, with this loss being amplified by adult re-challenge. Developmental exposure to PQ or MB alone produced minimal changes. However, following adult re-challenge, significant decreases in DA and nigral cell counts were observed, suggesting that exposure to either neurotoxicant alone produced a state of silent toxicity that was unmasked following adult re-exposure. Taken together, these findings indicate that exposure to pesticides during the PN period can produce permanent and progressive lesions of the nigrostriatal DA system, and enhanced adult susceptibility to these pesticides, suggesting that developmental exposure to neurotoxicants may be involved in the induction of neurodegenerative disorders and/or alter the normal aging process.

Topics: Aging; Animals; Animals, Newborn; Body Weight; Cell Count; Chromatography, High Pressure Liquid; Dopamine; Fungicides, Industrial; Herbicides; Homovanillic Acid; Immunohistochemistry; Male; Maneb; Mice; Mice, Inbred C57BL; Motor Activity; Paraquat; Parkinson Disease; Phenotype; Serotonin; Tyrosine 3-Monooxygenase