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1.
J Toxicol Environ Health A ; 84(1): 1-19, 2021 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-33016236

RESUMO

Formal occupational exposure limits (OELs) for polyalphaolefin (PAO) fluids have not been proposed. Specific PAO fluids are utilized as aircraft hydraulics or heat sink coolants for electronics and aircraft service air. Toxicity was compared for a PAO fluid in male and female Fischer 344 rats using acute inhalation (0, 100, 500, or 1000 mg/m3 aerosol for 6 hr) and two-week inhalation (0, 20, 100, or 300 mg/m3 aerosol for 6 hr/day, 5 days/week) studies. Neurobehavioral tests following acute exposure showed that both genders were less responsive after exposure to 1000 mg/m3 PAO, and to a lesser extent following 500 mg/m3 PAO. Body weight, food, and water consumption were also affected with recovery after 24 hr. Histopathology for the acute group demonstrated an exposure response increase in severity (minimal to mild) of lesions in the posterior nasal cavities and lungs. Severity of lesions was reduced in the recovery groups (normal to minimal). Acute effects were short-lived and recoverable. Following the two-week exposure, effects were limited to lesions only in the posterior nasal cavities and lungs of the high exposure group, with less severity than in the acute exposure high concentration group. Short-term repeated exposure did not result in any cumulative effects except for minimal respiratory tract changes in the 300 mg/m3 exposure group. Data-driven operational exposure limits (OpELs) were proposed based upon Acute Exposure Guideline Levels process resulting in values of 28, 28, 14, 3.5, and 1.7 mg/m3 for 10 and 30 min, 1, 4, and 8 hr, respectively.


Assuntos
Alcenos/toxicidade , Poluentes Ambientais/toxicidade , Exposição por Inalação/efeitos adversos , Animais , Relação Dose-Resposta a Droga , Feminino , Pulmão/efeitos dos fármacos , Masculino , Ratos , Ratos Endogâmicos F344 , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
2.
Chemosphere ; 263: 127985, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32854011

RESUMO

Although banished in some countries, triclosan (TCS) and triclocarban (TCC) have been detected in surface waters in concentrations ranging from ng L-1 to µg L-1 and have shown to affect non-target organisms posing risk to aquatic ecosystems. However, the majority of the studies consider higher levels of these chemicals and single exposure effects to investigate their potential risks, rather than using environmentally relevant concentrations and their binary mixture. In this study, the toxicity of TCS and TCC, and their binary mixture was assessed in catfish embryos (Rhamdia quelen, a south American native species) exposed to environmental concentrations during 96 h. Organisms were evaluated through the endpoints of developmental abnormalities (spine, fin, facial/cranial and thorax), biochemical biomarkers related to oxidative stress responses: catalase (CAT), superoxide dismutase (SOD), glutathione-S-transferase (GST) activities, protein carbonylation (PCO) and neurotoxicity by acetylcholinesterase activity (AChE). The data showed that TCS caused fin abnormalities, decrease of SOD activity and increase of AChE activity in the catfish embryos of 96hpf. On the other hand, TCC and the binary mixture showed a higher abnormality index for the 96hpf embryos, and an induction of CAT and GST activities for the mixture treatment. The results obtained were able to show potential, but not severe, toxicity of TCS and TCC even in low concentrations and a short period of exposure. The relevance of studies approaching real scenarios of exposure should be reinforced, considering environmental concentrations of chemicals, interactions of contaminants in complex mixtures and the use of a native species such as R. quelen exposed during initial stages of development.


Assuntos
Carbanilidas/toxicidade , Embrião não Mamífero/fisiologia , Triclosan/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Biomarcadores/metabolismo , Catalase/metabolismo , Peixes-Gato/embriologia , Peixes-Gato/metabolismo , Ecossistema , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Testes de Toxicidade Subaguda
3.
Aquat Toxicol ; 227: 105582, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32823071

RESUMO

While it is likely that ENPs may occur together with other contaminants in nature, the combined effects of exposure to both ENPs and environmental contaminants are not studied sufficiently. In this study, we investigated the acute and sublethal toxicity of PVP coated silver nanoparticles (AgNP) and ionic silver (Ag+; administered as AgNO3) to the marine copepod Calanus finmarchicus. We further studied effects of single exposures to AgNPs (nominal concentrations: low 15 µg L-1 NPL, high 150 µg L-1 NPH) or Ag+ (60 µg L-1), and effects of co-exposure to AgNPs, Ag+ and the water-soluble fraction (WSF; 100 µg L-1) of a crude oil (AgNP + WSF; Ag++WSF). The gene expression and the activity of antioxidant defense enzymes SOD, CAT and GST, as well as the gene expression of HSP90 and CYP330A1 were determined as sublethal endpoints. Results show that Ag+ was more acutely toxic compared to AgNPs, with 96 h LC50 concentrations of 403 µg L-1 for AgNPs, and 147 µg L-1 for Ag+. Organismal uptake of Ag following exposure was similar for AgNP and Ag+, and was not significantly different when co-exposed to WSF. Exposure to AgNPs alone caused increases in gene expressions of GST and SOD, whereas WSF exposure caused an induction in SOD. Responses in enzyme activities were generally low, with significant effects observed only on SOD activity in NPL and WSF exposures and on GST activity in NPL and NPH exposures. Combined AgNP and WSF exposures caused slightly altered responses in expression of SOD, GST and CYP330A1 genes compared to the single exposures of either AgNPs or WSF. However, there was no clear pattern of cumulative effects caused by co-exposures of AgNPs and WSF. The present study indicates that the exposure to AgNPs, Ag+, and to a lesser degree WSF cause an oxidative stress response in C. finmarchicus, which was slightly, but mostly not significantly altered in combined exposures. This indicated that the combined effects between Ag and WSF are relatively limited, at least with regard to oxidative stress.


Assuntos
Copépodes/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Petróleo/toxicidade , Prata/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Antioxidantes/metabolismo , Copépodes/genética , Copépodes/metabolismo , Interações Medicamentosas , Expressão Gênica/efeitos dos fármacos , Íons , Nanopartículas Metálicas/química , Estresse Oxidativo/genética , Água do Mar/química , Prata/química , Solubilidade , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda , Poluentes Químicos da Água/química
4.
Ecotoxicology ; 29(9): 1500-1515, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32445013

RESUMO

Glyphosate is an herbicide that inhibits the growth of weed plants, while chlorpyrifos is an insecticide commonly applied to control the pests' population. This study aimed to investigate the combined effects of chlorpyrifos and glyphosate on biochemical, immunological parameters, and oxidative stress biomarkers in freshwater crayfish Pontastacus leptodactylus for 21 days. The experimental design of this study was factorial (3 × 3), including 0.0, 0.4, and 0.8 mg L-1 glyphosate and 0.0, 2.5, and 5 µg L-1 chlorpyrifos. The exposure to chlorpyrifos, glyphosate alone and a mixture of them significantly decreased acetylcholinesterase, alkaline phosphatase, phenoloxidase activities, and total protein levels. The lactate dehydrogenase, glutamic-pyruvic-transaminase, and catalase activities, the contents of glucose, and malondialdehyde levels were increased in the crayfish. No significant changes were detected in glutamic-oxaloacetic-transaminase (SGOT) activity, triglyceride, and total antioxidant (TAO) levels in the crayfish treated with 0.4 mg L-1 glyphosate and the control group. Co-exposure of crayfish to chlorpyrifos and glyphosate increased SGOT activity and TAO levels. Although chlorpyrifos combined with glyphosate decreased the γ-Glutamyltransferase (GGT) activity, the GGT activity was significantly increased in the P. leptodactylus exposed during 21 days to 5 µg L-1 chlorpyrifos alone and 0.8 mg L-1 glyphosate alone. In comparison with the reference group, no significant changes were evidenced in the cholesterol levels in the P. leptodactylus treated with 2.5 µg L-1 chlorpyrifos, but its levels were significantly increased in the other treatment groups. In conclusion, the mix of glyphosate and chlorpyrifos exhibited synergic effects on the different toxicological biomarkers in the narrow-clawed crayfish. Co-exposure to pesticides may result in disruption of homeostasis in the crayfish by altering the biochemical and immunological parameters.


Assuntos
Astacoidea/fisiologia , Clorpirifos/toxicidade , Glicina/análogos & derivados , Praguicidas/toxicidade , Poluentes Químicos da Água/toxicidade , Acetilcolinesterase/metabolismo , Animais , Glicina/toxicidade , Herbicidas/toxicidade , Inseticidas/toxicidade , Testes de Toxicidade Subaguda
5.
Wei Sheng Yan Jiu ; 49(1): 8-27, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32290907

RESUMO

OBJECTIVE: To explore subacute toxic effects of benzo[a]pyrene on the cardiovascular system of male Wistar rats. METHODS: Forty SPF grade male Wistar rats were randomly divided into blank control group, solvent control group, low, medium and high dose group(B[a]P concentrations were 1. 0, 2. 5 and 6. 25 mg/kg, respectively), eight in each group. The solvent group was given the same amount of olive oil and the blank group was not treated at all for 28 consecutive days. After the end of the exposure, the left ventricular structural function and hemodynamic changes were observed with Prospect 3. 0 small animal ultrasound imager and BL-410 biological function test system. Pathological changes of rat thoracic aorta and left ventricle were observed by HE staining. RESULTS: The total difference in ejection fraction(EF), fractional shortening(FS) and left ventricular end diastolic pressure(LVEDP) between the groups was statistically significant(H=11. 497, P=0. 022; H=11. 422, P=0. 022; H=10. 104, P=0. 039). The EF and FS of the middle dose group were lower than the solvent group(adjusted P<0. 05), the LVEDP of the high dose group was higher than that of the solvent group(adjusted P<0. 05). The HE staining of thoracic aorta in the medium and high dose groups showed the loss of endothelial cells, the shedding of some endothelial cells, the exposure of subintimal collagen, the large gap of the middle layer. In the medium and high dose group, left ventricular transverse striations were blurred, muscle fibers reduced or disappeared, the myocardial space widened, inflammatory cells or the myocardial interspace bleeding phenomenon was occasionally observed. CONCLUSION: Benzo[a]pyrene can cause cardiovascular and endothelial damage in male Wistar rats.


Assuntos
Benzo(a)pireno/toxicidade , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/patologia , Animais , Células Endoteliais/patologia , Masculino , Miocárdio/patologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Testes de Toxicidade Subaguda
6.
Int J Nanomedicine ; 15: 1129-1148, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32110012

RESUMO

Introduction: Solid lipid nanoparticles (SLNs) are considered a promising system in enhancing the oral bioavailability of poorly water-soluble drugs; owing to their intrinsic ability to increase the solubility together with protecting the incorporated drugs from extensive metabolism. Objective: Exploiting such properties, SLNs loaded with gliclazide (GLZ) were developed in an attempt to improve the oral bioavailability and the anti-diabetic action of GLZ, together with prolonging its duration of action for better glycemic control. Methods: SLNs were prepared by ultra-sonication technique using glyceryl behenate (Compritol®888 ATO) as a lipid matrix and poloxamer 188 (PLX) as a stabilizer. A 2*3 asymmetrical factorial design was adopted to study the effect of different stabilizer concentrations at different sonication times on the shape, and size of the particles, PDI and drug loading. The selected optimum formulation was then freeze dried using trehalose di-hydrate as a cryo-protectant in different ratios with respect to glyceryl behenate concentration. After freeze drying, the formulation was tested for in-vitro drug release, pharmacokinetics, and pharmacodynamics. Safety of the selected formula was established after carrying out a subacute toxicity study. Results: The factorial design experiment resulted in an optimum formulation coded 10F2 (150 mg PLX/10 min sonication). Scanning electron micrographs showed spherical particles with smooth surface, whereas a ratio of 2:1 cryo-protectant:lipid was found to be optimum with particle size of 245.9 ± 26.2 nm, polydispersity index of 0.482 ± 0.026, and biphasic in-vitro release with an initial burst effect, followed by a prolonged release phase. On the other hand, the selected SLNs exhibited prolonged drug release when compared with the GLZ commercial immediate release (IR) tablets (Diamicron®). Pharmacokinetics study showed about 5-fold increase in GLZ oral bioavailability loaded in SLNs when compared with raw GLZ powder. Pharmacodynamics study on a diabetic rat model confirmed the better anti-diabetic action of GLZ loaded SLNs when compared to raw GLZ powder. Subacute toxicity study indicated the safety of SLNs upon repetitive oral administration.


Assuntos
Gliclazida/farmacocinética , Hipoglicemiantes/farmacocinética , Nanopartículas/administração & dosagem , Administração Oral , Animais , Disponibilidade Biológica , Diabetes Mellitus Experimental/tratamento farmacológico , Liberação Controlada de Fármacos , Ácidos Graxos/química , Liofilização , Gliclazida/administração & dosagem , Gliclazida/toxicidade , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/toxicidade , Lipídeos/química , Masculino , Nanopartículas/química , Tamanho da Partícula , Poloxâmero/química , Ratos Wistar , Solubilidade , Comprimidos/química , Testes de Toxicidade Subaguda
7.
Artigo em Inglês | MEDLINE | ID: mdl-31979393

RESUMO

Phthalates and bisphenol A, classified as endocrine disruptors, have weak estrogenic, anti-androgenic properties, and affect thyroid hormone regulation. The aim of this study on male rats was to compare the subacute toxic effects of low doses of single compounds (bis (2 -ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), and bisphenol A (BPA)) with the effects of their mixture through different biochemical, hormonal, and hematological parameters. Rats were divided into five experimental groups: Control (corn oil), DEHP (50 mg/kg b.w./day), DBP (50 mg/kg b.w./day), BPA (25 mg/kg b.w./day), and MIX (50 mg/kg b.w./day DEHP + 50 mg/kg b.w/day DBP + 25 mg/kg b.w./day BPA). Animals were sacrificed after 28 days of oral treatment and blood was collected for further analysis. The results demonstrated that the mixture produced significant changes in lipid profile, liver-related biochemical parameters, and glucose level. Furthermore, the opposite effects of single substances on the thyroxine level have been shown in comparison with the mixture, as well as a more pronounced effect of the mixture on testosterone level. This study contributes to the body of knowledge on the toxicology of mixtures and gives one more evidence of the paramount importance of mixture toxicity studies, especially in assessing the endocrine disruptive effects of chemicals.


Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Fenóis/toxicidade , Ácidos Ftálicos/toxicidade , Animais , Masculino , Ratos , Ratos Wistar , Testes de Toxicidade Subaguda
8.
Chemosphere ; 242: 125286, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31896186

RESUMO

Bisphenol-B (BPB), an analogue of bisphenol-A is used in the plastic industry. It has been found to leach from plastic containers leading to its contamination in canned food products. Moreover, it has also been detected in human samples such as sera and urine. BPB is recognized as a potential endocrine disrupting chemical owing to its estrogenic and anti-androgenic nature. Therefore, it was pertinent to study the effect of BPB exposure during the adolescence age (5-6 weeks old) in male mice. Weekly intraperitoneal injections of 5, 10 and 15% LD50 of BPB were given for 2 weeks to acute exposure groups and for 4 weeks to sub-acute exposure groups. BPB exposure induces change in enzymatic and non-enzymatic oxidative stress markers in sperm samples. DNA damage was also observed in sperm cells on acute and sub-acute exposures. Furthermore, BPB exposure led to a marked decline in sperm count and compromised sperm morphology. Computer assisted sperm analysis (CASA) revealed a significant decrease in sperm quality and progressive motility. Thus, both the acute and sub-acute exposures of adolescent male mice to BPB adversely affect the sperms' quality, functions and morphology.


Assuntos
Compostos Benzidrílicos/toxicidade , Dano ao DNA , Disruptores Endócrinos/toxicidade , Poluentes Ambientais/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Fenóis/toxicidade , Espermatozoides/efeitos dos fármacos , Fatores Etários , Animais , Humanos , Masculino , Camundongos , Oxirredução , Contagem de Espermatozoides , Espermatozoides/patologia , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
9.
Nanotoxicology ; 14(2): 250-262, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31855090

RESUMO

Lung deposition and retention measurements are now required by the newly revised OECD inhalation toxicity testing guidelines 412 and 413 when evaluating the clearance and biopersistence of poorly soluble nanomaterials, such as multi-walled carbon nanotubes (MWCNTs). However, evaluating the lung deposition concentration is challenging with certain nanomaterials, such as carbon-based and iron-based nanomaterials, as it is difficult to differentiate them from endogenous elements. Therefore, the current 28-day inhalation toxicity study investigated the lung retention kinetics of tangled MWCNTs. Male Sprague Dawley rats were exposed to MWCNTs at 0, 0.257, 1.439, and 4.253 mg/m3 for 28 days (6 h/day, 5 days/week, 4 weeks). Thereafter, the rats were sacrificed at day 1, 7, and 28 post-exposure and the pulmonary inflammatory response evaluated by analyzing the bronchoalveolar lavage fluid. Plus, the blood biochemistry, hematology, and histopathology of the lungs were also examined. The lung deposition and retention of MWCNTs were determined based on the elemental carbon content in the lungs after tissue digestion. The number of polymorphonuclear cells and LDH concentration were both found to be significantly higher with the medium and high concentrations (1.439 and 4.253 mg/m3) and dose dependent. The estimated retention half-life for the high concentration (4.253 mg/m3) was about 35 days. The results of this study indicate that tangled MWCNTs seem to have a relatively shorter retention half-life when compared to previous reports on rigid MWCNTs, and the no-observed adverse effect level (NOAEL) for the tested tangled MWCNTs was 0.257 mg/m3 in a previous rat 28-day subacute inhalation toxicity study.


Assuntos
Poluentes Atmosféricos/toxicidade , Exposição por Inalação/efeitos adversos , Pulmão/efeitos dos fármacos , Nanotubos de Carbono/toxicidade , Aerossóis , Animais , Líquido da Lavagem Broncoalveolar/química , Relação Dose-Resposta a Droga , Meia-Vida , Exposição por Inalação/análise , Pulmão/metabolismo , Pulmão/patologia , Masculino , Neutrófilos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Testes de Toxicidade Subaguda
10.
Regul Toxicol Pharmacol ; 110: 104538, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31751640

RESUMO

Bacillus coagulans SNZ 1969 is a rod-shaped, slightly acidophilic, gram-positive, spore forming and highly resilient bacteria. B. coagulans SNZ 1969 has GRAS (Generally Recognized As Safe) status for use as a probiotic in foods (US FDA number GRN-597). The present study was aimed to assess the safety of a proprietary strain Bacillus coagulans SNZ 1969 by conducting acute and sub-acute 28 days repeated dose oral toxicity studies in Wistar Rats. In the acute toxicity study, the rats were orally fed with 2000 mg/kg body weight (BW) (5 × 1011 CFU/g) of B. coagulans SNZ 1969 as a single dose to determine the LD50 values. In the sub-acute repeated dose toxicity study, six groups of experimental rats received 250, 500, 1000 mg/kgBW/day (5 × 1011 CFU/g) of the test item for 28 consecutive days. The control animals received only water. Four groups of rats were sacrificed after 28 days and the remaining two groups were kept as recovery groups and sacrificed after 42 days. The results of these study indicate that there were no treatment related changes in any of the parameters studied i.e. clinical signs, body weight, food intake, urinalysis, hematological examinations, clinical biochemistry, gross pathology and histopathology after 28 days of repeated administration. Based on the results it was concluded that the LD50 of Bacillus coagulans SNZ 1969 is more than 2000 mg/kg body weight and the NOAEL derived from this study was 1000 mg/kg/day for 28 days, this corresponds to the 5 × 1011 CFU/kg.


Assuntos
Bacillus coagulans , Aditivos Alimentares/toxicidade , Probióticos/toxicidade , Animais , Feminino , Dose Letal Mediana , Masculino , Nível de Efeito Adverso não Observado , Ratos Wistar , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
11.
Regul Toxicol Pharmacol ; 110: 104517, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31707131

RESUMO

Green coffee oil enriched with cafestol and kahweol was obtained by supercritical fluid extraction using carbon dioxide while its safety and possible effects from acute and subacute treatment were evaluated in rats. For acute toxicity study, single dose of green coffee oil (2000 mg/kg) was administered by gavage in female rats. For subacute study (28 days), 32 male rats received different doses of green coffee oil extract (25, 50, and 75 mg/kg/day). In the acute toxicity study, main findings of this treatment indicated no mortality, body weight decrease, no changes in hematological and biochemical parameters, and relative weight increase in heart and thymus, without histopathological alterations in all assessed organs. All these findings suggest that LD50 is higher than aforesaid dose. In the subacute toxicity, main findings showed body weight decrease mainly at the highest dose without food consumption change, serum glucose and tryglicerides levels decrease, and relative weight increase in liver. As evidenced in histopathological pictures, no changes were observed at all treated doses. Our study suggest that green coffee oil can be explored to clinically develop new hypocholesteromic and hypoglycemic agents. However, further studies evaluating long-term effects are needed in order to have sufficient safety evidence for its use in humans.


Assuntos
Coffea , Diterpenos/toxicidade , Óleos Vegetais/toxicidade , Administração Oral , Animais , Feminino , Masculino , Ratos Wistar , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
12.
Mol Cell Endocrinol ; 502: 110677, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31821856

RESUMO

Organotin compounds, such as tributyltin (TBT), are common environmental contaminants and suspected endocrine-disrupting chemicals. Tributyltin is found in antifouling paints, widely used in ships and other vessels. The present study evaluated whether a 15-day treatment with TBT at a dose of 100 ng/kg/day could induce histomorphological changes in the thyroid gland of rats. TBT promoted relevant alterations in the thyroid architecture, being the most relevant histological findings the presence of increased number of small-size follicles in the treated group. In qualitative analyses, colloid vacuolization, papillary budging structures, cystic degeneration and chronic thyroiditis, were observed. Moreover, histomorphometric analysis showed statistically significant changes in the follicular architecture of TBT-treated rats, mainly a decrease in the follicle area (colloid) and an increased epithelial height that resulted in an increased epithelial height/colloid ratio. Augmented collagen deposition was also seen in the thyroids of treated groups. In immunohistochemical (IHC) analyses, the localization of NIS protein was described and a significant increased proliferation index (evaluated by Ki67 positive cells) in the treated group was reported. As an indirect measurement of oxidative stress, mitochondrial protein SDHA was also analyzed by IHC analysis. Although the cytoplasmic expression of SDHA was observed in both groups, the staining intensity score was higher in TBT-treated group. Our results suggest that besides causing histomorphological changes, environmental relevant dose of TBT treatment can also induce oxidative alterations.


Assuntos
Disruptores Endócrinos/toxicidade , Glândula Tireoide/patologia , Testes de Toxicidade Subaguda/métodos , Compostos de Trialquitina/toxicidade , Animais , Colágeno/metabolismo , Masculino , Estresse Oxidativo , Ratos , Ratos Wistar , Succinato Desidrogenase/metabolismo , Simportadores/metabolismo , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/metabolismo
13.
J Ethnopharmacol ; 248: 112324, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31644940

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Bei Qi Wu Jia (BQWJ), a modern preparation of a traditional Chinese medicinal formula, is a combination of Radix Astragali and Acanthopanacis Senticosi. Although BQWJ has been used to treat insomnia, fatigue, and loss of appetite, toxicological safety studies are rare in the literature. AIM OF THE STUDY: To evaluate the acute and subacute toxicity of BQWJ extract after oral administration in mice and rats, respectively. MATERIALS AND METHODS: In the acute toxicity study, mice underwent oral administration of 67.5 g extract/kg/day. In the subacute toxicity study, rats underwent a single oral administration of 1.25, 2.5, 5.0, or 10.0 g/kg/day of BQWJ extract for 28 days. The animals' general behavior, body weight, food intake, biochemical and hematologic parameters, organ coefficients, and pathological morphology were analyzed. RESULTS: No evidence of toxicity was observed in the mice after acute exposure to BQWJ extract. The subacute results included no deaths and no changes in general behavior. Although BQWJ extract resulted in some significant changes in other parameters, these alterations cannot be considered treatment-related because they remained within normal ranges throughout the 28 days. CONCLUSIONS: In conclusion, the oral administration of BQWJ extract at doses of less than 67.5 g/kg/day for 1 day or 10.0 g/kg/day for 28 consecutive days can be considered safe and showed no distinct toxicity or side effects in this study.


Assuntos
Medicamentos de Ervas Chinesas/toxicidade , Administração Oral , Animais , Medicamentos de Ervas Chinesas/administração & dosagem , Feminino , Masculino , Camundongos , Nível de Efeito Adverso não Observado , Ratos Sprague-Dawley , Medição de Risco , Fatores de Tempo , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
14.
Biol Trace Elem Res ; 193(2): 466-482, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31030385

RESUMO

This study aimed to compare Cd exposure by intraperitoneal (i.p.) and oral routes, evaluating the testicular subacute and subchronic effects. Adult male mice were separated into three groups subdivided according to the experimental period (7 and 42 days after Cd exposure: subacute and subchronic effects, respectively): one group received water and two groups received CdCl2 (1.2 mg/kg i.p. and 24 mg/kg oral). The testicular concentration of essential minerals and Cd, activity of antioxidant enzymes and markers of oxidative stress, histology, and testicular histomorphometry were evaluated. The subacute effect of oral Cd showed reduced Fe concentration, while Ca and Cu increased in this route. The subchronic effect promoted decreasing in Mg in i.p. and oral routes, whereas Zn decreased only in the oral, and the Fe concentration did not change. SOD activity decreased in the oral subacute evaluation and in both pathways, i.p. and oral routes, in the subchronic evaluation, while GST activity increased, and MDA concentration decreased. Labeling of apoptotic cells was increased in the subacute and subchronic evaluation. Seminiferous epithelium degeneration, death of germ cells, and Leydig cell damages occurred in i.p. and oral routes. However, these damages were more intense in the oral route, mainly evaluating the subchronic effects. The results confirm that the severity of Cd-induced testicular injury depends on the pathway, as well as the duration of exposure.


Assuntos
Cádmio/toxicidade , Testículo/efeitos dos fármacos , Testes de Toxicidade Subaguda/métodos , Testes de Toxicidade Subcrônica/métodos , Administração Oral , Animais , Cádmio/administração & dosagem , Cálcio/metabolismo , Catalase/metabolismo , Cobre/metabolismo , Injeções Intraperitoneais , Ferro/metabolismo , Magnésio/metabolismo , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Testículo/metabolismo , Testículo/patologia , Zinco/metabolismo
15.
Andrologia ; 52(1): e13450, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31692026

RESUMO

The unclear bio-safety issue and potential risk of nanoparticles (NPs) on various organelles can be considered as a major challenge. In the present study, we have assessed the green synthesis of ZnO nanoparticles using Hyssop (Hyssopus officinalis) extract and their effects on PC3 cell line and BALB/c mice model. The cytotoxicity of the ZnO-NPs was assessed on PC3 cell line by MTT test after characterisation. Apoptotic effect of ZnO-NPs was determined by in vitro AO/PI staining. The histopathological assessments and determination of LH and FSH levels carried out as in vivo analysis in BALB/c adult male mice. The expression of major genes involved in spermatogenesis and sperm maturation (Adam3, Prm1, Spata19, Tnp2, Gpx5) were also analysed. The obtained result demonstrated that the IC50 for PC3 cell line treated with green-synthesised ZnO-NPs during 24 and 48 hr was reported 8.07 and 5 µg/ml respectively. Meanwhile, the induced apoptosis was recorded 26.6% ± 0.05, 44% ± 0.12 and 80% ± 0.07 of PC3 cells. The results of gene expression analysis revealed that the increase in the concentration of ZnO-NPs significantly (p < .05) down-regulated the Adam3, Prm1, Spata-19, Tnp2 and Gpx5 genes. The overall results of this research elucidated that ZnO-NPs impaired spermatogenesis, sperm maturation process and sperm motility.


Assuntos
Nanopartículas Metálicas/efeitos adversos , Neoplasias da Próstata/tratamento farmacológico , Espermatogênese/efeitos dos fármacos , Testículo/efeitos dos fármacos , Óxido de Zinco/efeitos adversos , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Química Verde/métodos , Humanos , Hyssopus/química , Concentração Inibidora 50 , Masculino , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/química , Camundongos , Camundongos Endogâmicos BALB C , Extratos Vegetais/química , Folhas de Planta/química , Próstata/citologia , Próstata/efeitos dos fármacos , Neoplasias da Próstata/patologia , Motilidade Espermática/efeitos dos fármacos , Testículo/patologia , Testes de Toxicidade Subaguda , Óxido de Zinco/administração & dosagem , Óxido de Zinco/síntese química
16.
Regul Toxicol Pharmacol ; 109: 104508, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31672509

RESUMO

The phenothiazine-derived antipsychotic drugs, such as chlorpromazine and thioridazine, are bactericidal against drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis, but produce undesirable side effects at clinically relevant doses. We have previously modified four novel phenothiazines and maintained their antimycobacterial activity. This study evaluated the pharmacological and toxicity profiles of these novel non-neuroleptic phenothiazines, PTZ3, PTZ4, PTZ31 and PTZ32, for their metabolic stability, kinetic solubility and potential cytotoxic effects in vitro. To further support the safet use of these drug candidates, the in vivo pharmacological and toxicity profiles were assessed in C57BL/6 mice via single or repeated oral gavage. In acute toxicity studies, all four modified phenothiazines showed favourable safety in mice. When treated daily with 100 mg/kg of PTZ3 and PTZ4 for 2 weeks, mice displayed no signs of toxicity. Alternatively, treatment with PTZ31 resulted in 20% mortality with no toxicity evident in biochemical or histological analysis, while exposure to PTZ32 resulted in a 45% survival with increased serum concentrations of uric acid and alkaline phosphatase. The combined non-neuroleptic and antimycobacterial effects of the novel phenothiazines PTZ3, PTZ4, PTZ31 and PTZ32 demonstrated favourable pharmacological and toxicity profiles in this study, highlight the potential of these compounds as suitable anti-tuberculosis drug candidates.


Assuntos
Antituberculosos/toxicidade , Macrófagos/efeitos dos fármacos , Fenotiazinas/toxicidade , Animais , Antituberculosos/administração & dosagem , Células Cultivadas , Feminino , Camundongos , Fenotiazinas/administração & dosagem , Cultura Primária de Células , Tioridazina/administração & dosagem , Tioridazina/toxicidade , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
17.
Regul Toxicol Pharmacol ; 109: 104486, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31580888

RESUMO

Artemisinin-piperaquine tablet (trade name Artequick, ATQ), is a novel combination therapy for the treatment of malaria and especially for resistant P.falciparum malaria. The aim of our study was to assess the potential sub-acute toxicity profile of ATQ by oral administration route in rhesus monkeys. Monkeys were administrated once daily with doses of ATQ (39.1, 78.2, 156.4 mg/kg) for 21 days and then followed-up a 56-day recovery period. The administration of ATQ at high dose produced significant changes in the clinical signs primarily involved in gastrointestinal and nervous systems. Body weight loss, significant decrease in food consumption and body temperature were observed in monkeys at high dose. Various hematological and biochemical parameters changes, and significant pathological lesions (adrenal gland, thymus and femur epiphyseal) were observed in the middle and high dose group at the end of the treatment period. However, the toxic effects of ATQ were reversed and delayed adverse drug reaction did not occur during the recovery period. Based on the results of this study, the no-observed-adverse-effect level for ATQ was considered to be 39.1 mg/kg in rhesus monkeys.


Assuntos
Antimaláricos/toxicidade , Artemisininas/toxicidade , Trato Gastrointestinal/efeitos dos fármacos , Sistema Nervoso/efeitos dos fármacos , Quinolinas/toxicidade , Administração Oral , Animais , Antimaláricos/administração & dosagem , Artemisininas/administração & dosagem , Temperatura Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Comportamento Alimentar/efeitos dos fármacos , Feminino , Macaca mulatta , Masculino , Nível de Efeito Adverso não Observado , Quinolinas/administração & dosagem , Comprimidos , Testes de Toxicidade Subaguda , Perda de Peso/efeitos dos fármacos
18.
Toxicol Appl Pharmacol ; 384: 114770, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31628919

RESUMO

The aim of the study was to evaluate the time course of the effects of urban air pollutants on the ocular surface, focusing on the morphological changes, the redox balance, and the inflammatory response of the cornea. 8-week-old mice were exposed to urban or filtered air (UA-group and FA-group, respectively) in exposure chambers for 1, 2, 4, and 12 weeks. After each time, the eyes were enucleated and the corneas were isolated for biochemical analysis. UA-group corneas exhibited a continuous increase in NADPH oxidase-4 levels throughout the exposure time, suggesting an increased production of reactive oxygen species (ROS). After 1 week, an early adaptive response to ROS was observed as an increase in antioxidant enzymes. After 4 weeks, the enzymatic antioxidants were decreased, meanwhile an increase of the glutathione was shown, as a later compensatory antioxidant response. However, redox imbalance took place, evidenced by the increased oxidized proteins, which persisted up to 12 weeks. At this time point, corneal epithelium hyperplasia was also observed. The inflammatory response was modulated by the increase in IL-10 levels after 1 week, which early regulates the release of TNF-α and IL-6. These results suggest that air pollution alters the ocular surface, supported by the observed cellular hyperplasia. The redox imbalance and the inflammatory response modulated by IL-10 play a key role in the response triggered by air pollutants on the cornea. Taking into account this time course study, the ocular surface should also be considered as a relevant target of urban air pollutants.


Assuntos
Poluentes Atmosféricos/toxicidade , Poluição do Ar/efeitos adversos , Epitélio Anterior/patologia , Animais , Brasil , Cidades , Epitélio Anterior/efeitos dos fármacos , Hiperplasia/induzido quimicamente , Hiperplasia/patologia , Interleucina-10/metabolismo , Masculino , Camundongos , NADPH Oxidase 4/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fatores de Tempo , Testes de Toxicidade Subaguda , Testes de Toxicidade Subcrônica
19.
Regul Toxicol Pharmacol ; 109: 104506, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31655093

RESUMO

Throughout history, the only way humans could raise their blood ketone levels was by several days of fasting or by following a strict low-carb, high-fat diet. A recently developed, dietary source of ketones, a ketone monoester, elevates d-ß-hydroxybutyrate (ßHB) to similar concentrations within minutes, with ßHB remaining raised for several hours. To date, the longest human safety study of the exogenous ketone ester was for 5 days, but longer consumption times may be desired. Here we report results for 24 healthy adults, aged 18-70 years, who drank 25 ml (26.8 g) of the ketone monoester, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, three times a day for 28 days (a total of 2.1 L). Anthropomorphic measurements, plus fasting blood and urine analyses were made weekly. It was found that elevating blood ßHB concentrations from 0.1 to 4.1 (±1.1) mM three times a day for 28 days had no effect on body weights or composition, fasting blood glucose, cholesterol, triglyceride or electrolyte concentrations, nor blood gases or kidney function, which were invariably normal. Mild nausea was reported following 6 of the 2,016 drinks consumed. We conclude that sustained exogenous ketosis using a ketone monoester is safe and well-tolerated by healthy adults.


Assuntos
Doença Crônica/terapia , Suplementos Nutricionais/toxicidade , Ésteres/toxicidade , Hidroxibutiratos/toxicidade , Cetonas/toxicidade , Adolescente , Adulto , Idoso , Dieta Cetogênica , Ésteres/administração & dosagem , Jejum , Voluntários Saudáveis , Humanos , Hidroxibutiratos/administração & dosagem , Cetonas/administração & dosagem , Cetose/sangue , Cetose/induzido quimicamente , Cetose/urina , Masculino , Pessoa de Meia-Idade , Testes de Toxicidade Subaguda/métodos , Adulto Jovem
20.
Nutrients ; 11(9)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31500145

RESUMO

The objective of this study was to determine the acute (one single dose), subacute (14 days), and sub-chronic (90 days) toxicity of an aqueous virgin olive oil (VOO) extract rich in hydroxytyrosol in rats. For acute/subacute toxicity, rats were divided into three groups. The control group received distilled water (n = 9), another experimental group received a single dose of 300 mg/kg (n = 3), and a third group received one dose of 2000 mg/kg (n = 4) during 14 days. The sub-chronic study included 60rats distributed in three groups (n = 20: 10 males and 10 females) receiving daily different three doses of the VOO extract in the drinking water during 90 days: (1) 100 mg/kg, (2) 300 mg/kg, and (3) 1000 mg/kg. In parallel, a fourth additional group (n = 20: 10 males and 10 females) did not receive any extract (control group). Clinical signs, body weight, functional observations of sensory and motor reactivity, hematological and biochemical analyses, and macroscopic and microscopic histopathology were evaluated. No adverse effects were observed after the administration of the different doses of the hydroxytyrosol-rich VOO extract, which suggests that the enrichment of VOO in its phenolic compound is safe, and can be used as functional foods for the treatment of chronic degenerative diseases.


Assuntos
Azeite de Oliva/toxicidade , Álcool Feniletílico/análogos & derivados , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda , Testes de Toxicidade Subcrônica , Animais , Feminino , Masculino , Nível de Efeito Adverso não Observado , Álcool Feniletílico/toxicidade , Ratos Wistar , Medição de Risco , Fatores de Tempo
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