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1.
Arch Environ Contam Toxicol ; 79(2): 233-245, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32613299

RESUMO

Natural resource managers are concerned about the impacts of aerial ultra-low volume spray (ULV) of insecticides for mosquito control (i.e., mosquito adulticides) and seek science-driven management recommendations that reduce risk but allow vector control for nearby human populations. Managers at the National Key Deer Refuge (Florida Keys, FL) are concerned for ULV effects upon conservation efforts for imperiled butterflies (Florida leafwing [Anaea troglodyta floridalis] and Bartram's hairstreak [Strymon acis bartrami] butterflies). No-spray zones were designated for protection of those butterflies, but their effectiveness for mitigation is unclear. To address this uncertainty, cholinesterase activity (ChE) and mortality were monitored for caged butterflies gulf fritillary [Agraulis vanilla] and great southern white [Ascia monuste]) deployed on the Refuge during three aerial ULV applications of the insecticide naled. Residue samplers also were deployed to estimate butterfly exposure. Spray efficacy against mosquitoes was assessed by deploying caged mosquitoes at the same locations as the butterflies. Average naled residue levels on filter paper samplers in the target area (1882-2898 µg/m2) was significantly greater than in the no-spray zone (9-1562 µg/m2). Differences between the no-spray zone and target area for butterfly mortality and ChE were inconsistent. Average mortality was significantly lower, and average ChE was significantly higher in the no-spray zone for larvae of one species but not for larvae of the other species. Mosquito mortality did not differ significantly between the two areas. Data from the present study reflect the inconsistent effectiveness of no-spray zones on the Refuge using standard methods employed at the time by the vector control agency in the Florida Keys and possibly by other vector control agencies in similar coastal environments. Furthermore, these findings helped to guide the design and to improve the conservation value of future no-spray zone delineations while allowing for treatment in areas where mosquito control is necessary for vector-borne disease reduction.


Assuntos
Borboletas/fisiologia , Inibidores da Colinesterase/toxicidade , Controle de Mosquitos/métodos , Naled/toxicidade , Animais , Borboletas/efeitos dos fármacos , Colinesterases/metabolismo , Cervos , Florida , Humanos , Inseticidas , Larva/efeitos dos fármacos , Medição de Risco
2.
J Environ Sci Health B ; 55(9): 803-812, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32602772

RESUMO

Organophosphorus pesticides induce gender-specific developmental neurotoxicity after birth, especially in adolescents and adults. However, whether and when the selectivity occurs in fetus remains unclear. In this study, we analyzed chlorpyrifos (CPF)-induced neurotoxicity in the early fetal brains of male and female mice. The gestational dams were administered 0, 1, 3, and 5 mg/(kg.d) CPF during gestational days (GD)7-11, and brains from the fetuses were isolated and analyzed on GD12. Fetal gender was identified by PCR technique based on male-specific Sry gene and Myog control gene. The body weight and head weight, the activity of acetylcholinesterase (AChE), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and the content of malondialdehyde (MDA), as well as the oxidative stress-related gene expression were examined. Our results showed that CPF pretreatment induced AChE inhibition in GD12 fetal brain. CPF treatment activated SOD and GPX but not CAT and MDA. For oxidative stress-related gene expression, CPF pretreatment increased mRNA expression of Sod1, Cat, Gpx1, and Gpx2 in the fetal brain on GD12. The statistical analysis did not show gender-selective CPF-induced toxicity. Moreover, our results showed that although the gestational exposure to CPF could elicit abnormalities in the early fetal brain, the toxicity observed was not gender-specific.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Clorpirifos/toxicidade , Inseticidas/toxicidade , Acetilcolinesterase/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Catalase/genética , Catalase/metabolismo , Inibidores da Colinesterase/toxicidade , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Camundongos Endogâmicos ICR , Síndromes Neurotóxicas/etiologia , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Fatores Sexuais , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Testes de Toxicidade/métodos
3.
Chemosphere ; 259: 127419, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32593003

RESUMO

Carbofuran is one of the most toxic broad-spectrum and systemic N-methyl carbamate pesticide, which is extensively applied as insecticide, nematicide and acaricide for agricultural, domestic and industrial purposes. It is extremely lethal to mammals, birds, fish and wildlife due to its anticholinesterase activity, which inhibits acetyl-cholinesterase and butyrylcholinesterse activity. In humans, carbofuran is associated with endocrine disrupting activity, reproductive disorders, cytotoxic and genotoxic abnormalities. Therefore, cleanup of carbofuran-contaminated environments is of utmost concern and urgently needs an adequate, advanced and effective remedial technology. Microbial technology (bacterial, fugal and algal species) is a very potent, pragmatic and ecofriendly approach for the removal of carbofuran. Microbial enzymes and their catabolic genes exhibit an exceptional potential for bioremediation strategies. To understand the specific mechanism of carbofuran degradation and involvement of carbofuran hydrolase enzymes and genes, highly efficient genomic approaches are required to provide reliable information and unfold metabolic pathways. This review briefly discusses the carbofuran toxicity and its toxicological impact into the environment, in-depth understanding of carbofuran degradation mechanism with microbial strains, metabolic pathways, molecular mechanisms and genetic basis involved in degradation.


Assuntos
Biodegradação Ambiental , Carbofurano/toxicidade , Inibidores da Colinesterase/toxicidade , Poluentes Ambientais/toxicidade , Acetilcolinesterase/metabolismo , Animais , Carbamatos , Carbofurano/metabolismo , Inibidores da Colinesterase/metabolismo , Poluentes Ambientais/metabolismo , Humanos , Hidrolases , Inseticidas/metabolismo , Inseticidas/toxicidade , Redes e Vias Metabólicas
4.
Toxicology ; 438: 152463, 2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-32294493

RESUMO

Methyl parathion (Me-Pa) is an extremely toxic organophosphorus pesticide still used in developing countries. It has been associated with decreased sperm function and fertility and with oxidative and DNA damage. The blood-testis barrier (BTB) is a structure formed by tight junction (TJ) proteins in Sertoli cells and has a critical role in spermatogenesis. We assessed the effect of repeated doses of Me-Pa (3-12 mg/kg/day for 5 days, i.p.) on sperm quality, lipid oxidation, DNA integrity, and BTB permeability in adult male mice and explored oxidation as a mechanism of toxicity. Me-Pa caused dose-dependent effects on sperm quality, lipoperoxidation, and DNA integrity. Testis histology results showed the disruption of spermatogenesis progression and atrophy of seminiferous tubules. The pesticide opened the BTB, as evidenced by the presence of a biotin tracer in the adluminal compartment of the seminiferous tubules. This effect was not observed after 45 days of exposure when a spermatogenic cycle had completed. The coadministration of the antioxidant α-tocopherol (50 mg/kg/day for 5 days, oral) prevented the effects of Me-Pa on sperm quality, DNA and the BTB, indicating the importance of oxidative stress in the damage generated by Me-Pa. As evidenced by immunochemistry, no changes were found in the localization of the TJ proteins of the BTB, although oxidation (carbonylation) of total proteins in testis homogenates was detected. Our results show that Me-Pa disturbs the BTB and that oxidation is involved in the observed toxic effects on sperm cells.


Assuntos
Barreira Hematotesticular/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Inibidores da Colinesterase/toxicidade , Dano ao DNA , Metil Paration/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Praguicidas/toxicidade , Espermatozoides/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/farmacologia , Barreira Hematotesticular/metabolismo , Barreira Hematotesticular/patologia , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos ICR , Carbonilação Proteica/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Espermatozoides/metabolismo , Espermatozoides/patologia
5.
PLoS One ; 15(3): e0230335, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32163499

RESUMO

Organophosphates (OPs) induce acute and chronic neurotoxicity, primarily by inhibiting acetylcholinesterase (AChE) activity as well as by necrosis, and apoptosis. Butyrylcholinesterase (BuChE), an exogenous bioscavenger of OPs, can be used as a treatment for OP exposure. It is prerequisite to develop in vitro brain models that can study BuChE post-treatment for acute OP exposure. In this study, we developed a three-dimensional (3D) brain-on-chip platform with human induced pluripotent stem cell (iPSC)-derived neurons and astrocytes to simulate human brain behavior. The platform consists of two compartments: 1) a hydrogel embedded with human iPSC-derived GABAergic neurons and astrocytes and 2) a perfusion channel with dynamic medium flow. The brain tissue constructs were exposed to Malathion (MT) at various concentrations and then treated with BuChE after 20 minutes of MT exposure. Results show that the iPSC-derived neurons and astrocytes directly interacted and formed synapses in the 3D matrix, and that treatment with BuChE improved viability after MT exposure up to a concentration of 10-3 M. We conclude that the 3D brain-on-chip platform with human iPSC-derived brain cells is a suitable model to study the neurotoxicity of OP exposure and evaluate therapeutic compounds for treatment.


Assuntos
Astrócitos/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Butirilcolinesterase/farmacologia , Inibidores da Colinesterase/toxicidade , Neurônios GABAérgicos/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/citologia , Malation/antagonistas & inibidores , Astrócitos/citologia , Astrócitos/metabolismo , Encéfalo/citologia , Células Cultivadas , Neurônios GABAérgicos/citologia , Neurônios GABAérgicos/metabolismo , Humanos , Malation/toxicidade
6.
Toxicol Appl Pharmacol ; 395: 114963, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32209366

RESUMO

BACKGROUND: Sarin is an irreversible organophosphate cholinesterase inhibitor. Following toxic signs, an extensive long-term brain damage is often reported. Thus, we evaluated the efficacy of a novel anticonvulsant drug retigabine, a modulator of neuronal voltage gated K+ channels, as a neuroprotective agent following sarin exposure. METHODS: Rats were exposed to 1 LD50 or 1.2 LD50 sarin and treated at onset of convulsions with retigabine (5 mg/kg, i.p.) alone or in combination with 5 mg/kg atropine and 7.5 mg/kg TMB-4 (TA) respectively. Brain biochemical and immunohistopathological analyses were processed 24 h and 1 week following 1 LD50 sarin exposure and at 4 weeks following exposure to 1.2 LD50 sarin. EEG activity in freely moving rats was also monitored by telemetry during the first week following exposure to 1.2 LD50 and behavior in the Open Field was evaluated 3 weeks post exposure. RESULTS: Treatment with retigabine following 1 LD50 sarin exposure or in combination with TA following 1.2 LD50 exposure significantly reduced mortality rate compared to the non-treated groups. In both experiments, the retigabine treatment significantly reduced gliosis, astrocytosis and brain damage as measured by translocator protein (TSPO). Following sarin exposure the combined treatment (retigabine+ TA) significantly minimized epileptiform seizure activity. Finally, in the Open Field behavioral test the non-treated sarin group showed an increased mobility which was reversed by the combined treatment. CONCLUSIONS: The M current modulator retigabine has been shown to be an effective adjunct therapy following OP induced convulsion, minimizing epileptiform seizure activity and attenuating the ensuing brain damage.


Assuntos
Anticonvulsivantes/administração & dosagem , Encefalopatias/induzido quimicamente , Encefalopatias/prevenção & controle , Carbamatos/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Fenilenodiaminas/administração & dosagem , Sarina/toxicidade , Animais , Atropina/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encefalopatias/patologia , Substâncias para a Guerra Química/toxicidade , Inibidores da Colinesterase/toxicidade , Masculino , Neuroglia/patologia , Neurônios/patologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/efeitos dos fármacos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/fisiologia , Ratos , Ratos Sprague-Dawley , Convulsões/induzido quimicamente , Convulsões/prevenção & controle , Trimedoxima/administração & dosagem
7.
Aquat Toxicol ; 221: 105424, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32058876

RESUMO

For decades, organophosphate (OP) insecticides have been used as chemical control agents in watersheds that support at-risk populations of Pacific salmon throughout western North America. Spray drift, runoff, and other processes transport OPs to critical surface water habitats for migratory salmonids. While most OPs share a common mechanism of action (i.e., inhibition of neuronal acetylcholinesterase, or AChE), they typically vary in toxic potency. Moreover, dose-response relationships for exposure and sublethal neurotoxicity (e.g., brain AChE inhibition) in salmonids have not been defined for many OPs. Here we exposed juvenile coho salmon (Oncorhynchus kisutch) to five common anticholinesterase insecticides (dimethoate, ethoprop, naled, phorate and phosmet) that are widely used on agricultural, commercial, residential, and public lands. Each of the five pesticides produced a concentration-dependent inhibition of AChE enzyme activity. The effective concentration for 50 % AChE inhibition (96-hr EC50) indicated the highest toxicity for phorate (EC50 = 0.57 µg/L) followed by phosmet (3.3 µg/L), naled (7.8 µg/L), ethoprop (90.6 µg/L) and dimethoate (273 µg/L). These findings can inform 1) relative hazard analyses for OP use near sensitive aquatic habitats, 2) predictions of sublethal OP mixture toxicity, and 3) ecological risk assessments for threatened or endangered species of Pacific salmon.


Assuntos
Acetilcolinesterase/metabolismo , Encéfalo/efeitos dos fármacos , Inibidores da Colinesterase/toxicidade , Inseticidas/toxicidade , Oncorhynchus kisutch/crescimento & desenvolvimento , Compostos Organofosforados/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Encéfalo/metabolismo , Pesqueiros , Oncorhynchus kisutch/metabolismo , Washington
8.
J Environ Sci Health B ; 55(5): 429-437, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32065017

RESUMO

We evaluated the real effects of pollutants through a multi-generation study. We tested whether short-term exposure (48 h) of successive (first and second) generations of Chironomus yoshimatsui neonates (<24-h-old) to two acetylcholinesterase inhibitor insecticides, pyraclofos, and pirimicarb, would change insecticide sensitivity and life-cycle parameters over four generations. Additionally, we tested whether acetylcholinesterase (AChE) activity levels would be associated with this sensitivity change. Sensitivities (48 h EC50 value, using immobility as the endpoint) in chironomids (<24-h-old) and insect life-cycle parameters (the number of larvae per egg mass and adult size) were investigated. Parental chironomids produced larvae that were less sensitive than those in the control group following the two 48 h pirimicarb exposure events, whereas exposure to pyraclofos did not affect sensitivity. The AChE activity in larvae with low sensitivity to pirimicarb was significantly higher than that in the control. Thus, increased AChE activity might be associated with low sensitivity. The life-cycle parameters in chironomids recovered from the effects of pyraclofos and pirimicarb suggested they could adapt to the insecticides by changing biomass allocation. Our study suggested potential chemical risks of insecticide stress and how aquatic organisms adapt to it.


Assuntos
Carbamatos/toxicidade , Chironomidae/efeitos dos fármacos , Inibidores da Colinesterase/toxicidade , Inseticidas/toxicidade , Organotiofosfatos/toxicidade , Pirimidinas/toxicidade , Adaptação Biológica/efeitos dos fármacos , Animais , Chironomidae/fisiologia , Ecotoxicologia/métodos , Larva/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade
9.
Ecotoxicol Environ Saf ; 191: 110222, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31982683

RESUMO

Cylindrospermopsin (CYN) is a cyanotoxicant which occurrence is increasing due to climate change. Cylindrospermopsin is able to exert damage in the organism at several levels, among them, in the nervous system. Moreover, it is important to take into account that it is not usually present isolated in nature, but in combination with some other pollutants, being the case of the pesticide chlorpyrifos (CPF). Thus, the aim of the present work was to assess the effects of the interaction of CYN in combination with CPF in the human neuroblastoma cell line SH-SY5Y by evaluating cytotoxicity and mechanistic endpoints. The mixtures 0.25 + 21, 0.5 + 42, 1 + 84 µg/mL of CYN + CPF based on cytotoxicity results, were evaluated, and the isobologram method detected an antagonistic effect after 24 and 48 h of exposure. Moreover, although no alterations of reactive oxygen species were detected, a significant decrease of glutathione levels was observed after exposure to both, CPF alone and the combination, at all the concentrations and times of exposure assayed. In addition, CYN + CPF caused a marked decrease in the acetylcholinesterase activity, providing similar values to CPF alone. However, these effects were less severe than expected. All these findings, together with the morphological study results, point out that it is important to take into account the interaction of CYN with other pollutants. Further research is required to contribute to the risk assessment of CYN and other contaminants considering more realistic exposure scenarios.


Assuntos
Toxinas Bacterianas/toxicidade , Clorpirifos/toxicidade , Inibidores da Colinesterase/toxicidade , Poluentes Ambientais/toxicidade , Inseticidas/toxicidade , Uracila/análogos & derivados , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Uracila/toxicidade
10.
Toxicology ; 431: 152379, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31962143

RESUMO

Organophosphates (OPs) are valuable as pesticides in agriculture and for controlling deadly vector-borne illnesses; however, they are highly toxic and associated with many deleterious health effects in humans including long-term neurological impairments. Antidotal treatment regimens are available to combat the symptoms of acute OP toxicity, which result from the irreversible inhibition of acetylcholinesterase (AChE). However, there are no established treatments for the long-term neurological consequences of OP exposure. In addition to AChE, OPs can negatively affect multiple protein targets as well as biological processes such as axonal transport. Given the fundamental nature of axonal transport to neuronal health, we rationalized that this process might serve as a general focus area for novel therapeutic strategies against OP toxicity. In the studies described here, we employed a multi-target, phenotypic screening, and drug repurposing strategy for the evaluations of potential novel OP-treatments using a primary neuronal culture model and time-lapse live imaging microscopy. Two multi-target compounds, lithium chloride (LiCl) and methylene blue (MB), which are FDA-approved for other indications, were evaluated for their ability to prevent the negative effects of the OP, diisopropylfluorophosphate (DFP) on axonal transport. The results indicated that both LiCl and MB prevented DFP-induced impairments in anterograde and retrograde axonal transport velocities in a concentration dependent manner. While in vivo studies will be required to confirm our in vitro findings, these experiments support the potential of LiCl and MB as repurposed drugs for the treatment of the long-term neurological deficits associated with OP exposure (currently an unmet medical need).


Assuntos
Transporte Axonal/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Inibidores da Colinesterase/toxicidade , Isoflurofato/antagonistas & inibidores , Isoflurofato/toxicidade , Cloreto de Lítio/farmacologia , Azul de Metileno/farmacologia , Neurônios/efeitos dos fármacos , Animais , Córtex Cerebral/citologia , Relação Dose-Resposta a Droga , Reposicionamento de Medicamentos , Masculino , Fosforilação , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley
11.
Food Chem Toxicol ; 135: 110865, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31618664

RESUMO

Development is especially sensitive to Chlorpyrifos (CPF) toxicity, associated with several neurodegenerative and neurodevelopmental disorders where motor function dysfunction is a core symptom. Amongst the alternative molecular targets to cholinesterases inhibition, developmental CPF alters different components in the most important neurotransmitter systems, although this depends on the exposure period. Exposure during the late postnatal preweaning stage is the least studied by far. This period includes essential neurodevelopmental processes and has an important translational meaning. The present study analyzed the influence of low doses of CPF on this developmental window on locomotor activity and the state of the different neurotransmitter systems by pharmacological challenges. Brain gene expression and microbiome modulation following CPF were also analyzed. CPF exposure long-term increased spontaneous vertical activity, female's activity following acute stress, hyposensitized the cholinergic system and hypersensitized the GABAergic system, up-regulated both muscarinic 2 receptor and GABA-A-α2 receptor subunit in the dorsal striatum and the frontal cortex, respectively and induced gut microbiota dysbiosis at both genus and species levels. The present study supports alternative molecular targets than the ChEs following late postnatal, preweaning exposure to low doses of CPF, focusing on both cholinergic and GABAergic systems and the gut microbiome as an important factor.


Assuntos
Encéfalo/efeitos dos fármacos , Clorpirifos/toxicidade , Inibidores da Colinesterase/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Inseticidas/toxicidade , Locomoção/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Feminino , Masculino , Gravidez , Ratos , Ratos Wistar , Receptor Muscarínico M2/metabolismo , Desmame , Ácido gama-Aminobutírico/metabolismo
12.
J Environ Sci Health B ; 55(4): 355-360, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31868080

RESUMO

The aim of this study was to evaluate the DNA damage in soybean growers during two agricultural periods of a crop season (high and low exposure) and a control group, as well as butyrylcholinesterase (BChE) activity during these exposure periods in order to estimate the degree of BChE inhibition for the exposed group. DNA damage in peripheral whole blood was evaluated by the comet assay and plasma BChE activity was accessed as a measure of exposure to cholinesterase inhibitors. None of the soybean growers reported using full Personal Protective Equipment (PPE). BChE was lower in high exposure period than in low exposure period and DNA damage index was significantly increased in the high exposure period than in the low exposure period. In addition, DNA damage in both exposure periods was higher than control group. No correlation was found between exposure time and DNA damage and BChE activity. However, negative correlation was observed between DNA damage in high and low exposure periods. The results indicate that soybean growers are exposed to cholinesterase inhibitors and to pesticides mixtures with genotoxic potential.


Assuntos
Butirilcolinesterase/sangue , Dano ao DNA , Fazendeiros , Exposição Ocupacional/análise , Praguicidas/toxicidade , Soja , Adulto , Agricultura , Brasil , Estudos de Casos e Controles , Inibidores da Colinesterase/toxicidade , Ensaio Cometa , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo
13.
Toxicol Lett ; 321: 83-89, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31863869

RESUMO

Acetylcholinesterase (AChE) is a pivotal enzyme in neurotransmission. Its inhibition leads to cholinergic crises and could ultimately result in death. A related enzyme, butyrylcholinesterase (BChE), may act in the CNS as a co-regulator in terminating nerve impulses and is a natural plasma scavenger upon exposure to organophosphate (OP) nerve agents that irreversibly inhibit both enzymes. With the aim of improving reactivation of cholinesterases phosphylated by nerve agents sarin, VX, cyclosarin, and tabun, ten phenyltetrahydroisoquinoline (PIQ) aldoximes were synthesized by Huisgen 1,3 dipolar cycloaddition between alkyne- and azide-building blocks. The PIQ moiety may serve as a peripheral site anchor positioning the aldoxime moiety at the AChE active site. In terms of evaluated dissociation inhibition constants, the aldoximes could be characterized as high-affinity ligands. Nevertheless, high binding affinity of these oximes to AChE or its phosphylated conjugates did not assure rapid and selective AChE reactivation. Rather, potential reactivators of phosphylated BChE, with its enlarged acyl pocket, were identified, especially in case of cyclosarin, where the reactivation rates of the lead reactivator was 100- and 6-times that of 2-PAM and HI-6, respectively. Nevertheless, the return of the enzyme activity was affected by the nerve agent conjugated to catalytic serine, which highlights the lack of the universality of reactivators with respect to both the target enzyme and OP structure.


Assuntos
Butirilcolinesterase/metabolismo , Reativadores da Colinesterase/farmacologia , Agentes Neurotóxicos/toxicidade , Intoxicação por Organofosfatos/tratamento farmacológico , Oximas/farmacologia , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Butirilcolinesterase/química , Inibidores da Colinesterase/toxicidade , Reativadores da Colinesterase/síntese química , Ativação Enzimática , Proteínas Ligadas por GPI/agonistas , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/química , Proteínas Ligadas por GPI/metabolismo , Humanos , Cinética , Intoxicação por Organofosfatos/enzimologia , Organofosfatos/toxicidade , Compostos Organofosforados/toxicidade , Compostos Organotiofosforados/toxicidade , Oximas/síntese química , Conformação Proteica , Sarina/toxicidade , Relação Estrutura-Atividade
14.
Ecotoxicol Environ Saf ; 187: 109673, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31698196

RESUMO

The herbicide glyphosate [N- (phosphonomethyl) glycine; PMG] and the insecticide chlorpyrifos [O, O-diethyl O- (3,5,6-trichloro-2-pyridinyl) -phosphorothioate, CPF] are widely used in agricultural practices around the world and can reach aquatic environments. Therefore, it is necessary to characterize the toxicity of these pesticides on non-target species. The use of biomarkers as a tool to assess responses of organisms exposed to pollutants requires the understanding of their natural fluctuation and the dose-response relationship. In the present work, the effect of the exposure to PMG and CPF on the acetylcholinesterase activity (AChE, biomarker of neurotoxicity) in Cnesterodon decemmaculatus, a native teleost, was evaluated in different environmental conditions. Semi-static bioassays of acute toxicity were carried out under controlled conditions during the four weather seasons of the year using animals of homogeneous size. Circannual rhythms in the basal levels of AChE activity in homogenates of the anterior section were confirmed. Statistically significant average inhibition of AChE activity (47.1 ±â€¯0.7% for 1 µg CPF × L-1; 69.7 ±â€¯2.5% for 5 µg CPF × L-1; 23.1 ±â€¯1.1% for 1 mg PMG × L-1 and 32.9 ±â€¯3.3% for 10 mg PMG × L-1) was determined during summer, winter and spring weather seasons. Interestingly, animals exhibit an increased susceptibility to exposure during the autumn season (inhibition of 55.4 ±â€¯0.6% for 1 µg CPF × L-1; 81.9 ±â€¯3.3% for 5 µg CPF × L-1; 41.4 ±â€¯1.7% for 1 mg PMG × L-1 and 61.1 ±â€¯0.3% for 10 mg PMG × L-1). A different sensitivity of the enzyme between seasons was evaluated by in vitro tests. The inhibition pattern for chlorpyrifos-oxon (CPF-oxon, the active metabolite of CPF) was not affected when test was performed using homogenates of unexposed specimens of summer or autumn. Otherwise, PMG in vitro inhibitory effect was not observed in a wide range of concentrations. The results confirm that AChE activity is a sensitive biomarker for exposure to CPF and PMG, even at environmentally relevant concentrations. Finally, this work highlights the existence of seasonal variations in the dose-response relationship, which could be due to variations in the metabolism of the pollutants.


Assuntos
Acetilcolinesterase/metabolismo , Clorpirifos/análogos & derivados , Inibidores da Colinesterase/toxicidade , Ciprinodontiformes/metabolismo , Glicina/análogos & derivados , Estações do Ano , Poluentes Químicos da Água/toxicidade , Animais , Biomarcadores/metabolismo , Clorpirifos/toxicidade , Relação Dose-Resposta a Droga , Água Doce/química , Glicina/toxicidade
15.
Artigo em Inglês | MEDLINE | ID: mdl-31648051

RESUMO

We aimed to ascertain whether ubiquitous plant-based polyphenolic flavonoid compound quercetin (Q) was capable of alleviating deltamethrin (DM) stress in a freshwater teleost, Channa punctata, with emphasis on levels of acetylcholinesterase (AChE), reduced glutathione (GSH), glutathione-S-transferase (GST), DNA/RNA contents and hematological parameters. We measured these parameters in various tissues of fish at 7 and 21 days of exposure to DM doses (0.03 and 0.15 µL L-1), Q (0.14 g L-1) and their combinations (0.03 µL DM L-1 + 0.14 g Q L-1 and 0.15 µL DM L-1 + 0.14 g Q L-1). Both the DM doses altered blood parameters, lowered DNA/RNA contents, AchE activities, GSH levels and augmented GST activities as a mark of neurotoxicity and oxidative stress in fish tissues. We found that 0.14 g L-1 Q ameliorated oxidative stress and AchE inhibitory effects, recovered DM-induced nucleic acid damage and alterations in blood parameters, with some tissue specificity and in duration-dependent manner. Thus, the results indicated that Q was capable of neuroprotection and enhancing the function of antioxidants in fish, which could be predicted to be useful for providing better protection to fish under aquaculture settings with improved Q-rich diets. Through this study with multiple biomarkers in several tissues of fish, valuable information for devising better strategies regarding pesticide risk assessment was obtained and it was recognized that an appropriate dose of Q was essential for its better functioning.


Assuntos
Peixes/metabolismo , Nitrilos/toxicidade , Piretrinas/toxicidade , Quercetina/farmacologia , Estresse Fisiológico/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Biomarcadores/sangue , Inibidores da Colinesterase/toxicidade , Água Doce , Inseticidas/toxicidade , Poluentes Químicos da Água/toxicidade
16.
Biomed Res Int ; 2019: 7901760, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781643

RESUMO

There is a substantial use of pesticides within the agricultural industry of Chile, with neurotoxic effects through mechanisms of acetylcholinesterase inhibition. These pesticides result in deterioration in health, increasing the risk of diseases such as Parkinson's and Alzheimer's in highly exposed occupational population. To date, there are no brief assessment tools to monitor cognitive impairment in agricultural workers chronically exposed to these pesticides. Method. 234 agricultural workers and 305 nonagricultural workers were assessed two times (test-retest) through a brief tool which comprised three tests (clock-drawing test (CDT); frontal assessment battery (FAB); trail making tests (TMT) A and B). The full scale of WAIS-IV was administered as a gold standard to 18% of the sample of agricultural workers. Factor analysis was used to evaluate the factor structure, and validity and test-retest reliability were assessed concurrently. Results. Cronbach's alpha values were satisfactory or above (>0.60). Test-retest correlations were all significantly correlated (p < 0.001). All the tests had a significant correlation with the full scale IQ score of WAIS-IV (p < 0.05). The Kaiser-Meyer-Olkin (KMO) measure was 0.74, and the Bartell sphericity test = p < 0.001. Three factors explaining 61.62% of the variance were extracted. Two items of the FAB test were dropped of the final factor solution. Normative data transformed into percentile scores and stratified by age and educational level were obtained for Chilean agricultural workers. Conclusion. The brief assessment tool has adequate metric properties as a screening instrument. This allows for a simple administration test (10 to 15 minutes) that can potentially be used for the rapid monitoring of cognitive deterioration in the face of occupational exposure to pesticides in agricultural workers.


Assuntos
Fazendeiros , Síndromes Neurotóxicas/diagnóstico , Exposição Ocupacional/análise , Praguicidas/toxicidade , Adulto , Idoso , Chile , Inibidores da Colinesterase/toxicidade , Disfunção Cognitiva , Análise Fatorial , Feminino , Humanos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Testes Neuropsicológicos , Testes Psicológicos , Reprodutibilidade dos Testes
17.
Int J Mol Sci ; 20(21)2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31717775

RESUMO

The joint toxicities of [BMIM]BF4, [BMIM]PF6, and [HMIM]BF4 on acetylcholinesterase (AChE) were systematically investigated by using a progressive approach from 1D single effect point, 2D concentration-response curve (CRC), to 3D equivalent-surface (ES) level. The equipartition equivalent-surface design (EESD) method was used to design 10 ternary mixtures, and the direct equipartition ray (EquRay) design was used to design 15 binary mixtures. The toxicities of ionic liquids (ILs) and their mixtures were determined using the microplate toxicity analysis (MTA) method. The concentration addition (CA), independent action (IA), and co-toxicity coefficient (CTC) were used as the additive reference model to analyze the toxic interaction of these mixtures. The results showed that the Weibull function fitted well the CRCs of the three ILs and their mixtures with the coefficient of determination (R2) greater than 0.99 and root-mean-square error (RMSE) less than 0.04. According to the CTC integrated with confidence interval (CI) method (CTCICI) developed in this study, the 25 mixtures were almost all additive action at 20% and 80% effect point levels. At 50% effect, at least half of the 25 mixtures were slightly synergistic action, and the remaining mixtures were additive action. Furthermore, the ESs and CRCs predicted by CA and IA were all within the CIs of mixture observed ESs and CRCs, respectively. Therefore, the toxic interactions of these 25 mixtures were actually additive action. The joint toxicity of the three ILs can be effectively evaluated by the ES method. We also studied the relationship between the mixture toxicities and component concentration proportions. This study can provide reference data for IL risk assessment of combined pollution.


Assuntos
Inibidores da Colinesterase/toxicidade , Líquidos Iônicos/toxicidade , Acetilcolinesterase/efeitos dos fármacos , Boratos/química , Boratos/toxicidade , Inibidores da Colinesterase/química , Sinergismo Farmacológico , Imidazóis/química , Imidazóis/toxicidade , Concentração Inibidora 50 , Líquidos Iônicos/química , Cinética , Modelos Químicos , Testes de Toxicidade
18.
Mutat Res ; 843: 52-56, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31421739

RESUMO

Exposure to pesticides leads to complex, long-lasting adverse effects on human health, and poses a substantial risk to those living in areas devoted to agriculture. Children are particularly vulnerable to the pesticide exposure, due to the developmental, dietary and physiological factors. Small body mass and typical exploratory behavior result in increased risk of intoxication. Thus, even exposure to low concentrations of pesticides, if of sufficient duration, may lead to permanent health disorders and limit their harmonious development. In this study 108 children, living in areas of an intense pesticide use and a control group (n = 92) of children from an agrotouristic area were investigated, whether DNA damage increased due to prolonged pesticide exposure. A presence of DNA breaks and oxidative damage to DNA bases, characterized as Fpg-sensitive sites, were detected by comet assay. Micronuclei (MN) formation was evaluated by cytokinesis-block MN assay. The exposure of children to pesticides resulted in increased number of MN in peripheral blood lymphocytes (P = 0.016), increased DNA strand breaks level (P = 0.002) and oxidative damage to DNA (P < 0.001). Negative correlation was demonstrated between the level of DNA strand breaks and acetylcholinesterase (AChE) activity in exposed group. In conclusion, despite just environmental pesticide exposure in the test group of children, significant biological effects were detected.


Assuntos
Dano ao DNA , Exposição Ambiental , Praguicidas/toxicidade , Acetilcolinesterase/sangue , Monitoramento Biológico/métodos , Criança , Inibidores da Colinesterase/toxicidade , Ensaio Cometa , DNA/sangue , DNA/efeitos dos fármacos , Quebras de DNA , DNA-Formamidopirimidina Glicosilase/farmacologia , Feminino , Contaminação de Alimentos , Guanina/análogos & derivados , Guanina/sangue , Humanos , Masculino , Testes para Micronúcleos , Pais , Polônia , População Rural
19.
Toxicol Lett ; 314: 153-163, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31408696

RESUMO

Eye exposure to organophosphate (OP) chemical warfare irreversible acetylcholinesterase inhibitors, results in long-term miosis and impaired visual function. In contrast to the well-documented miotic and ciliary muscle spasm observed following chemical warfare, OP ocular exposure, little is known regarding the ocular surface histopathological insult. The aim of the present study was to determine the degree of the ocular surface insult following sarin or VX ocular exposure and to evaluate potential anti-cholinergic treatments in counteracting this insult. Rats that were whole body exposed to various sarin concentrations (0.049-43 µg/L; 5 min exposure), showed a dose-dependent miotic response and light reflex impairment. Following whole body sarin exposure, a dose dependent ocular surface histopathological insult was developed. A week following exposure to a low concentration of 0.05 µg/L, conjunctival pathology was observed, while corneal insult was noticed only following exposure to a concentration of 0.5 µg/L and above. Both tissues presented poorer outcomes when exposed to higher sarin concentrations. In contrast, eyes topically exposed to 1 µg sarin demonstrated no ocular insult a week following exposure. On the contrary, topical exposure to 1 µg VX resulted in a significant corneal insult. Anticholinergic treatments such as 0.1% atropine or 2% homatropine, given shortly following VX exposure, counteracted this insult. The results of this study show that not only do anti-cholinergic treatments counteract the miotic response, but also prevent the histopathological insult observed when given shortly following OP exposure.


Assuntos
Antídotos/farmacologia , Piscadela/efeitos dos fármacos , Substâncias para a Guerra Química/toxicidade , Inibidores da Colinesterase/toxicidade , Olho/efeitos dos fármacos , Miose/prevenção & controle , Antagonistas Muscarínicos/farmacologia , Compostos Organotiofosforados/toxicidade , Sarina/toxicidade , Acetilcolinesterase/metabolismo , Animais , Citoproteção , Relação Dose-Resposta a Droga , Olho/enzimologia , Olho/patologia , Olho/fisiopatologia , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Masculino , Miose/induzido quimicamente , Miose/patologia , Miose/fisiopatologia , Ratos Long-Evans , Fatores de Tempo
20.
Inhal Toxicol ; 31(5): 203-211, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31359796

RESUMO

Objective: Sarin is an irreversible organophosphate cholinesterase inhibitor and a highly toxic, volatile warfare agent. Rats and guinea pigs exposed to sarin display cholinergic excitotoxicity which includes hyper-salivation, respiratory distress, tremors, seizures, and death. Here we focused on the characterization of the airways injury induced by direct exposure of the lungs to sarin vapor and compared it to that induced by the intramuscularly route. Materials and methods: Rats were exposed to sarin either in vapor (∼1LCT50, 34.2 ± 0.8 µg/l/min, 10 min) or by i.m. (∼1LD50, 80 µg/kg), and lung injury was evaluated by broncho-alveolar lavage (BAL). Results and discussion: BAL analysis revealed route-dependent effects in rats: vapor exposed animals showed elevation of inflammatory cytokines, protein, and neutrophil cells. These elevations were seen at 24 h and were still significantly higher compared to control values at 1 week following vapor exposure. These elevations were not detected in rats exposed to sarin i.m. Histological evaluation of the brains revealed typical changes following sarin poisoning independent of the route of administration. The airways damage following vapor exposure in rats was also compared to that induced in guinea pigs. The latter showed increased eosinophilia and histamine levels that constitutes an anaphylactic response not seen in rats. Conclusions: These data clearly point out the importance of using the appropriate route of administration in studying the deleterious effects of volatile nerve agents, as well as the selection of the appropriate animal species. Since airways form major target organs for the development of injury following inhalation toxicity, they should be included in any comprehensive evaluation of countermeasures efficacy.


Assuntos
Substâncias para a Guerra Química/toxicidade , Pulmão/patologia , Sarina/administração & dosagem , Sarina/toxicidade , Administração por Inalação , Animais , Lavagem Broncoalveolar , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/toxicidade , Cobaias , Inflamação , Injeções Intramusculares , Dose Letal Mediana , Pulmão/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley
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