RESUMO
Recent epidemiologic studies have demonstrated a link between organochlorine and pesticide exposure to an enhanced risk for neurodegenerative disorders such as Parkinson's disease (PD). A common biological phenomenon underlying cell injury associated with both polychlorinated biphenyl (PCB) exposure and dopaminergic neurodegeneration during aging is oxidative stress (OS). In this study, we tested the hypothesis that oral PCB exposure, via food ingestion, impairs dopamine systems in the adult murine brain. We determined whether PCB exposure was associated with OS in dopaminergic neurons, a population of cells that selectively degenerate in PD. After 4 weeks of oral exposure to the PCB mixture Aroclor 1254, several congeners, mostly ortho substituted, accumulated throughout the brain. Significant increases in locomotor activity were observed within 2 weeks, which persisted after cessation of PCB exposure. Stereologic analyses revealed a significant loss of dopaminergic neurons within the substantia nigra and ventral tegmental area. However, striatal dopamine levels were elevated, suggesting that compensatory mechanisms exist to maintain dopamine homeostasis, which could contribute to the observed increases in locomotor activity following PCB exposure. Biochemical experiments revealed alterations in OS markers, including increases in SOD and HO-1 levels and the presence of oxidatively modified lipids and proteins. These findings were accompanied by elevated iron levels within the striatal and midbrain regions, perhaps due to the observed dysregulation of transferrin receptors and ferritin levels following PCB exposure. In this study, we suggest that both OS and the uncoupling of iron regulation contribute to dopamine neuron degeneration and hyperactivity following PCB exposure.
Assuntos
/toxicidade , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Mesencéfalo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Administração Oral , Animais , Morte Celular/efeitos dos fármacos , /metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Relação Dose-Resposta a Droga , Poluentes Ambientais/administração & dosagem , Poluentes Ambientais/metabolismo , Heme Oxigenase-1/metabolismo , Hipercinese/induzido quimicamente , Hipercinese/metabolismo , Hipercinese/fisiopatologia , Ferro/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Proteínas de Membrana/metabolismo , Mesencéfalo/metabolismo , Mesencéfalo/patologia , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Carbonilação Proteica/efeitos dos fármacos , Ratos , Superóxido Dismutase/metabolismo , Fatores de Tempo , Distribuição Tecidual , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Animal models, consistent with the hypothesis of direct interaction of paraquat (PQ) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) with specific areas of the central nervous system have been developed to study Parkinson's disease (PD) in mice. These models have necessitated the creation of an analytical method for unambiguous identification and quantitation of PQ and structurally similar MPTP and 1-methyl-4-phenylpyridinium ion (MPP+) in brain tissue. A method for determination of these compounds was developed using microwave-assisted solvent extraction (MASE) and liquid chromatography-mass spectrometry. Extraction solvent and microwave conditions such as power and time were optimized to produce recoveries of 90% for PQ 78% for MPTP and 97% for its metabolite MPP+. The chromatographic separation was performed on a C8, column and detection was carried out using an ion trap as an analyzer with electrospray ionization. Mass spectrometer parameters such as heated capillary temperature, spray voltage, capillary voltage and others were also optimized for each analyte. Analysis was done in selective ion-monitoring (SIM) mode using m/z 186 for PQ, m/z 174 for MPTP, and m/z 170 for MPP+. The method detection limit for paraquat in matrix was 100 pg, 40 pg for MPTP, and 20 pg MPP+.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/análise , Paraquat/análise , Piperidinas/análise , Pirazóis/análise , Espectrometria de Massas em Tandem/métodos , Animais , Encéfalo/patologia , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Dopaminérgicos , Receptor alfa de Estrogênio/agonistas , Herbicidas , Camundongos , Micro-Ondas , Doença de Parkinson , SolventesRESUMO
Elevated lead (Pb) exposure and high stress both target low socio-economic status populations. Both also act on the hypothalamic-pituitary-adrenal (HPA) axis. Pb disrupts cognition through effects on the mesocorticolimbic dopamine pathway. Stress hormones act on this same pathway via the HPA axis. The fact that Pb and stress are likely interactive risk factors served as the rationale for a series of studies in our laboratory. These demonstrate that stress can modify Pb effects, that Pb can modify stress responsivity, and, notably, that Pb + stress effects can occur in the absence of an effect of either alone in rats. Furthermore, maternal only Pb exposure can permanently alter basal corticosterone levels, stress responsivity (i.e. permanent modification of HPA axis function) and brain catecholamines in offspring of both genders. Interactive effects of Pb + stress are not limited to early development: even Pb exposures initiated post-weaning alter basal corticosterone and stress responsivity. Outcomes differ in relation to gender, brain region, stressor and time of measurement, making Pb + stress interactions complex. Altered HPA axis function may serve as a mechanism for the behavioural and catecholaminergic neurotoxicity associated with Pb, as well as for the increased incidence of disease and dysfunctions associated with low socio-economic status. The permanent consequences of maternal only Pb exposure suggest that Pb screening programmes should include pregnant women at risk for elevated Pb exposure, and that stress should be considered as an additional risk factor. Pb + stress effects observed in the absence of either risk factor alone raise questions about the capacity of current hazard identification approaches to adequately identify human health risks posed by neurotoxicants.
Assuntos
Poluentes Ambientais/toxicidade , Chumbo/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Estresse Psicológico/complicações , Animais , Corticosterona/sangue , Dopamina/metabolismo , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Exposição Materna , Troca Materno-Fetal , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Gravidez , Serotonina/metabolismoRESUMO
BACKGROUND: Paraquat (PQ) has been implicated as a risk factor for the Parkinson disease phenotype (PDP) in humans and mice using epidemiologic or experimental approaches. The toxicokinetics (TK) and toxicodynamics (TD) of PQ in the brain are not well understood. OBJECTIVES: The TK and TD of PQ in brain were measured after single or repeated doses. METHODS: Brain regions were analyzed for PQ levels, amount of lipid peroxidation, and functional activity of the 20S proteasome. RESULTS: Paraquat (10 mg/kg, ip) was found to be persistent in mouse ventral midbrain (VM) with an apparent half-life of approximately 28 days and was cumulative with a linear pattern between one and five doses. PQ was also absorbed orally with a concentration in brain rising linearly after single doses between 10 and 50 mg/kg. The level of tissue lipid peroxides (LPO) was differentially elevated in three regions, being highest in VM, lower in striatum (STR), and least in frontal cortex (FCtx), with the earliest significant elevation detected at 1 day. An elevated level of LPO was still present in VM after 28 days. Despite the cumulative tissue levels of PQ after one, three, and five doses, the level of LPO was not further increased. The activity of the 20S proteasome in the striatum was altered after a single dose and reduced after five doses. CONCLUSIONS: These data have implications for PQ as a risk factor in humans and in rodent models of the PDP.
Assuntos
Encéfalo/efeitos dos fármacos , Herbicidas , Peroxidação de Lipídeos/efeitos dos fármacos , Paraquat , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Administração Oral , Animais , Modelos Animais de Doenças , Meia-Vida , Herbicidas/farmacocinética , Herbicidas/toxicidade , Injeções Intramusculares , Masculino , Camundongos , Paraquat/farmacocinética , Paraquat/toxicidade , Doença de Parkinson Secundária/induzido quimicamenteRESUMO
Parkinson's Disease (PD) is a degenerative neurological disorder that typically manifests symptoms in late adulthood, after loss of dopaminergic neurons in the nigrostriatal system. A lack of heritability for idiopathic PD has implicated adulthood environmental factors in the etiology of the disease. However, compelling evidence from animal models published within the past few years has shown that a range of environmental factors occurring during the perinatal period (including exposure to the common pesticides paraquat and maneb, organochlorine pesticides, and iron-enriched diet) and the prenatal period (including the pesticide maneb, cocaine, and the bacterial product LPS) can either directly cause a reduction in the number of dopamine neurons, or cause an increased susceptibility to degeneration of these neurons with subsequent environmental insults or with aging alone. In this review, these models are described for potential relevance in linking PD with the Fetal Basis of Adult Disease (FeBAD) hypothesis. Additionally, challenges in studying the neurodevelopmental basis of neurodegeneration experimentally and epidemiologically are presented.
Assuntos
Exposição Ambiental/efeitos adversos , Doenças Neurodegenerativas/etiologia , Doença de Parkinson/etiologia , Efeitos Tardios da Exposição Pré-Natal , Animais , Dopamina/metabolismo , Feminino , Humanos , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , GravidezRESUMO
Pulmonary fibrosis is one of the most severe consequences of exposure to paraquat, an herbicide that causes rapid alveolar inflammation and epithelial cell damage. Paraquat is known to induce toxicity in cells by stimulating oxygen utilization via redox cycling and the generation of reactive oxygen intermediates. However, the enzymatic activity mediating this reaction in lung cells is not completely understood. Using self-referencing microsensors, we measured the effects of paraquat on oxygen flux into murine lung epithelial cells. Paraquat (10-100 microm) was found to cause a 2-4-fold increase in cellular oxygen flux. The mitochondrial poisons cyanide, rotenone, and antimycin A prevented mitochondrial- but not paraquat-mediated oxygen flux into cells. In contrast, diphenyleneiodonium (10 microm), an NADPH oxidase inhibitor, blocked the effects of paraquat without altering mitochondrial respiration. NADPH oxidases, enzymes that are highly expressed in lung epithelial cells, utilize molecular oxygen to generate superoxide anion. We discovered that lung epithelial cells possess a distinct cytoplasmic diphenyleneiodonium-sensitive NAD(P)H:paraquat oxidoreductase. This enzyme utilizes oxygen, requires NADH or NADPH, and readily generates the reduced paraquat radical. Purification and sequence analysis identified this enzyme activity as thioredoxin reductase. Purified paraquat reductase from the cells contained thioredoxin reductase activity, and purified rat liver thioredoxin reductase or recombinant enzyme possessed paraquat reductase activity. Reactive oxygen intermediates and subsequent oxidative stress generated from this enzyme are likely to contribute to paraquat-induced lung toxicity.
Assuntos
Cianetos/farmacologia , Células Epiteliais/efeitos dos fármacos , Pulmão/efeitos dos fármacos , NADH NADPH Oxirredutases/metabolismo , Paraquat/farmacologia , Respiração/efeitos dos fármacos , Tiorredoxina Dissulfeto Redutase/fisiologia , Animais , Células CHO , Cricetinae , Cricetulus , Eletrofisiologia , Ativação Enzimática , Células Epiteliais/metabolismo , Camundongos , Oxigênio/metabolismo , Ratos , Tiorredoxina Dissulfeto Redutase/metabolismoRESUMO
This paper from The Human Health working group of SGOMSEC 16 examines a broad range of issues on gender effects in toxicology. Gender differences in toxicology begin at the gamete and embryo stage, continuing through development and maturation and into old age. Sex influences exposure, toxicokinetics, and toxicodynamics. The effects of sex have often been overlooked in both epidemiology and toxicology. In addition to the obvious modifying effects of the sex hormones and conditions affecting the male and female reproductive organs and sex roles, both genetic and hormonal effects influence many aspects of life and toxic responses. All aspects of toxicology should consider gender-balanced designs so that a more comprehensive understanding of differences and similarities can be obtained. Differential gene expression is a new frontier in toxicology. Risk assessment should account for gender and life cycle differences. The biological basis for altered sex ratios observed in several populations should be sought in animal models, and expanded to other compounds that might exert sex-selective effects. Wherever possible and feasible, toxicologic and environmental epidemiological studies should be designed and have sufficient statistical power to quantify differential gender-based exposures and outcomes.
Assuntos
Exposição Ambiental , Regulação da Expressão Gênica/efeitos dos fármacos , Substâncias Perigosas/toxicidade , Nível de Saúde , Caracteres Sexuais , Osso e Ossos/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Métodos Epidemiológicos , Feminino , Humanos , Rim/efeitos dos fármacos , Masculino , Farmacocinética , Reprodução/efeitos dos fármacos , Medição de Risco , Toxicologia/métodosRESUMO
A deficit in proteasome function in Parkinson's disease has been speculated. We characterized the ubiquitin-proteasome system in three regions of brain from transgenic and nontransgenic littermates. Mice expressing a doubly mutated form of human alpha-synuclein had significant impairments whereas mice expressing the wild-type gene had lesser changes compared to nontransgenic littermates. Significant abnormalities in line hm2 alpha-SYN-39 included declines in 20S-mediated proteolytic activity, the level of the 19S proteasome subunits Rpt1 and Rpn2, and the level of soluble total high MW ubiquitin cross-reacting proteins. Line hw alpha-SYN-5 had significant, but restricted proteasome abnormalities. The severity of impairment was proportional to the substantia nigra dopaminergic neuronal loss previously identified. There were significant correlations between the level of Rpn2 with the level of Rpt1, the activity of the 20S proteasome, and the level of soluble high MW ubiquitin cross-reacting proteins. These abnormalities in symptomatic line hm2 alpha-SYN-39 mice are consistent with abnormalities identified in tissue from patients with Parkinson's disease.
Assuntos
Envelhecimento , Encéfalo/metabolismo , Doença de Parkinson/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , alfa-Sinucleína/genética , Animais , Modelos Animais de Doenças , Humanos , Immunoblotting , Camundongos , Camundongos Transgênicos , Mutação , Doença de Parkinson/genéticaRESUMO
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.
Assuntos
Maneb/toxicidade , Paraquat/toxicidade , Doença de Parkinson , Efeitos Tardios da Exposição Pré-Natal , Substância Negra/efeitos dos fármacos , Fatores Etários , Animais , Animais Recém-Nascidos , Dopamina/metabolismo , Sinergismo Farmacológico , Feminino , Fungicidas Industriais/toxicidade , Herbicidas/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Atividade Motora/efeitos dos fármacos , Fenótipo , Gravidez , Substância Negra/citologia , Substância Negra/metabolismoRESUMO
The widespread use of atrazine (ATR) and its persistence in the environment have resulted in documented human exposure. Alterations in hypothalamic catecholamines have been suggested as the mechanistic basis of the toxicity of ATR to hormonal systems in females and the reproductive tract in males. Because multiple catecholamine systems are present in the brain, however, ATR could have far broader effects than are currently understood. Catecholaminergic systems such as the two major long-length dopaminergic tracts of the central nervous system play key roles in mediating a wide array of critical behavioral functions. In this study we examined the hypothesis that ATR would adversely affect these brain dopaminergic systems. Male rats chronically exposed to 5 or 10 mg/kg ATR in the diet for 6 months exhibited persistent hyperactivity and altered behavioral responsivity to amphetamine. Moreover, when measured 2 weeks after the end of exposure, the levels of various monoamines and the numbers of tyrosine hydroxylase-positive (TH+) and -negative (TH-) cells measured using unbiased stereology were reduced in both dopaminergic tracts. Acute exposures to 100 or 200 mg/kg ATR given intraperitoneally to evaluate potential mechanisms reduced both basal and potassium-evoked striatal dopamine release. Collectively, these studies demonstrate that ATR can produce neurotoxicity in dopaminergic systems that are critical to the mediation of movement as well as cognition and executive function. Therefore, ATR may be an environmental risk factor contributing to dopaminergic system disorders, underscoring the need for further investigation of its mechanism(s) of action and corresponding assessment of its associated human health risks.
Assuntos
Atrazina/toxicidade , Encéfalo/efeitos dos fármacos , Dopamina/metabolismo , Herbicidas/toxicidade , Atividade Motora/efeitos dos fármacos , Anfetamina/farmacologia , Animais , Encéfalo/citologia , Encéfalo/fisiologia , Masculino , Microdiálise , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Ratos , Ratos Long-Evans , Tirosina 3-Mono-OxigenaseRESUMO
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.
Assuntos
Glutationa Peroxidase/biossíntese , Maneb/farmacologia , Paraquat/farmacologia , Doença de Parkinson/patologia , Superóxido Dismutase/biossíntese , Animais , Apoptose , Western Blotting , Peso Corporal , Córtex Cerebral/metabolismo , Corpo Estriado/metabolismo , Dopamina/metabolismo , Dopamina/farmacologia , Fungicidas Industriais/farmacologia , Herbicidas/farmacologia , Peróxido de Hidrogênio/metabolismo , Imuno-Histoquímica , Metabolismo dos Lipídeos , Peroxidação de Lipídeos , Mesencéfalo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Estresse Oxidativo , Doença de Parkinson/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Serotonina , Transdução de Sinais , Substância Negra/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Proteína bcl-XRESUMO
Whereas Parkinson's disease is a neurodegenerative disorder that typically onsets after 60 years of age, the possibility that it could result from insults sustained during development has been proposed. Experimental evidence based on the combined paraquat + maneb model of the Parkinson's disease (PD) phenotype summarized here provides support for such an assertion. Postnatal exposures of mice to these pesticides led not only to a permanent and selective loss of dopaminergic neurons in the substantia nigra pars compacta but also enhanced the impact of these pesticides administered during adulthood relative to developmental only or adult only treatment. Exposure to maneb alone during gestation resulted in a dramatic response to paraquat in adulthood, including notable reductions in levels of dopamine and metabolites and a loss of nigral dopamine (DA) neurons, despite the fact that paraquat does not share structural similarity to or mechanisms of action with maneb. Collectively, these studies provide developmental environmental models of the PD phenotype. In addition, they demonstrate the fact that silent neurotoxicity produced by developmental insults can be unmasked by challenges later during life as well as the potential for cumulative neurotoxicity over the life span.
Assuntos
Doença de Parkinson/etiologia , Praguicidas/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal , Fatores Etários , Animais , Modelos Animais de Doenças , Dopamina/metabolismo , Feminino , Ácido Glutâmico/metabolismo , Humanos , Camundongos , Doença de Parkinson/congênito , GravidezRESUMO
A lack of strong evidence for genetic heritability of idiopathic Parkinson's disease (PD) has focused attention on environmental toxicants in the disease etiology, particularly agrichemicals. PD is associated with advanced age, but it is unclear whether specific neuronal damage could result from insults during development. This study hypothesized that prenatal exposure to pesticides would disrupt the development of the nigrostriatal dopamine (DA) system and enhance its vulnerability to dopaminergic neurotoxicant exposures later in life. Pregnant C57BL/6J mice were treated on gestational days 10-17 with saline or the pesticides maneb (MB, 1 mg/kg) or paraquat (PQ, 0.3 mg/kg). When offspring were evaluated in adulthood, there were no significant effects of prenatal MB or PQ exposure on locomotor activity. Subsequently, offspring were treated for 8 consecutive days with saline, MB (30 mg/kg), or PQ (5 mg/kg). One week after the last exposure, only males exposed to prenatal MB and adulthood PQ showed significant reductions in locomotor activity (95%) and changes in striatal neurochemistry. Stereological assessment of the substantia nigra pars compacta (SNpc) and ventral tegmental area correspondingly confirmed selective dopaminergic-neuron loss in SNpc. The lack of changes in other exposure groups suggests a specificity to the sequence of exposures as well as gender specificity. These results suggest that prenatal exposure to MB produces selective, permanent alterations of the nigrostriatal dopaminergic system and enhances adult susceptibility to PQ exposure. This study implicates a role for developmental neurotoxicant exposure in the induction of neurodegenerative disorders such as PD.
Assuntos
Feto/efeitos dos fármacos , Feto/fisiologia , Doença de Parkinson , Efeitos Tardios da Exposição Pré-Natal , Animais , Dopamina/metabolismo , Feminino , Feto/anatomia & histologia , Fungicidas Industriais/farmacologia , Herbicidas/farmacologia , Humanos , Masculino , Maneb/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Paraquat/farmacologia , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Gravidez , Fatores de Risco , Substância Negra/citologia , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Triadimefon (TDF) is a triazole fungicide that acts as an indirect dopamine (DA) agonist by binding to the dopamine transporter (DAT) and increasing levels of synaptic DA. Studies in this laboratory have found that repeated dosing with TDF in adult mice leads to the development and robust expression of behavioral sensitization, a response mediated by dopaminergic and glutamatergic neurotransmitter systems, and causing long-term changes in dopaminergic function. Few studies have focused on the potential for TDF to be a developmental neurotoxicant. As such, the objective of the present study was to determine whether postnatal exposure to TDF would permanently alter DA systems and thereby influence TDF-induced expression of behavioral sensitization during adulthood. Male C57BL/6 mice were dosed intraperitoneally (i.p.) with 25 mg/kg TDF (TDF25), or oil (veh) from postnatal day (PND) 8 to 21. At 8-9 weeks of age, mice were split into four groups and treated with 75 mg/kg TDF (TDF75) or vehicle twice a week for a total of seven injections, with locomotor activity measured immediately after each injection. After a 2-week withdrawal period, mice were further split into eight groups, and challenged with TDF75 or vehicle to test for the expression of behavioral sensitization. Postnatal TDF exposure attenuated both the induction and expression of TDF-induced vertical but not horizontal sensitization in adults. Postnatal TDF exposure also produced long-term decreases in basal striatal dihydroxyphenylacetic acid (DOPAC) levels and nucleus accumbens shell DAT binding. These results indicate for the first time that TDF may be considered an environmental risk factor for developmental dopaminergic neurotoxicity.
Assuntos
Comportamento Animal/efeitos dos fármacos , Fungicidas Industriais/toxicidade , Triazóis/toxicidade , Animais , Animais Recém-Nascidos , Autorradiografia , Peso Corporal , Química Encefálica/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Neurotransmissores/metabolismoRESUMO
Lead exposure is higher among children with low socioeconomic status (SES) compared with other children in the United States. Low SES itself is a known risk factor for various diseases and dysfunctions, effects that have been ascribed to chronic stress and associated elevation of glucocorticoids. Chronically elevated glucocorticoids and Pb provoke similar behavioral changes, and both can act on mesocorticolimbic systems of the brain. In this study we examined the hypothesis that these co-occurring risk factors, Pb and environmental stress, would interact and modulate each others' effects. Using a rodent model, we focused on the specific contributions of maternal stress (restraint) and maternal Pb exposure (150 ppm in drinking water) on corticosterone levels of offspring, as well as on neurotransmitter changes and a behavioral baseline (fixed-interval schedule-controlled performance) with known sensitivities to Pb. We observed interactions of Pb and stress that differed in relation to outcome measure and sex. In addition, potentiated effects (effects of Pb plus stress but showing no changes produced by either alone) were observed more frequently in females. Importantly, Pb alone (in males) and Pb plus stress (in females) permanently elevated corticosterone levels in offspring; even short-term Pb exposure to dams could cause this effect. Such increases could suggest a potential new mechanism by which Pb exposure could directly or indirectly enhance susceptibility to diseases and dysfunctions and induce cognitive deficits. Moreover, the interactive effects of Pb and stress, and particularly the potentiated effects of Pb plus stress, raise questions about whether current risk assessment strategies sufficiently consider the potential for modulation of toxicity that can accrue from intercurrent risk factors.
Assuntos
Transtornos Cognitivos/induzido quimicamente , Corticosterona/sangue , Poluentes Ambientais/toxicidade , Chumbo/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Estresse Psicológico , Administração Oral , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Transtornos Cognitivos/fisiopatologia , Poluentes Ambientais/administração & dosagem , Feminino , Chumbo/administração & dosagem , Masculino , Modelos Animais , Gravidez , Ratos , Ratos Long-Evans , Fatores de Risco , Fatores SexuaisRESUMO
Triadimefon (TDF), a widely used triazole fungicide, blocks reuptake of the neurotransmitter dopamine (DA), similarly to cocaine. Preliminary studies show that intermittent intraperitoneal injections of TDF increase ambulatory and vertical activity across repeated injections [Neurotoxicology (in press)] leading to the hypothesis tested here, that exposure to TDF may influence the development and expression of behavioral sensitization, a model of psychostimulant-induced psychosis. Exposure of adult male C57BL/6 mice to 75 mg/kg i.p. TDF (TDF75) twice a week for 7 weeks increased vertical activity at each injection. Following a 2-week withdrawal period, a TDF challenge to test for expression of behavioral sensitization revealed further increases in vertical activity levels relative to all other conditions. TDF induction/expression of behavioral sensitization was associated with long-term, perhaps permanent modulation of dopaminergic function that included increases in striatal dihydroxyphenylacetic acid (DOPAC) and DA turnover, increases in medial prefrontal cortex (mPFC) dopamine transporter (DAT) binding, as well as decreases in DA D1 and increases in DA D2 and DAT receptor binding that appeared to target the nucleus accumbens shell (NAs) subregion. Thus, TDF exposure may serve as an environmental risk factor for DA system dysfunctions.
Assuntos
Comportamento Animal/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Fungicidas Industriais/toxicidade , Glicoproteínas de Membrana , Triazóis/toxicidade , Animais , Autorradiografia , Peso Corporal/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina , Eletroquímica , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Neurotransmissores/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Receptores de Dopamina D1/efeitos dos fármacos , Serotonina/metabolismoRESUMO
While advancing age is the only unequivocally accepted risk factor for idiopathic Parkinson's disease, it has been postulated that exposure to environmental neurotoxicants combined with ageing could increase the risk for developing Parkinson's disease. The current study tested this hypothesis by exposing C57BL/6 mice that were 6 weeks, 5 months or 18 months old to the herbicide paraquat, the fungicide maneb or paraquat + maneb, a combination that produces a Parkinson's disease phenotype in young adult mice. Paraquat + maneb-induced reductions in locomotor activity and motor coordination were age dependent, with 18-month-old mice most affected and exhibiting failure to recover 24 h post-treatment. Three months post-treatment, reductions in locomotor activity and deficits in motor coordination were sustained in 5-month-old and further reduced in 18-month-old paraquat + maneb groups. Progressive reductions in dopamine metabolites and dopamine turnover were greatest in 18-month-old paraquat + maneb and paraquat groups 3 months post-treatment. Increased tyrosine hydroxylase enzyme activity compensated for striatal tyrosine hydroxylase protein and/or dopamine loss following treatment in 6-week-old and 5-month-old, but not 18-month-old paraquat and paraquat + maneb mice. Numbers of nigrostriatal dopaminergic neurons were reduced in all age groups following paraquat alone and paraquat + maneb exposure, but these losses, along with decreases in striatal tyrosine hydroxylase protein levels, were progressive in 18-month-old paraquat and paraquat + maneb groups between 2 weeks and 3 months post-exposure. Collectively, these data demonstrate enhanced sensitivity of the ageing nigrostriatal dopamine pathway to these pesticides, particularly paraquat + maneb, resulting in irreversible and progressive neurotoxicity.
Assuntos
Envelhecimento , Corpo Estriado/efeitos dos fármacos , Maneb/intoxicação , Neurônios/efeitos dos fármacos , Neurotoxinas/farmacologia , Paraquat/intoxicação , Doença de Parkinson Secundária/induzido quimicamente , Substância Negra/efeitos dos fármacos , Envelhecimento/metabolismo , Animais , Contagem de Células , Corpo Estriado/metabolismo , Suscetibilidade a Doenças , Dopamina/metabolismo , Combinação de Medicamentos , Glutamato Descarboxilase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Neurônios/metabolismo , Doença de Parkinson Secundária/genética , Doença de Parkinson Secundária/patologia , Doença de Parkinson Secundária/fisiopatologia , Fenótipo , Serotonina/metabolismo , Substância Negra/metabolismo , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Exposure to pesticides may be a risk factor for Parkinson's disease based on epidemiologic data in humans, animal models and in vitro studies. Different dithiocarbamate pesticides potentiate the toxicity of both 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and paraquat in mouse models of Parkinsonism by an unknown mechanism. This study examined the effects of commercially used dithiocarbamates on [3H]dopamine transport in striatal synaptosomal vesicles and on the concentration of [14C]paraquat in vivo in mice. Different ethylenebis-dithiocarbamates and diethyl-dithiocarbamate increased dopamine accumulation in synaptosomes, whereas dimethyl-dithiocarbamate and methyl-dithiocarbamate did not. Increased dopamine accumulation in synaptosomes was dose dependent and was related to the carbon backbone of these molecules. The dithiocarbamates that increased accumulation of dopamine did not alter the influx of dopamine, but rather delayed the efflux out of synaptosomes. These same dithiocarbamates also increased the tissue content of [14C]paraquat in vivo by a mechanism that appeared to be distinct from the dopamine transporter. There was a consistent relationship between the dithiocarbamates that increased synaptosomal accumulation of dopamine and tissue content of paraquat, with those previously demonstrated to enhance paraquat toxicity in vivo. These results suggest that selective dithiocarbamates may alter the kinetics of different endogenous and exogenous compounds to enhance their neurotoxicity.
Assuntos
Química Encefálica/efeitos dos fármacos , Encéfalo/metabolismo , Dopamina/metabolismo , Glicoproteínas de Membrana , Proteínas do Tecido Nervoso , Paraquat/análise , Sinaptossomos/metabolismo , Tiocarbamatos/farmacologia , Animais , Transporte Biológico/efeitos dos fármacos , Cocaína/farmacologia , Dopamina/análise , Dopamina/farmacocinética , Proteínas da Membrana Plasmática de Transporte de Dopamina , Relação Dose-Resposta a Droga , Etilenobis (ditiocarbamatos)/farmacocinética , Etilenobis (ditiocarbamatos)/farmacologia , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Compostos Organometálicos/farmacocinética , Compostos Organometálicos/farmacologia , Paraquat/farmacocinética , Praguicidas/farmacocinética , Praguicidas/farmacologia , Sinaptossomos/química , Sinaptossomos/efeitos dos fármacos , Tiocarbamatos/farmacocinéticaRESUMO
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.