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1.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34065933

RESUMO

Neonicotinoid insecticides are nicotine-derived molecules which exert acute neurotoxic effects over the insect central nervous system by activating nicotinic acetylcholine receptors (nAChRs). However, these receptors are also present in the mammalian central and peripheral nervous system, where the effects of neonicotinoids are faintly known. In mammals, cholinergic synapses are crucial for the control of vascular tone, blood pressure and skeletal muscle contraction. We therefore hypothesized that neonicotinoids could affect cholinergic networks in mammals and sought to highlight functional consequences of acute intoxication in rats with sub-lethal concentrations of the highly used acetamiprid (ACE) and clothianidin (CLO). In this view, we characterized their electrophysiological effects on rat α3ß4 nAChRs, knowing that it is predominantly expressed in ganglia of the vegetative nervous system and the adrenal medulla, which initiates catecholamine secretion. Both molecules exhibited a weak agonist effect on α3ß4 receptors. Accordingly, their influence on epinephrine secretion from rat adrenal glands was also weak at 100 µM, but it was stronger at 500 µM. Challenging ACE or CLO together with nicotine (NIC) ended up with paradoxical effects on secretion. In addition, we measured the rat arterial blood pressure (ABP) in vivo by arterial catheterization. As expected, NIC induced a significant increase in ABP. ACE and CLO did not affect the ABP in the same conditions. However, simultaneous exposure of rats to both NIC and ACE/CLO promoted an increase of ABP and induced a biphasic response. Modeling the interaction of ACE or CLO on α3ß4 nAChR is consistent with a binding site located in the agonist pocket of the receptor. We present a transversal experimental approach of mammal intoxication with neonicotinoids at different scales, including in vitro, ex vivo, in vivo and in silico. It paves the way of the acute and chronic toxicity for this class of insecticides on mammalian organisms.


Assuntos
Epinefrina/metabolismo , Inseticidas/toxicidade , Neonicotinoides/toxicidade , Nicotina/toxicidade , Receptores Nicotínicos/metabolismo , Medula Suprarrenal/efeitos dos fármacos , Medula Suprarrenal/metabolismo , Animais , Pressão Arterial/efeitos dos fármacos , Modelos Animais de Doenças , Agonismo Parcial de Drogas , Gânglios/efeitos dos fármacos , Gânglios/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Guanidinas/toxicidade , Masculino , Ratos , Tiazóis/toxicidade , Testes de Toxicidade Subaguda
2.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806369

RESUMO

Isothiazolinone (IT) biocides are potent antibacterial substances commonly used as preservatives or disinfectants, and 2-n-Octyl-4-isothiazolin-3-one (OIT; octhilinone) is a common IT biocide that is present in leather products, glue, paints, and cleaning products. Although humans are exposed to OIT through personal and industrial use, the potentially deleterious effects of OIT on human health are still unknown. To investigate the effects of OIT on the vascular system, which is continuously exposed to xenobiotics through systemic circulation, we treated brain endothelial cells with OIT. OIT treatment significantly activated caspase-3-mediated apoptosis and reduced the bioenergetic function of mitochondria in a bEnd.3 cell-based in vitro blood-brain barrier (BBB) model. Interestingly, OIT significantly altered the thiol redox status, as evidenced by reduced glutathione levels and protein S-nitrosylation. The endothelial barrier function of bEnd.3 cells was significantly impaired by OIT treatment. OIT affected mitochondrial dynamics through mitophagy and altered mitochondrial morphology in bEnd.3 cells. N-acetyl cysteine significantly reversed the effects of OIT on the metabolic capacity and endothelial function of bEnd.3 cells. Taken together, we demonstrated that the alteration of the thiol redox status and mitochondrial damage contributed to OIT-induced BBB dysfunction, and we hope that our findings will improve our understanding of the potential hazardous health effects of IT biocides.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Desinfetantes/toxicidade , Tiazóis/toxicidade , Acetilcisteína/farmacologia , Animais , Antioxidantes/farmacologia , Barreira Hematoencefálica/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular , Desinfetantes/antagonistas & inibidores , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Metabolismo Energético/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteólise/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Compostos de Sulfidrila/metabolismo , Tiazóis/antagonistas & inibidores , Proteínas de Junções Íntimas/metabolismo
3.
Ecotoxicol Environ Saf ; 217: 112234, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33864981

RESUMO

The toxicity tests of nineteen commonly used pesticides were carried out to compare the sensitivity differences between predatory mite Neoseiulus cucumeris and its prey Tetranychus cinnabarinus by a "leaf spray method" in laboratory microcosms. For two avermectins, emamectin benzoate and abamectin, exhibited high bioactivity against T. cinnabarinusf with LR50 values of 0.04 and 0.05 g a.i./ha, respectively, but these two insecticides showed the opposite toxic effects to N. cucumeris. These two agents showed strong selectivity for the two test species with Selective Toxicity Rate (STR) values of 950 and 620, respectively. However, for five neonicotinoids, the LR50s of dinotefuran, thiamethoxam, imidacloprid, and acetamiprid were all greater than the recommended rates in the field except for clothianidin, and they showed no obvious toxicity difference to the two species with STR values ranging from 0.58 to 2.00. For two organophosphates, malathion is more toxic to N. cucumeris than T. cinnabarinus, however, dimethoate showed a higher toxic effect on T. cinnabarinus. In addition, the toxicity of four pyrethroids, bifenthrin, deltamethrin, cyhalothrin and gamma-cyhalothrin to N. cucumeris was higher than that of T. cinnabarinus, except for alpha-cypermethrin. For five acaricides, spirodiclofen, spirotetramat and pyridaben had no obvious selectivity to the two organisms, while diafenthiuron and chlorfenapyr were found to be highly toxic to T. cinnabarinus than N. cucumeris with STR values of 14.2 and 68.5, respectively. Thus, some pesticides above-mentioned like emamectin benzoate, abamectin, diafenthiuron and chlorfenapyr exhibited potential to be used in the management programs of T. cinnabarinus, especially in organically based production systems where there are fewer chemical control measures available, which need to combine with natural enemies to achieve the best control effect.


Assuntos
Praguicidas/toxicidade , Aranhas/fisiologia , Tetranychidae/fisiologia , Acaricidas/farmacologia , Animais , Guanidinas/toxicidade , Ácaros/efeitos dos fármacos , Neonicotinoides/toxicidade , Nitrilas/toxicidade , Nitrocompostos/toxicidade , Piretrinas/farmacologia , Piretrinas/toxicidade , Tiazóis/toxicidade
4.
Aquat Toxicol ; 235: 105820, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33819826

RESUMO

Amphibians are declining globally. Exposure to pesticides has been implicated in decreasing amphibian immune function, thus increasing their susceptibility to parasites and disease and thereby negatively affecting individuals and populations. Amphibians are likely exposed to neonicotinoids because these widely used insecticides are highly soluble in water and because amphibian freshwater habitats are often embedded in agroecosystems. Herein, we investigate the effects of long-term exposure to two individual neonicotinoids (clothianidin or thiamethoxam) at either low or high concentrations (2.5 or 250 µg/L) on northern leopard frog (Lithobates pipiens) blood cell profiles and concentrations of corticosterone, an energy-mediating hormone associated with stress. Larval frogs from Gosner stage 25 to 46 were exposed to pesticide and control treatments in outdoor mesocosms. Corticosterone concentrations were measured after 6 d of exposure, and blood cell profiles were assessed once frogs reached Gosner stage 46 (following 8 w of exposure). No significant changes were found in erythrocyte counts, leukocyte counts, monocyte to leukocyte ratios or corticosterone concentrations between treatments. However, exposure to either 2.5 or 250 µg/L of clothianidin, or 250 µg/L of thiamethoxam decreased neutrophil to lymphocyte ratios and neutrophil to leukocyte ratios, and exposure to 2.5 µg/L of clothianidin or 250 µg/L of thiamethoxam decreased eosinophil to leukocyte ratios. Our results indicate that long-term exposure to neonicotinoids can alter leukocyte profiles, indicative of a stress response. Future studies should investigate whether chronic exposure to neonicotinoids affect multiple measures of stress differently or influences the susceptibility of amphibians to parasites and pathogens. Our work underscores the importance of continued use of multiple measures of stress for different amphibian species when undertaking ecotoxicological assessments.


Assuntos
Praguicidas/toxicidade , Rana pipiens/fisiologia , Poluentes Químicos da Água/toxicidade , Animais , Anuros , Benchmarking , Células Sanguíneas , Corticosterona/sangue , Guanidinas/toxicidade , Inseticidas/farmacologia , Inseticidas/toxicidade , Larva/efeitos dos fármacos , Neonicotinoides/toxicidade , Praguicidas/farmacologia , Tiametoxam/farmacologia , Tiametoxam/toxicidade , Tiazóis/toxicidade
5.
Ecotoxicol Environ Saf ; 212: 112015, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33561775

RESUMO

Osmia excavata is an important pollinator in commercial fruit orchards. Little information has been published about ecotoxicity to O. excavata, especially the larvae. To clarify the risk of commonly used insecticides with different modes of action to the larvae of O. excavata, six insecticides (clothianidin, acetamiprid, sulfoxaflor, lambda-cyhalothrin, chlorfenapyr and abamectin) were selected for evaluation of their acute lethal toxicity and sublethal effects. Clothianidin and abamectin were the two most toxic insecticides to the larvae of O. excavata with LD50 values of 0.007 (0.006-0.008) and 0.0004 (0.0003-0.0006) µg active ingredient (a.i.) bee-1, respectively. And their ecological risks were high according to the hazard quotient values (HQ > 2500). Sulfoxaflor was identified as the only safe insecticide for O. excavata (HQ < 50) under field conditions. Sublethal toxicity tests showed that larval weight was significantly decreased by ingesting food treated with clothianidin, lambda-cyhalothrin and abamectin (less than the maximum field registered concentrations on fruit trees) due to interference with consumption per larva and reduction of the efficiency of conversion of ingested food. Additionally, above three insecticides significantly prolonged larval developmental duration before cocooning and decreased eclosion rate. Overall, there results suggested that clothianidin and abamectin should not be applied, especially during the flowering phase, the application frequency of lambda-cyhalothrin should be minimized for the purpose of conserving O. excavata. Our results provided important evidences for selecting appropriate insecticides for use in fruit orchards.


Assuntos
Abelhas/efeitos dos fármacos , Inseticidas/toxicidade , Larva/efeitos dos fármacos , Animais , Abelhas/crescimento & desenvolvimento , Produtos Agrícolas/crescimento & desenvolvimento , Relação Dose-Resposta a Droga , Ecotoxicologia , Guanidinas/toxicidade , Dose Letal Mediana , Neonicotinoides/toxicidade , Nitrilas/toxicidade , Polinização , Piretrinas/toxicidade , Piridinas/toxicidade , Medição de Risco , Compostos de Enxofre/toxicidade , Tiazóis/toxicidade
6.
Toxicol Lett ; 342: 95-103, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33609686

RESUMO

Neonicotinoids, which act as agonists of the nicotinic acetylcholine receptors of insects, are widely used pesticides worldwide. Although epidemiological studies revealed that the detection amounts of neonicotinoids in urine are higher in the elderly population than other age-groups, there is no available information regarding the risks of neonicotinoids to older mammals. This study was aimed to investigate aging-related differences in the behavioral effects of the neonicotinoid pesticide clothianidin (CLO). We acutely administered a sub-NOAEL level (5 mg/kg) of CLO to adult (12-week-old) and aging (90-week-old) mice and conducted four behavioral tests focusing on the emotional behavior. In addition, we measured the concentrations of CLO and its metabolites in blood, brain and urine. There were age-related changes in most parameters in all behavioral tests, and CLO significantly decreased the locomotor activity in the open field test and elevated plus-maze test in the aging group, but not in the adult group. The concentrations of most CLO and its metabolites were significantly higher in the blood and brain and were slightly lower in the urine in the aging group compared to the adult group. These findings should contribute to our understanding of age-related differences in the adverse effects of neonicotinoids in mammals.


Assuntos
Comportamento Animal/efeitos dos fármacos , Guanidinas/toxicidade , Inseticidas/toxicidade , Neonicotinoides/toxicidade , Tiazóis/toxicidade , Envelhecimento , Animais , Relação Dose-Resposta a Droga , Guanidinas/administração & dosagem , Inseticidas/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neonicotinoides/administração & dosagem , Tiazóis/administração & dosagem
7.
Chemosphere ; 262: 127735, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32777610

RESUMO

Despite the restriction of the use of neonicotinoids in the EU, including thiamethoxam and clothianidin, the debate over their risk on honey bees has not been fully settled. This study presents results of a three-year study working with 180 honey bee colonies in ten replicates. Colonies were sorted into three treatments (60 colonies per treatment) exposed to sunflower blooms grown from seeds treated with thiamethoxam, clothianidin and a non-treated control. Each colony was assessed at six moments: one before to exposition to sunflower, two during the exposition (short-time risk), two after exposition (medium-time risk) and one after wintering (long-time risk). The health and development of the colonies were assessed by monitoring adult bee population, brood development, status of the queen, food reserves and survival. No significant difference among treatments when raw data was considered. However, when evolution from initial status of the colony was evaluated, a significant difference was observed from the first week of exposure to sunflower blooms. In this period, the number of adult bees and the amount of brood were slightly lower in the bee hives exposed to neonicotinoids, although such differences disappeared in subsequent evaluations. The concentration of residues in samples of beebread and adult bees was at the level of ng·g-1. Magnitude of the effect of the treatment factor on the variability of colony health and development related parameters was low. The most important factor was the hive, followed by the replicate and year, and to a lesser extent the initial strength of the colonies.


Assuntos
Abelhas/efeitos dos fármacos , Guanidinas/toxicidade , Helianthus , Inseticidas/toxicidade , Neonicotinoides/toxicidade , Sementes/efeitos dos fármacos , Tiametoxam/toxicidade , Tiazóis/toxicidade , Animais , Abelhas/fisiologia , Ecotoxicologia/métodos , Flores , Guanidinas/análise , Helianthus/efeitos dos fármacos , Inseticidas/análise , Neonicotinoides/análise , Resíduos de Praguicidas/análise , Polinização , Própole/análise , Sementes/química , Espanha , Tiametoxam/análise , Tiazóis/análise
8.
PLoS One ; 15(9): e0238707, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32925934

RESUMO

Clothianidin is a second-generation neonicotinoid insecticide, widely used against sap-sucking insect pest including melon aphid, Aphis gossypii Glover (Hemiptera: Aphididae). This pest causes severe economic damage to Cucurbitaceae plants worldwide. In this study, we investigated clothianidin resistance development under continuous selection pressure. Moreover, the age-stage, two-sex life table approach was used to evaluate the impact of clothianidin resistance on the fitness of A. gossypii. A clothianidin resistant strain (CT-R) with a 23.17-fold resistance level was developed from a susceptible strain (CT-S) after continuous selection for 24 generations. Life table results showed a significant reduction in the relative fitness (0.847) of CT-R strain compared to the CT-S strain of A. gossypii. The developmental duration, oviposition days, total pre-oviposition period (TPOP), longevity, and fecundity of CT-R strain were found to be significantly lower when compared to CT-S strain. The demographic parameters, including the intrinsic rate of increase (r), finite rate of increase (λ), net reproductive rate (R0), and mean generation time (T) were also significantly decreased in CT-R strain compared to the CT-S strain. Both the reproductive and survival rates were affected by clothianidin resistance in CT-R strain compared with the CT-S strain of A. gossypii. Overall, our results demonstrate that in-depth knowledge about the trade-off at play between resistance degree and fitness cost might be useful to design resistance management strategies against A. gossypii.


Assuntos
Afídeos/genética , Cucurbitaceae/parasitologia , Aptidão Genética , Guanidinas/toxicidade , Resistência a Inseticidas/genética , Neonicotinoides/toxicidade , Tiazóis/toxicidade , Envelhecimento/fisiologia , Animais , Afídeos/efeitos dos fármacos , Afídeos/crescimento & desenvolvimento , Feminino , Fertilidade , Estágios do Ciclo de Vida/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Análise de Sobrevida
9.
Chem Biol Interact ; 330: 109244, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32861748

RESUMO

The 2-aminothiazole functionality has long been established as a privileged structural feature and therefore frequently exploited in the process of drug discovery and development. It has been introduced into numerous compounds due to its capacity for targeting a wide range of therapeutic target proteins. On the other hand, the aminothiazole group has also been classified as a toxicophore susceptible to metabolic activation and the ensuing reactive metabolite formation, hence caution is warranted when used in drug design. This review is divided into three parts entailing: (i) the general characteristics of the aminothiazole group, (ii) the advantages of the aminothiazole group in medicinal chemistry, and (iii) the impact of the integrated aminothiazole group on compound safety profile.


Assuntos
Descoberta de Drogas/métodos , Tiazóis/química , Animais , Humanos , Relação Estrutura-Atividade , Tiazóis/metabolismo , Tiazóis/toxicidade
10.
PLoS One ; 15(7): e0229052, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32614853

RESUMO

Rice paddy irrigation ponds can sustain surprisingly high taxonomic richness and make significant contributions to regional biodiversity. We evaluated the impacts of pesticides and other environmental stressors (including eutrophication, decreased macrophyte coverage, physical habitat destruction, and invasive alien species) on the taxonomic richness of freshwater animals in 21 irrigation ponds in Japan. We sampled a wide range of freshwater animals (reptiles, amphibians, fishes, mollusks, crustaceans, insects, annelids, bryozoans, and sponges) and surveyed environmental variables related to pesticide contamination and other stressors listed above. Statistical analyses comprised contraction of highly correlated environmental variables, best-subset model selection, stepwise model selection, and permutation tests. Results showed that: (i) probenazole (fungicide) was a significant stressor on fish (i.e., contamination with this compound had a significantly negative correlation with fish taxonomic richness), (ii) the interaction of BPMC (insecticide; also known as fenobucarb) and bluegill (invasive alien fish) was a significant stressor on a "large insect" category (Coleoptera, Ephemeroptera, Hemiptera, Lepidoptera, Odonata, and Trichoptera), (iii) the interaction of BPMC and concrete bank protection was a significant stressor on an "invertebrate" category, (iv) the combined impacts of BPMC and the other stressors on the invertebrate and large insect categories resulted in an estimated mean loss of taxonomic richness by 15% and 77%, respectively, in comparison with a hypothetical pond with preferable conditions.


Assuntos
Invertebrados/efeitos dos fármacos , Praguicidas/toxicidade , Animais , Biodiversidade , Carbamatos/toxicidade , Ecossistema , Monitoramento Ambiental , Espécies Introduzidas , Invertebrados/fisiologia , Lagoas , Tiazóis/toxicidade , Vertebrados/fisiologia
11.
PLoS One ; 15(6): e0234820, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32559247

RESUMO

Understanding how neonicotinoid insecticides affect non-target arthropods, especially pollinators, is an area of high priority and popular debate. Few studies have considered how pollinators interact and detect neonicotinoids, and almost none have examined for these effects in anthophilous Diptera such as hover flies (Syrphidae). We investigated behavioral responses of two species of hover flies, Eristalis arbustorum L. (Eristalinae) and Toxomerus marginatus Say (Syrphinae), when given a choice between artificial flowers with uncontaminated sucrose solution and neonicotinoid-contaminated (clothianidin) sucrose solution at field-realistic levels 2.5 ppb (average) and 150 ppb (high). We examined for 1) evidence that wild-caught flies could detect the insecticide gustatorily by analyzing amount of time spent feeding on floral treatments, and 2) whether flies could discriminate floral treatments visually by comparing visitation rates, spectral reflectance differences, and hover fly photoreceptor sensitivities. We did not find evidence that either species fed more or less on either of the treatment solutions. Furthermore, T. marginatus did not appear to visit one of the flower choices over the other. Eristalis arbustorum, however, visited uncontaminated flowers more often than contaminated flowers. Spectral differences between the flower treatments overlap with Eristalis photoreceptor sensitivities, opening the possibility that E. arbustorum could discriminate sucrose-clothianidin solution visually. The relevance of our findings in field settings are uncertain but they do highlight the importance of visual cues in lab-based choice experiments involving insecticides. We strongly encourage further research in this area and the consideration of both behavioral responses and sensory mechanisms when determining insecticidal impacts on beneficial arthropods.


Assuntos
Comportamento Animal/efeitos dos fármacos , Dípteros/fisiologia , Guanidinas/toxicidade , Inseticidas/toxicidade , Neonicotinoides/toxicidade , Sacarose/química , Tiazóis/toxicidade , Animais , Flores/química , Cadeias de Markov , Método de Monte Carlo , Polinização
12.
Sci Rep ; 10(1): 4099, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32139713

RESUMO

Exposure to chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT) has been associated with allergic contact dermatitis and occupational asthma. Despite this association however, no study has investigated the effects of CMIT/MIT exposure on the development of atopic dermatitis (AD). This study was conducted to investigate the influence of epicutaneous exposure to CMIT/MIT on AD in a mouse model and the underlying biological mechanisms. BALB/C mice were exposed to CMIT/MIT for 3 weeks and AD was developed using ovalbumin (OVA) epidermal sensitization. CMIT/MIT epicutaneous exposure in normal mice significantly enhanced AD-like phenotypes (e.g., transepidermal water loss, clinical score, total serum immunoglobulin E level and infiltration of inflammatory cells). In addition, CMIT/MIT exposure significantly augmented the mRNA expression level of T helper (Th) 2-related cytokines (thymic stromal lymphopoietin, interleukin (IL)-6 and IL-13), Th2 chemokine (chemokine (C-C motif) ligand 17) and the population of CD4+IL-4+ cells in the skin. Moreover, mice exposed to CMIT/MIT in the OVA challenge had greater AD-like phenotypes, higher IL-4 and IL-17A skin mRNA expression levels, and a larger population of CD4+IL-4+- and IL-17A+-producing cells in the skin-draining lymph nodes. Our current findings in a mouse model thus suggest that CMIT/MIT exposure may cause AD symptoms through the dysregulation of Th2/Th17-related immune responses.


Assuntos
Dermatite Atópica/induzido quimicamente , Poluentes Ambientais/toxicidade , Fatores Imunológicos/toxicidade , Células Th17/imunologia , Células Th2/imunologia , Tiazóis/toxicidade , Animais , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Modelos Animais de Doenças , Feminino , Imunidade , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/farmacologia , Pele/efeitos dos fármacos , Pele/patologia
13.
Molecules ; 25(4)2020 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-32102175

RESUMO

The importance of isothiazole and of compounds containing the isothiazole nucleus has been growing over the last few years. Isothiazolinones are used in cosmetic and as chemical additives for occupational and industrial usage due to their bacteriostatic and fungiostatic activity. Despite their effectiveness as biocides, isothiazolinones are strong sensitizers, producing skin irritations and allergies and may pose ecotoxicological hazards. Therefore, their use is restricted by EU legislation. Considering the relevance and importance of isothiazolinone biocides, the present review describes the state-of-the-art knowledge regarding their synthesis, antibacterial components, toxicity (including structure-activity-toxicity relationships) outlines, and (photo)chemical stability. Due to the increasing prevalence and impact of isothiazolinones in consumer's health, analytical methods for the identification and determination of this type of biocides were also discussed.


Assuntos
Desinfetantes/química , Desinfetantes/toxicidade , Tiazóis/química , Tiazóis/toxicidade , Animais , Antibacterianos/química , Antibacterianos/toxicidade , Cosméticos/química , Humanos , Fotoquímica
14.
Eur J Med Chem ; 189: 112046, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31962263

RESUMO

Studying the structure-activity relationships (SAR) of oxadiazolylthiazole antibiotics unexpectedly led us to identify ethylenediamine- and propylenediamine-analogs as potential antimycotic novel lead structures. Replacement of the ethylenediamine moiety for the lead compound 7 with cis-diaminocyclohexyl group (compound 18) significantly enhanced the antifungal activity. In addition to the high safety margin of 18 against mammalian cells, it showed highly selective broad-spectrum activity against fungal cells without inhibiting the human normal microbiota. The antifungal activity of 18 was investigated against 20 drug-resistant clinically important fungi, including Candida species, Cryptococcus, and Aspergillus fumigatus strains. In addition to the low MIC values that mostly ranged between 0.125 and 2.0 µg/mL, compound 18 outperformed fluconazole in disrupting mature Candida biofilm.


Assuntos
Antifúngicos/farmacologia , Oxidiazóis/farmacologia , Tiazóis/farmacologia , Antifúngicos/toxicidade , Aspergillus/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Células CACO-2 , Candida/efeitos dos fármacos , Candida/fisiologia , Cryptococcus/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Oxidiazóis/toxicidade , Estereoisomerismo , Tiazóis/toxicidade
15.
J Vet Med Sci ; 82(3): 360-372, 2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-31983703

RESUMO

Neonicotinoid pesticides (NNs) act as agonists on nicotinic acetylcholine receptors (nAChRs) of insects, and there have been concerns about the effects of NNs on the health of mammals. Since nAChRs are expressed in immune cells, it is possible that NNs disturb the immune system. However, few reports have examined the immunotoxicity of clothianidin (CLO), a widely-used NN. Here, we report the effects of CLO on immune organs and type IV allergic reactions in ear auricles. We orally administered CLO at 0, 30 and 300 mg/kg/day (CLO-0, 30 and 300) to Sprague-Dawley rats for 28 days. The effects were evaluated by organ and body weights, histopathology, and immunohistochemistry (TCRαß, CD4, CD8, CD11b, CD68, CD103). In addition, some cecal contents were subjected to preliminary gut microbiota analysis, because microbiota contribute to host homeostasis, including the immunity. Our results showed loose stool, suppression of body weight gain, significant changes in organ weights (thymus: decreased; liver: increased) and changes of the gut microbiota in the CLO-300 group. There were no obvious histopathological changes in immune organs. Granulomas of the ear auricles were found in one rat of each of the CLO-30 and 300 groups, but CLO had no apparent effect on the thickness or immunohistochemistry in the ear auricles. We present new evidence that CLO affects the thymus and intestine, and might enhance the local inflammatory response. These findings should contribute to the appropriate evaluation of the safety of NNs in the future.


Assuntos
Guanidinas/toxicidade , Sistema Imunitário/efeitos dos fármacos , Inseticidas/toxicidade , Neonicotinoides/toxicidade , Tiazóis/toxicidade , Administração Oral , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Granuloma/induzido quimicamente , Guanidinas/administração & dosagem , Hipersensibilidade Tardia/induzido quimicamente , Imuno-Histoquímica , Inseticidas/administração & dosagem , Masculino , Neonicotinoides/administração & dosagem , Agonistas Nicotínicos , Tamanho do Órgão/efeitos dos fármacos , Ratos Sprague-Dawley , Tiazóis/administração & dosagem , Timo/efeitos dos fármacos
16.
Toxicol Lett ; 322: 32-38, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31923464

RESUMO

Neonicotinoids (NNs), a widely used class of systemic pesticides, are regarded as exhibiting selective toxicity in insects. However, NNs are suspected of exerting adverse effects on mammals as well, including humans. To date, only adult male animal models have been subjected to general toxicity studies of NNs; fetuses have yet to be considered in this context. Here, we focused on the NN clothianidin (CLO) for the first quantitative LC-MS/MS analysis of maternal-to-fetal transfer and residual property of once-daily (single or multiple days), orally administered CLO and its metabolites in mice. The results revealed the presence of CLO and its five metabolites at approximately the same respective blood levels in both dams and fetuses. In the dams, CLO showed a peak value 1 h after administration, after which levels rapidly decreased at 3 and 6 h. In the fetuses of each group, levels of CLO were almost the same as those observed in the corresponding dams. The present results clearly demonstrated rapid passage of CLO through the placental barrier. However, metabolite-dependent differences observed in blood pharmacokinetics and residual levels. This is the first quantitative demonstration of the presence of CLO and its metabolites in fetal mouse blood.


Assuntos
Sangue Fetal/metabolismo , Guanidinas/sangue , Inseticidas/sangue , Troca Materno-Fetal , Neonicotinoides/sangue , Tiazóis/sangue , Animais , Biotransformação , Feminino , Guanidinas/administração & dosagem , Guanidinas/farmacocinética , Guanidinas/toxicidade , Inseticidas/administração & dosagem , Inseticidas/farmacocinética , Inseticidas/toxicidade , Exposição Materna , Camundongos Endogâmicos ICR , Neonicotinoides/administração & dosagem , Neonicotinoides/farmacocinética , Neonicotinoides/toxicidade , Gravidez , Medição de Risco , Tiazóis/administração & dosagem , Tiazóis/farmacocinética , Tiazóis/toxicidade , Toxicocinética
17.
J Med Chem ; 63(1): 418-424, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31702924

RESUMO

Paradoxically, some TRPV1 agonists are, at the organismal level, both nonpungent and clinically useful as topical analgesics. Here, we describe the scaled-up synthesis and characterization in mouse models of a novel, nonpungent vanilloid. Potent analgesic activity was observed in models of neuropathic pain, and the compound blocked capsaicin induced allodynia, showing dermal accumulation with little transdermal absorption. Finally, it displayed much weaker systemic toxicity compared to capsaicin and was negative in assays of genotoxicity.


Assuntos
Analgésicos/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Canais de Cátion TRPV/agonistas , Tiazóis/uso terapêutico , Analgésicos/síntese química , Analgésicos/farmacocinética , Analgésicos/toxicidade , Animais , Células CHO , Capsaicina , Cricetulus , Descoberta de Drogas , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Camundongos Endogâmicos ICR , Neuralgia/tratamento farmacológico , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/toxicidade , Suínos , Tiazóis/síntese química , Tiazóis/farmacocinética , Tiazóis/toxicidade
18.
Ecotoxicol Environ Saf ; 188: 109880, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31711777

RESUMO

An increase in the area treated with the fungicide thifluzamide has triggered concerns for soil ecosystem service providers such as earthworms. Here, we assessed effects of thifluzamide on earthworm (Eisenia fetida) biomarker indicators of stress responses and reproduction following exposure to 0, 0.1, 1.0, and 10.0 mg of thifluzamide kg-1 soil for 7, 14, 21, and 28 d (biomarker indicators) and 30 d (reproduction). Growth and reproduction were inhibited by exposure to thifluzamide at 10.0 mg/kg, and the activities of succinate dehydrogenase (SDH) and respiratory chain complex II were inhibited by exposure to 1.0 and 10.0 mg/kg thifluzamide for the majority of the 28-d experiment. Reactive oxygen species (ROS) increased across all thifluzamide treatments, and the activities of superoxide dismutase (SOD) and glutathione-S-transferase (GST) tended to be inhibited by thifluzamide. Upon exposure to thifluzamide, the activities of catalase (CAT) and guaiacol peroxidase (POD) initially increased and then decreased. Increased levels of malondialdehyde (MDA) were detected only at seven days after exposure, and genotoxicity increased as the thifluzamide concentration increased. The results suggest that thifluzamide presents a potential risk to earthworms at the concentration of 10.0 mg/kg, and its use should be moderated to reduce damage to soil ecosystem function.


Assuntos
Anilidas/toxicidade , Oligoquetos/efeitos dos fármacos , Praguicidas/toxicidade , Poluentes do Solo/toxicidade , Tiazóis/toxicidade , Anilidas/análise , Animais , Antioxidantes/metabolismo , Dano ao DNA , Biomarcadores Ambientais/efeitos dos fármacos , Oligoquetos/crescimento & desenvolvimento , Oligoquetos/metabolismo , Oligoquetos/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Praguicidas/análise , Reprodução/efeitos dos fármacos , Poluentes do Solo/análise , Tiazóis/análise
19.
Environ Mol Mutagen ; 61(3): 300-315, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31633836

RESUMO

Tricyclazole (8-methyl-[1,2,4]triazolo[3,4-b][1,3]benzothiazole) is a fungicide used globally on rice for treatment of the seasonal rice blast disease. Human exposure to this fungicide can occur via dietary and nondietary routes. In a battery of in vitro assays, tricyclazole did not induce gene mutations in bacteria (Ames test) or at the Hprt locus of CHO cells. It was also negative for the induction of micronuclei in human lymphocyte cultures and unscheduled DNA synthesis (UDS) in primary rat hepatocyte. Paradoxically, tricyclazole induced a mutagenic response at the Tk locus of the mouse lymphoma L5178Ycells (MLA), which occurred equally among small/large colony phenotypes. Selection of preexisting mutants leading to a false-positive response in the MLA was ruled out in follow-up experiments. In vivo, tricyclazole was negative in the rat liver UDS assay, mouse bone micronucleus test and a transgenic (MutaMouse) gene mutation assay in glandular stomach, liver, and kidney. Other supporting evidence for the lack of genotoxicity for tricyclazole comes from an in vivo study for sister chromatid exchanges in Chinese hamsters, and a dominant lethal test in the male germ cells of mice. The combined evidence from the genotoxicity studies together with the evidence from toxicokinetic, carcinogenicity, developmental, and reproductive toxicity studies confirm that mutagenicity does not occur in relevant in vivo systems. Data were also compared to potential animal and human exposure, mechanistic data on biological targets and data on analogues, confirming adequacy of the available data for hazard identification and risk assessment. Environ. Mol. Mutagen. 61:300-315, 2020. © 2019 Wiley Periodicals, Inc.


Assuntos
Fungicidas Industriais/toxicidade , Mutagênicos/toxicidade , Tiazóis/toxicidade , Animais , DNA/genética , Dano ao DNA/efeitos dos fármacos , Humanos , Mutagênese/efeitos dos fármacos , Testes de Mutagenicidade/métodos
20.
Toxicol In Vitro ; 62: 104661, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31629900

RESUMO

Methylisothiazolinone (MIT) has been used in wide spectrum of fields due to its ability to inhibit microbial proliferation with low toxicity. Meanwhile, in Korea, the concern about the hazardous effects of MIT was amplified by the occurrence of patients that have humidifier disinfectant-associated pulmonary disease. However, the toxic mechanism for the pathological lesion is still unclear. In our previous study, we identified that cell viability decreased more rapidly in bronchial epithelial cells (BEAS-2B cells) compared to keratinocytes and liver epithelial cells under the same exposure condition. In this study we demonstrated that MIT (2, 4 and 8 µg/mL) induced dose-dependent cytotoxicity 24 h after exposure to BEAS-2B cells. Additionally, MIT impaired structure and function of intracellular organelles via oxidative stress, ultimately leading to apoptotic cell death. We also found notable activation of matrix metalloproteinases (MMPs) and clear aggregation of nucleolus proteins in MIT-treated cells. Furthermore, MIT increased secretion of proinflammatory cytokines (Interleukin (IL)-1ß, IL-6, and interferon-γ) and a chemokine (IL-8), and microarray and the KEGG pathway analysis proposed possible carcinogenesis following exposure to MIT. Taken together, we conclude that MIT induces apoptotic cell death and inflammatory response by activating MMPs in BEAS-2B cells. We also suggest that further study is necessary to clarify the possible carcinogenesis of MIT.


Assuntos
Anti-Infecciosos/toxicidade , Brônquios/citologia , Células Epiteliais/efeitos dos fármacos , Metaloproteinases da Matriz/metabolismo , Tiazóis/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular , Citocinas/metabolismo , Células Epiteliais/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Organelas/efeitos dos fármacos , Organelas/ultraestrutura , Estresse Oxidativo/efeitos dos fármacos
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