RESUMEN
This study analysed the clinical patterns and outcomes of elderly patients with organophosphate intoxication. A total of 71 elderly patients with organophosphate poisoning were seen between 2008 and 2017. Patients were stratified into two subgroups: survivors (n = 57) or nonsurvivors (n = 14). Chlorpyrifos accounted for 33.8% of the cases, followed by methamidophos (12.7%) and mevinphos (11.3%). Mood, adjustment and psychotic disorder were noted in 39.4%, 33.8% and 2.8% of patients, respectively. All patients were treated with atropine and pralidoxime therapies. Acute cholinergic crisis developed in all cases (100.0%). The complications included respiratory failure (52.1%), aspiration pneumonia (50.7%), acute kidney injury (43.7%), severe consciousness disturbance (25.4%), shock (14.1%) and seizures (4.2%). Some patients also developed intermediate syndrome (15.5%) and delayed neuropathy (4.2%). The nonsurvivors suffered higher rates of hypotension (P < 0.001), shock (P < 0.001) and kidney injury (P = 0.001) than survivors did. Kaplan-Meier analysis indicated that patients with shock suffered lower cumulative survival than did patients without shock (log-rank test, P < 0.001). In a multivariate-Cox-regression model, shock was a significant predictor of mortality after intoxication (odds ratio 18.182, 95% confidence interval 2.045-166.667, P = 0.009). The mortality rate was 19.7%. Acute cholinergic crisis, intermediate syndrome, and delayed neuropathy developed in 100.0%, 15.5%, and 4.2% of patients, respectively.
Asunto(s)
Lesión Renal Aguda/tratamiento farmacológico , Antídotos/uso terapéutico , Insecticidas/toxicidad , Intoxicación por Organofosfatos/tratamiento farmacológico , Neumonía por Aspiración/tratamiento farmacológico , Insuficiencia Respiratoria/tratamiento farmacológico , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/mortalidad , Lesión Renal Aguda/fisiopatología , Afecto/efectos de los fármacos , Anciano , Atropina/uso terapéutico , Cloropirifos/antagonistas & inhibidores , Cloropirifos/toxicidad , Femenino , Humanos , Insecticidas/antagonistas & inhibidores , Masculino , Mevinfos/antagonistas & inhibidores , Mevinfos/toxicidad , Persona de Mediana Edad , Intoxicación por Organofosfatos/etiología , Intoxicación por Organofosfatos/mortalidad , Intoxicación por Organofosfatos/fisiopatología , Compuestos Organotiofosforados/antagonistas & inhibidores , Compuestos Organotiofosforados/toxicidad , Neumonía por Aspiración/inducido químicamente , Neumonía por Aspiración/mortalidad , Neumonía por Aspiración/fisiopatología , Compuestos de Pralidoxima/uso terapéutico , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/etiología , Trastornos Psicóticos/mortalidad , Trastornos Psicóticos/fisiopatología , Insuficiencia Respiratoria/inducido químicamente , Insuficiencia Respiratoria/mortalidad , Insuficiencia Respiratoria/fisiopatología , Estudios Retrospectivos , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Convulsiones/mortalidad , Convulsiones/fisiopatología , Choque/inducido químicamente , Choque/tratamiento farmacológico , Choque/mortalidad , Choque/fisiopatología , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
In Thailand, people in the highland communities whose occupational exposure to pesticides used the root of Litsea martabanica as a detoxifying agent. However, the scientific data to support the traditional use of this plant are insufficient. This study aimed to evaluate the antioxidant activity and anti-pesticide potential of L. martabanica root extract. Antioxidant properties were investigated by 2,2'-diphenyl-1-picrylhydrazyl (DPPH) assay, superoxide radicals scavenging assay, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assay, ferric reducing antioxidant power (FRAP), and total phenolic content determination. In all assays, L. martabanica extracts and their fractions exhibited high antioxidant activities differently. The water extract is traditionally used as a detoxifying agent. Therefore, it was chosen for in vivo experiments. The rats received the extract in a way that mimics the traditional methods of tribal communities followed by chlorpyrifos for 16 days. The results showed that acetylcholinesterase activity decreases in pesticide-exposed rats. Treatment with the extract caused increasing acetylcholinesterase activity in the rats. Therefore, L. martabanica extract may potentially be used as a detoxifying agent, especially for the chlorpyrifos pesticide. The antioxidant properties of L. martabanica may provide a beneficial effect by protecting liver cells from damage caused by free radicals. Histopathology results revealed no liver cell necrosis and showed the regeneration of liver cells in the treatment group. L. martabanica extract did not cause changes in behavior, liver weight, hematological and biochemical profiles of the rats.
Asunto(s)
Antídotos/farmacología , Antioxidantes/farmacología , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Cloropirifos/toxicidad , Insecticidas/toxicidad , Litsea/química , Acetilcolinesterasa/metabolismo , Alanina Transaminasa/metabolismo , Fosfatasa Alcalina/metabolismo , Animales , Antídotos/aislamiento & purificación , Antioxidantes/aislamiento & purificación , Aspartato Aminotransferasas/metabolismo , Benzotiazoles/antagonistas & inhibidores , Benzotiazoles/química , Bilirrubina/metabolismo , Compuestos de Bifenilo/antagonistas & inhibidores , Compuestos de Bifenilo/química , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Cloropirifos/antagonistas & inhibidores , Creatinina/metabolismo , Insecticidas/antagonistas & inhibidores , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Fitoterapia/métodos , Picratos/antagonistas & inhibidores , Picratos/química , Extractos Vegetales/química , Raíces de Plantas/química , Ratas , Ratas Sprague-Dawley , Ácidos Sulfónicos/antagonistas & inhibidores , Ácidos Sulfónicos/químicaRESUMEN
Exposure to organophosphorus insecticides causes several health problems to animals and humans. Red beetroot (RBR) is rich in antioxidant ingredients and possesses a promising hepatoprotective activity. This study evaluated the potential of RBR extract to prevent chlorpyrifos (CPF)-induced liver injury, with an emphasis on oxidative stress, inflammation and apoptosis. Rats received 10 mg/kg CPF and were treated with 300 mg/kg RBR extract for 28 days. CPF caused liver injury evidenced by elevated serum levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and bilirubin, along with several histological alterations. Hepatic lipid peroxidation (LPO) and nitric oxide (NO) levels, as well as inducible nitric oxide synthase (iNOS) and pro-inflammatory cytokines were increased in CPF-intoxicated rats. RBR prevented CPF-induced histological alterations, and ameliorated liver function, LPO, NO, iNOS and pro-inflammatory cytokines. RBR boosted glutathione and antioxidant enzymes, and increased Nrf2 expression. In addition, RBR diminished Bax and caspase-3, and increased Bcl-2 expression. In conclusion, RBR prevented CPF-induced liver injury via attenuation of oxidative stress, inflammation and apoptosis. RBR enhanced antioxidant defenses, suggesting that it could be used as a potential therapeutic intervention to minimize CPF hepatotoxicity.
Asunto(s)
Beta vulgaris/química , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Cloropirifos/antagonistas & inhibidores , Inflamación/tratamiento farmacológico , Extractos Vegetales/farmacología , Animales , Antioxidantes/análisis , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Biomarcadores/análisis , Biomarcadores/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Cloropirifos/química , Inflamación/inducido químicamente , Inflamación/metabolismo , Estructura Molecular , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Raíces de Plantas/química , Ratas , Ratas WistarRESUMEN
Chlorpyrifos (CPF) is an organophosphorus pesticide that can damage the central nervous system in children upon exposure. Taxifolin (Tax) exerts protective effects against neurotoxins; however, the mechanism has not yet been illustrated. The current study used BV2 cells to investigate the protective mechanism underlying the organophosphorus pesticide taxifolin on CPF-induced neurotoxicity, which might present a therapeutic potential for the prevention and treatment of the nervous system diseases in children. BV2 cells were randomly divided into 4 groups: DMSO, CPF, Tax, and Taxâ¯+â¯CPF. The viability, morphocytology, oxidative stress, inflammatory reaction, and autophagocytosis have been studied in the cells using Western blot analysis, CCK-8 assay, enzyme-linked immunosorbent assay, and immunofluorescence to estimate the level of LC3 II. As a result, CPF was found to exert a significant toxic effect on BV2 cells that was characterized by rounded cell body, atrophic synapse, poor adhesion, cell aggregation, inflammation, oxidative reaction, and autophagy. Tax treatment has a protective effect on CPF-induced neurotoxicity via downregulation of ROS, TNF-α, IFN-γ, and p62 levels and increased LC3 II level, which in turn, improved the viability and activity of BV2 cells. This phenomenon suggested that Tax can reduce the inflammation and oxidative stress and promote autophagy. Furthermore, the current study suggested that the protective mechanism of Tax on CPF-induced BV2 cell toxicity was via up-regulation of pAMPK level and activation of Nrf2/HO-1 signaling pathway.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Cloropirifos/antagonistas & inhibidores , Cloropirifos/toxicidad , Inhibidores de la Colinesterasa/toxicidad , Síndromes de Neurotoxicidad/patología , Quercetina/análogos & derivados , Animales , Autofagia/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Ratones , Proteínas Asociadas a Microtúbulos/biosíntesis , Proteínas Asociadas a Microtúbulos/genética , Estrés Oxidativo/efectos de los fármacos , Fagocitosis/efectos de los fármacos , Quercetina/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
Chlorpyrifos (CPF) has been considered as one of the most potent organophosphates and is linked to several neurological disorders. On the other hand, Quercetin is a vital plant flavanoid and has been reported to regulate a number of physiological processes in the central nervous system. The present study was conducted to investigate the protective potential of quercetin during chlorpyrifos induced neurotoxicity. Female Wistar rats weighing 150-200 g were divided into four different groups viz: Normal control, CPF treated (13.5 mg/kg.b.wt. every alternate day), Quercetin treated (50 mg/kg.b.wt./day) and combined CPF and quercetin-treated. All the treatments were carried out for a total duration of eight weeks. Chlorpyrifos treatment showed significant alterations in the cognitive behavior and motor activities of rats, which were appreciably improved upon simultaneous supplementation with quercetin. Further, CPF treatment caused a significant inhibition in the enzyme activities of acetylcholinesterase and choline acetyltransferase, but caused an increase in the levels of acetylcholine in the brain. Further, chlorpyrifos exposure significantly elevated the levels of lipid peroxidation and protein carbonyl contents as well as the activities of catalase, superoxide dismutase, which were interestingly found to be decreased following co-treatment with quercetin. In contrast, CPF treatment decreased the activities of glutathione reductase, transferase, as well as levels of reduced and total glutathione in both the cerebrum and cerebellum but co-administration of quercetin, increased these levels. Chlorpyrifos treatment altered the neuro-histoarchitecture, which showed improvement upon quercetin supplementation. Hence, this study suggests that quercetin can be used as a prophylactic intervention to prevent CPF induced neurotoxicity.
Asunto(s)
Encéfalo/efectos de los fármacos , Cloropirifos/toxicidad , Fármacos Neuroprotectores/farmacología , Neurotoxinas/toxicidad , Quercetina/farmacología , Acetilcolina/análisis , Acetilcolinesterasa/metabolismo , Animales , Encéfalo/enzimología , Encéfalo/metabolismo , Química Encefálica/efectos de los fármacos , Catalasa/metabolismo , Cloropirifos/antagonistas & inhibidores , Colina O-Acetiltransferasa/metabolismo , Femenino , Peroxidación de Lípido/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Neurotoxinas/antagonistas & inhibidores , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismoRESUMEN
Exposure to pesticide chlorpyrifos (CPF) has been implicated in reproductive deficits in both humans and animals. Diphenyl diselenide (DPDS) is an organoselenium compound widely reported to elicit potent pharmacological activities in several chemically-induced toxicity and disease models. However, there is paucity of scientific information on the influence of DPDS on CPF-induced reproductive dysfunction. The present study investigated the influence of DPDS on CPF-induced functional changes along the hypothalamic-pituitary- testicular axis in rats. CPF was administered alone at 5â¯mg/kg body weight or orally co-treated with DPDS at 2.5 and 5â¯mg/kg body weight for 35 consecutive days. Results showed that DPDS co-treatment significantly (pâ¯<â¯0.05) abrogated CPF-induced oxidative stress by increasing the antioxidant enzymes activities and glutathione content, decreasing the hydrogen peroxide and lipid peroxidation levels in the hypothalamus, testes and epididymis of the treated rats. Moreover, DPDS co-treatment significantly ameliorated CPF-induced histological alterations in the hypothalamus, testes and epididymis of the treated rats. Besides, the significant augmentation of luteinizing hormone, follicle-stimulating hormone and testosterone levels as well as the testicular activities of acid phosphatase, alkaline phosphatase and lactate dehydrogenase by DPDS was accompanied by an increase in sperm quality and quantity in the treated rats. Taken together, DPDS abrogates CPF mediated toxicity along the hypothalamic-pituitary-testicular axis in rats via inhibition of lipid peroxidation, enhancement of antioxidant enzymes activities and testicular function. Thus, DPDS may be a possible chemoprotective drug candidate against CPF-induced male reproductive deficits in humans.
Asunto(s)
Derivados del Benceno/farmacología , Cloropirifos/antagonistas & inhibidores , Cloropirifos/toxicidad , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Compuestos de Organoselenio/farmacología , Testículo/efectos de los fármacos , Animales , Antioxidantes/farmacología , Biomarcadores/sangre , Epidídimo/efectos de los fármacos , Epidídimo/metabolismo , Epidídimo/patología , Hormona Folículo Estimulante/sangre , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/patología , Insecticidas/antagonistas & inhibidores , Insecticidas/toxicidad , Peroxidación de Lípido/efectos de los fármacos , Hormona Luteinizante/sangre , Masculino , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacología , Ratas , Ratas Wistar , Testículo/metabolismo , Testículo/patología , Testosterona/sangreRESUMEN
In this study, the effect of Tunceli garlic (Allium tuncelianium) on hemoglobin (Hb) level, oxidative radical production of neutrophils (Nitoblue tetrazolium assay-NBT activity) and total immunoglobulin (TI) content in carp (Cyprinus carpio) exposed to chlorpyrifos (CPF) was investigated. The 96 hour LC50 value of CPF on C. carpio was calculated to as 0.230 mg/L. The fishes were exposed to sublethal concentration of chlorpyrifos (1/8 of LC50 value: 0.029 mg/L), and Tunceli garlic (20 and 40 g/kg diet) was simultaneously administered for 21 days. Blood samples were taken from the fishes at 7, 14 and 21 days and analysed to determine the Hb levels, the NBT activity and the TI content. There was a significant decrease in the Hb level, the NBT activity and the TI content of CPF-treated fish. However, Tunceli garlic reversed the Hb level, the NBT activity and the TI content. In conclusion, this study demonstrated that CPF had a negative effect on the immunological values of the fish. The simultaneous administration of Tunceli garlic was neutralised CPF-induced toxicity.
Asunto(s)
Antioxidantes/farmacología , Cloropirifos/antagonistas & inhibidores , Ajo/química , Insecticidas/antagonistas & inhibidores , Neutrófilos/efectos de los fármacos , Extractos Vegetales/farmacología , Animales , Antioxidantes/química , Carpas/inmunología , Carpas/metabolismo , Cloropirifos/toxicidad , Hemoglobinas/metabolismo , Inmunoglobulinas/biosíntesis , Insecticidas/toxicidad , Dosificación Letal Mediana , Neutrófilos/citología , Neutrófilos/inmunología , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/química , Contaminantes Químicos del Agua/antagonistas & inhibidores , Contaminantes Químicos del Agua/toxicidadRESUMEN
Background: Chlorpyrifos is an highly toxic pesticide, which can induce immunotoxicity with deleterious effects on health worldwide. On the other hand, American plants can provide derivatives with protective and immunostimulating activity. Thus, plant potential against chlorpyrifos should be assayed. Objective: To identify bioactive aqueous extracts from Lantana grisebachii (LG), Aspidosperma quebracho-blanco (AQ), Peumus boldus (PB), and Ilex paraguariensis (IP), against chlorpyrifos-induced toxicity on female Balb/c splenocytes. Material and method: Splenocytes were treated in vitro for 72 hours with 0-35 µg/mL of chlorpyrifos, 0-100 µg/mL of each extract (LG, AQ, PB, IP), and 0-5 µg/mL of concanavalin A. Then, cellular viability and death (resazurin-based and propidium iodide stainings), hydroperoxides, lipoperoxides (xylenol orange-based assay), ?-glutamyl transpeptidase activity (Szasz method) were measured and analyzed statistically. Results: Chlorpyrifos reduced splenocyte viability in a dose-dependent manner, which was counteracted by AQ and IP, which was less active in concanavalin A-responsive cells (p<0.05). Chlorpyrifos toxicity involved ?-glutamyltranspeptidase induction with a consequent peroxide reduction, whereas AQ and mainly IP antagonized these responses (p<0.05). Conclusions: The extracts of Ilex paraguariensis and Aspidosperma quebracho-blanco protected splenocytes in vitro against chlorpyrifos. This effect depended on cellular type, given that concanavalin A-responsive cells were more susceptible to this toxic.
Antecedentes: Clorpirifos es un pesticida altamente tóxico, que puede producir inmunotoxicidad con efectos deletéreos sobre la salud a nivel mundial. Por otro lado, las plantas americanas pueden tener derivados con actividad protectora e inmunoestimulante. Por lo tanto, debe evaluarse el potencial de estas plantas frente a clorpirifos. Objetivo: Identificar extractos acuosos bioactivos de Lantana grisebachii (LG), Aspidosperma quebracho-blanco (AQ), Peumus boldus (PB), e Ilex paraguariensis (IP), contra la toxicidad de clorpirifos sobre esplenocitos de hembras Balb/c. Resultados: Esplenocitos fueron tratados in vitro por 72 horas con 0-35 µg/mL de clorpirifos, 0-100 µg/mL de cada extracto (LG, AQ, PB, IP) y 0-5 µg/mL de concanavalina A. Luego, se midió y analizó estadísticamente viabilidad y muerte celular (tinciones de resazurina y yoduro de propidio), hidroperóxidos, lipoperóxidos (ensayos basados en naranja de xilenol), actividad de la ?-glutamiltranspeptidasa (método de Szasz). Conclusiones: Los extractos de Ilex paraguariensis y Aspidosperma quebracho-blanco protegieron in vitro a los esplenocitos frente a clorpirifos. Este efecto dependió del tipo celular, dado que las células inducibles por concanavalina A fueron más susceptibles a este tóxico.
Asunto(s)
Cloropirifos/antagonistas & inhibidores , Extractos Vegetales/farmacología , Sustancias Protectoras/farmacología , Bazo/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Aspidosperma/química , Supervivencia Celular/efectos de los fármacos , Cloropirifos/toxicidad , Concanavalina A/farmacología , Femenino , Ilex paraguariensis/química , Lantana/química , Ratones Endogámicos BALB C , Modelos Animales , Peróxidos/metabolismo , Peumus/química , Bazo/citologíaRESUMEN
Oxidative stress can lead to expression of inflammatory transcription factors, which are important regulatory elements in the induction of inflammatory responses. One of the transcription factors, nuclear transcription factor kappa-B (NF-κB) plays a significant role in the inflammation regulatory process. Inflammatory cell death has been implicated in neuronal cell death in some neurodegenerative disorders such as Parkinson's disease (PD). In this study, we investigated the molecular mechanisms underlying apoptosis initiated by chlorpyrifos (CPF)-mediated oxidative stress. Based on the cytotoxic mechanism of CPF, we examined the neuroprotective effects of rosiglitazone (RGZ), a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, against CPF-induced neuronal cell death. The treatment of SH-SY5Y cells with CPF induced oxidative stress. In addition, CPF activated the p38, JNK and ERK mitogen-activated protein kinases (MAPKs), and induced increases in the inflammatory genes such as COX-2 and TNF-α. CPF also induced nuclear translocation of NF-κB and inhibitors of NF-κB abolished the CPF-induced COX-2 expression. Pretreatment with RGZ significantly reduced ROS generation and enhanced HO-1 expression in CPF-exposed cells. RGZ blocked the activation of both p38 and JNK signaling, while ERK activation was strengthened. RGZ also attenuated CPF-induced cell death through the reduction of NF-κB-mediated proinflammatory factors. Results from this study suggest that RGZ may exert an anti-apoptotic effect against CPF-induced cytotoxicity by attenuation of oxidative stress as well as inhibition of the inflammatory cascade via inactivation of signaling by p38 and JNK, and NF-κB.
Asunto(s)
Apoptosis/efectos de los fármacos , Cloropirifos/toxicidad , Mediadores de Inflamación/antagonistas & inhibidores , Estrés Oxidativo/efectos de los fármacos , Tiazolidinedionas/farmacología , Apoptosis/fisiología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Cloropirifos/antagonistas & inhibidores , Humanos , Mediadores de Inflamación/toxicidad , Estrés Oxidativo/fisiología , RosiglitazonaRESUMEN
Chlorpyrifos (CPF) is one of the most widely used organophosphate insecticides with several harmful effects, including neurotoxicity. Although many studies have addressed the neurotoxicity induced by CPF, most data on neurodevelopmental damage was obtained from animal models. We are the first group to use human neural precursor cells (hNPCs) derived from human embryonic stem cells (hESCs) as a developing neuron model to evaluate the mechanisms involved in CPF-induced neurotoxicity. CPF was cytotoxic to these cells in a concentration-dependent manner, as shown by decreased cell viability and increased lactate dehydrogenase release. Furthermore, CPF reduced the expression of AKT and ERK proteins which are involved in intracellular survival pathways. Exposure of hNPCs to CPF led to the production of reactive oxygen species (ROS), and the antioxidant N-acetyl-cystein (NAC) attenuated ROS production induced by CPF. In addition, CPF increased cytochrome c release into the cytosol and activated caspase-9 and -3, indicating that cell death induced by CPF was due to apoptosis in hNPCs. Consistent with these findings, CPF treatment reduced the level of Bcl-2 protein and increased the level of Bax protein. Especially, CPF increased the translocation of BAX into the mitochondria. CPF also induced nuclear accumulation of NF-κB and p53 proteins in a concentration-dependent manner, and their inhibitors attenuated CPF-induced cytotoxicity. In addition, an inhibitor of NF-κB nuclear translocation blocked the increase of p53 in CPF-treated hNPCs. These findings show that CPF induced hNPCs death in part through NF-κB activation via ROS generation, enabling the interaction of p53 with Bcl-2 and Bax and subsequent release of cytochrome c. Collectively, these results represent a unique molecular characterization of CPF-induced cytotoxicity in hNPCs. These data suggest that CPF may affect neurodevelopment in a manner similar to that of several known and suspected neurotoxicants.
Asunto(s)
Apoptosis/efectos de los fármacos , Cloropirifos/toxicidad , FN-kappa B/metabolismo , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Acetilcisteína/farmacología , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Células Cultivadas , Cloropirifos/antagonistas & inhibidores , Citocromos c/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Insecticidas/antagonistas & inhibidores , Insecticidas/toxicidad , L-Lactato Deshidrogenasa/metabolismo , Malondialdehído/metabolismo , FN-kappa B/antagonistas & inhibidores , Células-Madre Neurales/patología , Estrés Oxidativo/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Proteína X Asociada a bcl-2/metabolismoRESUMEN
The aim of the present study was to evaluate the effect of chronic chlorpyrifos (CPF) exposure on erythrocyte osmotic fragility, the role of lipid peroxidation and the ameliorative effect of vitamin E on the erythrocyte fragility. Twenty young adult male Wistar rats divided into four groups of five animals each served as subjects for this study. Groups I (control) and II were exposed to soya oil (2 ml/kg) and vitamin E (75 mg/kg), respectively. Rats in group III were exposed to CPF (10.6 mg/kg 1/8th of the previously determined LD50 of 85 mg/kg over a period of 48 h), while those in group IV were pretreated with vitamin E (75 mg/kg) and then exposed to CPF, 30 min later. The regimens were administered orally by gavage once daily for a period of 17 weeks. Blood samples collected at the end of the test period were analyzed for erythrocyte osmotic fragility, while the washed erythrocytes were used to evaluate malondialdehyde (MDA) concentration, as an index of lipid peroxidation. The study showed that repeated CPF exposure caused increased erythrocyte fragility and MDA concentration. Pretreatment with vitamin E ameliorated CPF-induced increase in erythrocyte fragility and lipoperoxidative changes in Wistar rats.
Asunto(s)
Antioxidantes/farmacología , Cloropirifos/antagonistas & inhibidores , Cloropirifos/toxicidad , Eritrocitos/efectos de los fármacos , Insecticidas/toxicidad , Fragilidad Osmótica/efectos de los fármacos , Vitamina E/farmacología , Animales , Eritrocitos/metabolismo , Técnicas In Vitro , Peroxidación de Lípido/efectos de los fármacos , Masculino , Malondialdehído/metabolismo , Ratas , Ratas Wistar , Cloruro de Sodio/farmacologíaRESUMEN
Oxidative stress has been hypothesized to provide a mechanism by which apparently unrelated chemicals can nevertheless produce similar developmental neurotoxic outcomes. We used differentiating PC12 cells to compare the effects of agents from four different classes and then to evaluate antioxidant amelioration: fipronil, perfluorooctanesulfonamide (PFOSA), dieldrin and chlorpyrifos. The rank order for lipid peroxidation corresponded to the ability to evoke cell loss: fipronil>PFOSA>dieldrin>chlorpyrifos. The same sequence was found for an index of cell enlargement (protein/DNA ratio) but the effects on neurite outgrowth (membrane/total protein) diverged, with fipronil producing a decrease and PFOSA an increase. Cotreatment with antioxidants reduced (ascorbate) or eliminated (Vitamin E) lipid peroxidation caused by each of the agents but failed to protect against cell loss, with the sole exception of chlorpyrifos, for which we earlier showed partial protection by Vitamin E; addition of higher NGF concentrations protected neither against oxidative stress nor cell loss. Despite the failure to prevent cell loss, ascorbate protected the cells from the effects of PFOSA on neuritic outgrowth; NGF, and to a lesser extent, ascorbate, offset the effects of fipronil on both cell enlargement and neuritogenesis. At the same time, the ameliorant treatments also worsened some of the other toxicant effects. Our results point out the problems in concluding that, just because a neurotoxicant produces oxidative stress, antioxidant therapy will be effective in preventing damage. Instead, additional mechanisms for each agent may provide alternative routes to neurotoxicity, or may be additive or synergistic with oxidative stress.
Asunto(s)
Antioxidantes/farmacología , Peroxidación de Lípido/efectos de los fármacos , Sistema Nervioso/efectos de los fármacos , Síndromes de Neurotoxicidad/tratamiento farmacológico , Neurotoxinas/antagonistas & inhibidores , Estrés Oxidativo/efectos de los fármacos , Ácidos Alcanesulfónicos/antagonistas & inhibidores , Ácidos Alcanesulfónicos/toxicidad , Animales , Antioxidantes/uso terapéutico , Ácido Ascórbico/farmacología , Ácido Ascórbico/uso terapéutico , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Aumento de la Célula/efectos de los fármacos , Cloropirifos/antagonistas & inhibidores , Cloropirifos/toxicidad , Dieldrín/antagonistas & inhibidores , Dieldrín/toxicidad , Fluorocarburos/antagonistas & inhibidores , Fluorocarburos/toxicidad , Peroxidación de Lípido/fisiología , Factores de Crecimiento Nervioso/farmacología , Factores de Crecimiento Nervioso/uso terapéutico , Sistema Nervioso/crecimiento & desarrollo , Neuritas/efectos de los fármacos , Neuritas/ultraestructura , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/fisiopatología , Neurotoxinas/toxicidad , Estrés Oxidativo/fisiología , Células PC12 , Pirazoles/antagonistas & inhibidores , Pirazoles/toxicidad , Ratas , Vitamina E/farmacología , Vitamina E/uso terapéuticoRESUMEN
Brassinosteroids (BRs) are known to protect crops from the toxicity of herbicides, fungicides and insecticides. It is shown here that application of 24-epibrassinolide (EBR) accelerated metabolism of various pesticides and consequently reduced their residual levels in cucumber ( Cucumis sativus L). Chlorpyrifos, a widely used insecticide, caused significant reductions of net photosynthetic rate (Pn) and quantum yield of PSII (Phi(PSII)) in cucumber leaves. EBR pretreatment alleviated the declines of Pn and Phi(PSII) caused by chlorpyrifos application, and this effect of EBR was associated with reductions of chlorpyrifos residues. To understand how EBR promotes chlorpyrifos metabolism, the effects of EBR on activity and expression of enzymes involved in pesticide metabolism were analyzed. EBR had a positive effect on the activation of glutathione S-transferase (GST), peroxidase (POD), and glutathione reductase (GR) after treatment with chlorpyrifos, although the effect on GR was attenuated at later time points when plants were treated with 1 mM chlorpyrifos. In addition, EBR enhanced the expression of P450 and MRP, which encode P450 monooxygenase and ABC-type transporter, respectively. However, the expression of GST was consistently lower than that of plants treated with only chlorpyrifos. Importantly, the stimulatory effect of EBR on pesticide metabolism was also observed for cypermethrin, chlorothalonil, and carbendazim, which was attributed to the enhanced activity and genes involved in pesticide metabolism. The results suggest that BRs may be promising, environmentally friendly, natural substances suitable for wide application to reduce the risks of human and environment exposure to pesticides.
Asunto(s)
Colestanoles/farmacología , Cucumis sativus/metabolismo , Plaguicidas/metabolismo , Esteroides Heterocíclicos/farmacología , Brasinoesteroides , Cloropirifos/antagonistas & inhibidores , Cloropirifos/farmacología , Cucumis sativus/efectos de los fármacos , Cucumis sativus/enzimología , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Activación Enzimática/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Glutatión Reductasa/metabolismo , Glutatión Transferasa/metabolismo , Peroxidasa/metabolismo , Reguladores del Crecimiento de las PlantasRESUMEN
The objective of the study was to evaluate the potential risk of DNA damage due to exposure to a mixture of the most widely used pesticides, namely endosulfan, chlorpyriphos and thiram at an environmentally relevant concentration (5 microM each) and the DNA protective capacity of sulforaphane (SFN) (10-30 microg/mL). DNA damage in human lymphocytes was ascertained with Single Cell Gel Electrophoresis (SCGE), also called Comet Assay. For positive control, H(2)O(2) at 100 mM was used. The pesticide mixture produced DNA damage at the concentration used in the lymphocytes. SFN was able to offer a statistically significant (P < 0.01), concentration-dependant protection to DNA damage between 10-20 microg/mL in both the pre-incubation and co-incubation strategies. The results indicate that exposure to low levels of these pesticide mixtures can induce DNA damage, and the presence of SFN in diet may reduce the incidence of genetic damage, especially in farm workers. However, it is not clear whether SFN is involved in quenching of the free radicals generated by the pesticide mixture or it is involved in DNA repair mechanism.
Asunto(s)
Cloropirifos/antagonistas & inhibidores , Daño del ADN/efectos de los fármacos , Endosulfano/antagonistas & inhibidores , Plaguicidas/antagonistas & inhibidores , Sustancias Protectoras/farmacología , Tiocianatos/farmacología , Tiram/antagonistas & inhibidores , Adulto , Cloropirifos/toxicidad , Ensayo Cometa , Endosulfano/toxicidad , Humanos , Isotiocianatos , Linfocitos/química , Linfocitos/efectos de los fármacos , Masculino , Plaguicidas/toxicidad , Sulfóxidos , Tiram/toxicidadRESUMEN
This original study investigates the role of Opuntia ficus indica (cactus) cladodes extract against liver damage induced in male SWISS mice by an organophosphorous insecticide, the chlorpyrifos (CPF). Liver damage was evaluated by the measure of its weight and the quantification of some biochemical parameters, such as alanine amino transferase (ALAT), aspartate amino transferase (ASAT), phosphatase alkaline (PAL), lactate dehydrogenase (LDH), cholesterol and albumin in serum by spectrophotometric techniques. The experimental approach lasted 48 h and consisted of 6 treatments of six mice each one; (1) control, (2) 10 mg/kg (b.w) CPF, (3) 10mg/kg (b.w) CPF with 100 mg/kg (b.w) cactus, (4) 150 mg/kg (b.w)CPF, (5) 150 mg/kg (b.w) CPF with 1.5 g/kg cactus, (6) 1.5 g/kg cactus. Both chlorpyrifos and cactus were administrated orally via gavages. Our results showed that CPF affects significantly all parameters studied. However, when this pesticide was administrated associated to cactus, we noticed a recovery of all their levels. In the other hand, cactus alone did not affect the studied parameters. These results allow us to conclude firstly that CPF is hepatotoxic and secondly that Opuntia ficus indica stem extract protects the liver and decreases the toxicity induced by this organophosphorous pesticide.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Cloropirifos/antagonistas & inhibidores , Insecticidas/antagonistas & inhibidores , Opuntia , Extractos Vegetales/uso terapéutico , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/enzimología , Cloropirifos/toxicidad , Relación Dosis-Respuesta a Droga , Insecticidas/toxicidad , Masculino , Ratones , Tamaño de los Órganos/efectos de los fármacos , FitoterapiaRESUMEN
The mechanism by which chlorpyrifos exerts its toxicity in fetal and perinatal animals has yet to be elucidated. Since the placenta is responsible for transport of nutrients and is a major supplier hormone to the fetus, exposure to xenobiotics that alter the function or viability of placenta cells could ostensibly alter the development of the fetus. In this study, JAR cells were used to determine if CPF and the metabolites 3,5,6-trichloro-2-pyridinol (TCP) and chlorpyrifos-oxon (CPO) are toxic to the placenta. Our results indicate that chlorpyrifos (CPF), and its metabolite chlorpyrifos-oxon (CPO) caused a dose-dependent reduction in cellular viability with CPF being more toxic than its metabolites. Chlorpyrifos-induced toxicity was characterized by the loss of mitochondrial potential, the appearance of nuclear condensation and fragmentation, down-regulation of Bcl-2 as well as up-regulation of TNFalpha and FAS mRNA. Pharmacological inhibition of FAS, nicotinic and TNF-alpha receptors did not attenuate CPF-induced toxicity. Atropine exhibited minimal ability to reverse toxicity. Furthermore, signal transduction inhibitors PD98059, SP600125, LY294002 and U0126 failed to attenuate toxicity; however, SB202190 (inhibitor of p38alpha and p38beta MAPK) sensitized cells to CPF-induced toxicity. Pan-caspase inhibitor Q-VD-OPh produced a slight but significant reversal of CPF-induced toxicity indicating that the major caspase pathways are not integral to CPF-induced toxicity. Taken collectively, these results suggest that chlorpyrifos induces apoptosis in placental cells through pathways not dependent on FAS/TNF signaling, activation of caspases or inhibition of cholinesterase. In addition, our data further indicates that activation of p38 MAPK is integral to the protection cells against CPF-induced injury.
Asunto(s)
Apoptosis/efectos de los fármacos , Cloropirifos/toxicidad , Inhibidores de la Colinesterasa/toxicidad , Placenta/citología , Placenta/efectos de los fármacos , Adulto , Atropina/farmacología , Bencimidazoles , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Línea Celular Tumoral , Cloropirifos/antagonistas & inhibidores , Reactivadores de la Colinesterasa/farmacología , Inhibidores Enzimáticos/farmacología , Femenino , Colorantes Fluorescentes , Humanos , Mitocondrias/efectos de los fármacos , Embarazo , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genética , Regulación hacia Arriba/efectos de los fármacos , Receptor fas/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidoresRESUMEN
The acute interactive toxicity following exposure to two common organophosphorus (OP) insecticides, chlorpyrifos (CPF) and methyl parathion (MPS), was investigated in adult male rats. Oral LD1 values were estimated by dose-response studies (CPF = 80 mg/kg; MPS = 4 mg/kg, in peanut oil, 1 ml/kg). Rats were treated with both toxicants (0.5 or 1 x LD1) either concurrently or sequentially, with 4-h intervals between dosing. Functional signs of toxicity (1-96 h) and cumulative lethality (96 h) were recorded. Rats treated with CPF (1 x LD1) did not show any signs of toxicity although MPS (1 x LD1) elicited slight to moderate signs (involuntary movements) within 1-2 h. Concurrent exposure (LD1 dosages of both CPF and MPS) caused slight signs of toxicity only apparent between 24 and 48 h after dosing. When rats were treated sequentially with MPS first followed by CPF 4 h later, slight signs of toxicity were noted between 6 and 24 h, whereas reversing the sequence resulted in 100% lethality within 1 h of the second dosage. Following exposure to lower dosages (0.5 x LD1), the CPF first group showed higher signs of cholinergic toxicity compared with MPS first or concurrent groups. Cholinesterase inhibition in plasma, diaphragm, and frontal cortex was generally higher in rats treated sequentially with CPF first than in those treated initially with MPS from 4 to 24 h after dosing. Plasma and liver carboxylesterase inhibition at 4 h was also significantly higher in the CPF first (62-90%) compared with MPS first (22-43%) group, while at 8 and 24 h, there was no significant difference between any of the treatment groups. ChE inhibition assays to evaluate in vitro hepatic detoxification of oxons indicated that carboxylesterase (CE)- and A-esterase-mediated pathways are markedly less important for methyl paraoxon (MPO) than chlorpyrifos oxon (CPO) detoxification. CPF pretreatment blocked hepatic detoxification of methyl paraoxon while MPS pretreatment had minimal effect on hepatic CPO detoxification ex vivo. These findings suggest that the sequence of exposure to two insecticides that elicit toxicity through a common mechanism can markedly influence the cumulative action at the target site (acetylcholinesterase, AChE) and consequent functional toxicity.
Asunto(s)
Cloropirifos/análogos & derivados , Cloropirifos/toxicidad , Inhibidores de la Colinesterasa/toxicidad , Insecticidas/toxicidad , Metil Paratión/toxicidad , Paraoxon/análogos & derivados , Acetilcolinesterasa/sangre , Acetilcolinesterasa/metabolismo , Animales , Carboxilesterasa/sangre , Carboxilesterasa/metabolismo , Cloropirifos/antagonistas & inhibidores , Diafragma/efectos de los fármacos , Diafragma/enzimología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Insecticidas/antagonistas & inhibidores , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Metil Paratión/antagonistas & inhibidores , Paraoxon/toxicidad , Ratas , Ratas Sprague-DawleyRESUMEN
Although nicotine is now well recognized as a developmental neurotoxicant, it also may have neuroprotectant properties. In the current study, we used PC12 cells to characterize the specific developmental phases in which these effects are expressed. In undifferentiated cells, nicotine had a modest effect on DNA synthesis (10% reduction), which was nevertheless selective, as no significant reductions were seen for RNA or protein synthesis. The effects were blocked by mecamylamine, indicating mediation by nicotinic acetylcholine receptors. Initiation of differentiation with nerve growth factor, which greatly increases the receptor concentration, produced a commensurate increase in the sensitivity of DNA synthesis to nicotine, while RNA and protein synthesis again remained unaffected. The organophosphate insecticide, chlorpyrifos, also interferes with DNA synthesis in undifferentiated PC12 cells, but by mechanisms independent of nicotinic receptors. Accordingly, the effects of a combination of nicotine and chlorpyrifos should be additive. However, simultaneous exposure of undifferentiated cells to both agents produced less-than-additive effects at low concentrations of chlorpyrifos, and at high chlorpyrifos concentrations, nicotine produced outright protection: the combination of nicotine and chlorpyrifos had lesser effects than chlorpyrifos alone. The same neuroprotection was seen when cells were exposed to nicotine for 24 h, washed free of the drug for 24 h, and then exposed to chlorpyrifos. The results indicate that nicotine interferes with neural cell replication, with peak effects in early stages of differentiation. At the same time, nicotine promotes trophic actions that protect against neurotoxicants that work through other mechanisms.
Asunto(s)
Cloropirifos/toxicidad , Inhibidores de la Colinesterasa/toxicidad , ADN/biosíntesis , Fármacos Neuroprotectores , Síndromes de Neurotoxicidad/patología , Nicotina/toxicidad , Agonistas Nicotínicos/toxicidad , Inhibidores de la Síntesis del Ácido Nucleico , Animales , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Cloropirifos/antagonistas & inhibidores , Mecamilamina/farmacología , Factor de Crecimiento Nervioso/farmacología , Proteínas del Tejido Nervioso/biosíntesis , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/farmacología , Células PC12 , ARN/biosíntesis , Ratas , Receptores Nicotínicos/efectos de los fármacosRESUMEN
The present study was performed to investigate the protective effects of zinc (227 mg/L in drinking water) treatment in chlorpyrifos (13.5 mg/kg body weight, orally) induced hepatotoxicity in male rats. Animals received chlorpyrifos and/or zinc treatments for 8 wk. A 99mTc-mebrofenin clearance test was done to determine the biological half-life (Tbiol) of the radiopharmaceutical in liver for the determination of the hepatobiliary function of the animals. At the end of treatment periods, samples were collected for the measurement of zinc levels in serum and liver. Electron microscopic studies were performed to study hepatic ultrastructure following various treatments. When compared to normal controls, chlorpyrifos treatment resulted in reduced hepatic and serum zinc levels (p < 0.01). The biological half-life (Tbiol) of 99mTc-mebrofenin in liver was increased (p < 0.01) significantly in chlorpyrifos-treated animals, reflecting a poor excretion of the radiopharmaceutical from the liver. Simultaneous zinc supplementation retained the increased hepatic Tbiol values of 99mTc-mebrofenin within normal limits. Zinc treatment also protected hepatocytes from the marked disruptions in the membranous organelles and narrowing/blocking of biliary channels, which was otherwise a common observation following chlorpyrifos treatment. These data clearly show the protective effects of zinc in animals subjected to organophosphate poisoning.
Asunto(s)
Cloropirifos/toxicidad , Hígado/efectos de los fármacos , Hígado/lesiones , Zinc/administración & dosificación , Compuestos de Anilina , Animales , Antioxidantes/administración & dosificación , Antioxidantes/metabolismo , Cloropirifos/antagonistas & inhibidores , Suplementos Dietéticos , Glicina , Semivida , Iminoácidos/farmacocinética , Insecticidas/antagonistas & inhibidores , Insecticidas/toxicidad , Hígado/metabolismo , Hígado/ultraestructura , Masculino , Microscopía Electrónica , Compuestos de Organotecnecio/farmacocinética , Ratas , Ratas Sprague-Dawley , Aumento de Peso/efectos de los fármacos , Zinc/metabolismoRESUMEN
Organophosphate pesticides such as chlorpyrifos reduce core temperature (Tc) in laboratory rodents. The mechanism(s) responsible for the chlorpyrifos-induced hypothermia are not well known. This study assessed the role of a key effector for thermoregulation in the rat, vasomotor control of heat loss from the tail, and its possible cholinergic control during chlorpyrifos-induced hypothermia. Tc and motor activity were monitored by telemetry in female Long-Evans rats maintained at an ambient temperature (Ta) of 25 degrees. Tail skin temperature (Tsk(t)) was measured hourly. Rats were dosed with chlorpyrifos (0 or 25 mg/kg orally). Two hr later the rats were dosed with saline or scopolamine (1.0 mg/kg intraperitoneally). Two hr after chlorpyrifos treatment there was a marked elevation in Tsk(t)) concomitant with a 0.5 degrees reduction in Tc. Scopolamine administered to control rats led to a marked elevation in Tc with little change in Tsk(t). Rats treated with chlorpyrifos and administered scopolamine underwent a marked vasoconstriction and elevation in Tc. Vasodilation of the tail is an important thermoeffector to reduce Tc during the acute stages of chlorpyrifos exposure. The blockade of the response by scopolamine suggests that the hypothermic and vasodilatory response to chlorpyrifos is mediated via a cholinergic muscarinic pathway in the CNS.