RESUMEN
ETHNOPHARMACOLOGY RELEVANCE: Palm buds are a natural green resource of the forest, which are not only rich in nutrients but contain a large number of phenolic acids and flavonoids, among other components. It has a variety of biological activities such as antioxidant and uterine smooth muscle stimulation. AIM OF THE STUDY: To evaluate the safety of palm buds for use as a nutraceutical product and food by evaluating the toxicity, subacute toxicity and genotoxicity of the young palm buds. Also studied for its immune-enhancing activity. MATERIALS AND METHODS: Acute toxicity tests were performed in mice using the maximum tolerance method, and the manifestations of toxicity and deaths were recorded after administration of 10,000 mg/mL for 14 consecutive d (days) of observations. To assess subacute toxicity, mice were treated with palm buds (750, 1500, or 3000 mg/mL) daily for 28 days. The teratogenicity of palm buds was assessed by the Ames test, the mouse bone marrow cell micronucleus test, and the mouse spermatozoa malformation test. In addition, we evaluated the immune-enhancing ability of palm buds by the mouse carbon profile test, delayed-type metamorphosis reaction, and serum hemolysin assay. RESULTS: In the acute toxicity study, the Median Lethal Dose (LD50) was greater than 10,000 mg/kg bw in both male and female rats. There were also no deaths or serious toxicities in the subacute study. The no-observed-adverse-effect level (NOAEL) was 3000 mg/kg bw. However, the mice's food intake decreased after one week. The medium and high dose groups had a reducing effect on body weight in mice of both sexes. In addition, the changes in organ coefficients of the liver, kidney and stomach in male mice were significantly higher in the high-dose group (3.23 ± 0.35, 0.75 ± 0.05, 0.57 ± 0.05 g) than in the control group (2.94 ± 0.18, 0.58 ± 0.05, 0.50 ± 0.02 g). Hematological analyses showed that all the indices of the rats in each palm sprout dose group were within the normal range. The results of blood biochemical indicators showed that there was a significant reduction in TP in the blood of male mice in the high-dose group (44.6 ± 7.8 g/L) compared to the control group (58.3 ± 15.1 g/L). In histopathological analysis, none of the significant histopathological changes were observed. The results of the immunological experiment in mice showed that the liver coefficient and thymus coefficient of the high-dose group (8400 mg/kg) were significantly lower than the control group. There was no remarkable difference in auricle swelling between each dose palm bud group (1400, 2800, or 8400 mg/kg) and the control group. The anti-volume number of the high-dose group was significantly increased. CONCLUSION: Palm buds have non-toxic effects in vivo and have little effect on non-specific and cellular immunity in the test mice within the dose range of this experiment. The immunoenhancement in mice is mainly achieved through humoral immunity. In conclusion, our results suggest that palm buds are safe for use as healthcare products and food.
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Arecaceae , Pruebas de Toxicidad Aguda , Animales , Femenino , Masculino , Arecaceae/química , Ratones , Extractos Vegetales/toxicidad , Extractos Vegetales/farmacología , Extractos Vegetales/administración & dosificación , Factores Inmunológicos/toxicidad , Ratas , Pruebas de Toxicidad Subaguda , Relación Dosis-Respuesta a Droga , Pruebas de Micronúcleos , Pruebas de Mutagenicidad , Proteínas Hemolisinas/toxicidad , Dosificación Letal MedianaRESUMEN
The Ames test is used worldwide to initially screen the mutagenic potential of new chemicals. In the standard Ames test, S. typhimurium strains (TA100, TA98, TA1535, and TA1537) and Escherichia coli (WP2uvrA) are treated with substances with/without cytochrome P450s (CYPs)-induced rat S9 fractions for identifying mutagens and pro-mutagens. However, many substances show completely different toxicity patterns depending on whether the liver S9 fraction belongs to rats or humans. The natural product Polygoni Multiflori Radix (PMR) can also show bacterial reverse mutation, followed by the rat or human liver S9 fraction. While PMR elicits reverse mutations in the TA1537 strain in rat liver S9 but not in human liver S9, this mechanism has not been verified yet. To explain this, the differences in metabolic enzymes compositions commonly observed between rats and humans have been implicated. This study aimed to explore the key factors that cause differences in the genotoxicity of PMR between rat and human liver S9 metabolic enzymes. The results of next-generation sequencing (NGS) analysis showed that both rat and human metabolic enzymes caused similar mutations in TA1537. However, when the metabolic enzymes in each S9 fraction were analyzed using ion mobility tandem mass spectrometry (IM-MS), rat- and human-specific enzymes were identified among the cytochrome (CYP) family, especially aryl hydrocarbon receptor (AHR)-related CYPs. These findings suggest that CYP1A1 isoforms contribute to the mechanism of PMR in the Ames test. Therefore, an in vitro Ames test might be more reliable in predicting genotoxicity for both rodents and humans. This will also help overcome the limitations of laboratory animal-based toxicity evaluations, which provide unreliable results due to interspecies differences between humans and rodents.
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Pruebas de Mutagenicidad , Mutágenos , Salmonella typhimurium , Animales , Humanos , Pruebas de Mutagenicidad/métodos , Ratas , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genética , Mutágenos/toxicidad , Hígado/efectos de los fármacos , Hígado/metabolismo , Activación Metabólica , Escherichia coli/genética , Escherichia coli/efectos de los fármacos , Escherichia coli/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Sistema Enzimático del Citocromo P-450/genética , Mutación , Daño del ADN/efectos de los fármacos , Fallopia multiflora/química , MasculinoRESUMEN
The assessment of mutagenicity is essential in drug discovery, as it may lead to cancer and germ cells damage. Although in silico methods have been proposed for mutagenicity prediction, their performance is hindered by the scarcity of labeled molecules. However, experimental mutagenicity testing can be time-consuming and costly. One solution to reduce the annotation cost is active learning, where the algorithm actively selects the most valuable molecules from a vast chemical space and presents them to the oracle (e.g., a human expert) for annotation, thereby rapidly improving the model's predictive performance with a smaller annotation cost. In this paper, we propose muTOX-AL, a deep active learning framework, which can actively explore the chemical space and identify the most valuable molecules, resulting in competitive performance with a small number of labeled samples. The experimental results show that, compared to the random sampling strategy, muTOX-AL can reduce the number of training molecules by about 57%. Additionally, muTOX-AL exhibits outstanding molecular structural discriminability, allowing it to pick molecules with high structural similarity but opposite properties.
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Aprendizaje Profundo , Mutágenos , Mutágenos/toxicidad , Mutágenos/química , Humanos , Pruebas de Mutagenicidad/métodos , Algoritmos , Descubrimiento de Drogas/métodos , Simulación por ComputadorRESUMEN
Olive mill wastewater (OMWW), with its high level of phenolic compounds, simultaneously represents a serious environmental challenge and a great resource with potential nutraceutical activities. To increase the knowledge of OMWW's biological effects, with an aim to developing a food supplement, we performed a chemical characterisation of the extract using the Liquid Chromatography-Quadrupole Time-of-flight spectrometry (LC-QTOF) and an in vitro genotoxicity/antigenotoxicity assessment on HepaRG ™ cells. Chemical analysis revealed that the most abundant phenolic compound was hydroxytyrosol. Biological tests showed that the extract was not cytotoxic at the lowest tested concentrations (from 0.25 to 2.5 mg/mL), unlike the highest concentrations (from 5 to 20 mg/mL). Regarding genotoxic activity, when tested at non-cytotoxic concentrations, the extract did not display any effect. Additionally, the lowest tested OMWW concentrations showed antigenotoxic activity (J-shaped dose-response effect) against a known mutagenic substance, reducing the extent of DNA damage in the co-exposure treatment. The antigenotoxic effect was also obtained in the post-exposure procedure, although only at the extract concentrations of 0.015625 and 0.03125 mg/mL. This behaviour was not confirmed in the pre-exposure protocol. In conclusion, the present study established a maximum non-toxic OMWW extract dose for the HepaRG cell model, smoothing the path for future research.
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Daño del ADN , Olea , Aguas Residuales , Aguas Residuales/toxicidad , Aguas Residuales/química , Humanos , Olea/química , Daño del ADN/efectos de los fármacos , Línea Celular , Extractos Vegetales/toxicidad , Extractos Vegetales/química , Pruebas de Mutagenicidad , Fenoles/toxicidad , Fenoles/análisis , Mutágenos/toxicidadRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Abutilon indicum, a shrub of the Malvaceae family, is found abundantly in tropical countries like India. A. indicum is widely used for its high medicinal properties. Traditionally, A. indicum seed powder is consumed to treat piles, constipation, chronic cystitis, gonorrhea, gleet, and pregnancy-related problems. Despite having numerous medicinal properties and widespread traditional use of A. indicum seeds, scientific validation, and toxicity studies have yet to be documented. AIMS OF THE STUDY: The primary objective of this study is to conduct a comprehensive study on phytochemical profiling, in-vitro cytotoxicity, mutagenicity, and in-vivo acute and sub-acute toxicity, and genotoxicity on animal models of methanolic extract of A. indicum seed (MAS). MATERIALS AND METHODS: The qualitative analysis of MAS was explored through FTIR and HR LC-MS. For in-vitro cytotoxicity, the HEK-293 cell line was used, and the TA100 (Staphylococcus typhimurium) bacterial strain was used for the Ames mutagenicity test. A single oral dose of 250, 500, 1000, or 2000 mg/kg body weight of MAS was given to each male and female rat for acute toxicity study and observed for 14 days for any toxicity signs. In the sub-acute toxicity study, 250, 500, or 1000 mg/kg body weight of MAS was administered orally to each rat for 28 days. The experimental animals were weighed weekly, and general behavior was monitored regularly. After 28 days of the experiment, the rats were sacrificed, and different serum biochemical, hematological, and histological analyses were performed. The blood samples of different doses of MAS were used for genotoxicity study through comet assay. RESULTS: FTIR analysis found different functional groups, which indicated the presence of phenolics, flavonoids, and alkaloids. HR LC-MS analysis depicts several components with different biological functions. The cell cytotoxicity and Ames mutagenicity results showed minimal toxicity and mutagenicity up to a certain dose. The acute toxicity study conducted in Wistar albino rats demonstrated zero mortality among the animals, and the LD50 value for seed extract was determined to be 2000 mg/kg body weight. Sub-acute toxicity assessments indicated that the administration of seed extract resulted in no adverse effects at dosages of 250 and 500 mg/kg body weight. However, at higher doses, specifically 1000 mg/kg body weight, the liver of the experimental rats exhibited some toxic effects. In the genotoxicity study, minimal DNA damage was found in 250 and 500 mg/kg doses, respectively, but slightly greater DNA damage was found in 1000 mg/kg doses in both male and female rats. CONCLUSIONS: The consumption of A. indicum seed powder is deemed safe; however, doses exceeding 500 mg/kg body weight may raise concerns regarding use. These findings pave the path for the creation of innovative medicines with improved efficacy and safety profiles.
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Malvaceae , Pruebas de Mutagenicidad , Extractos Vegetales , Semillas , Animales , Extractos Vegetales/toxicidad , Extractos Vegetales/administración & dosificación , Femenino , Semillas/química , Masculino , Humanos , Ratas , Células HEK293 , Malvaceae/química , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genética , Metanol/química , Pruebas de Toxicidad Aguda , Relación Dosis-Respuesta a Droga , Supervivencia Celular/efectos de los fármacos , Ratas Wistar , Ratas Sprague-DawleyRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Valeriana officinalis L., commonly known as "valerian", is a traditional herbal medicine distributed in the north temperate zones of America, Europe and Asia. In traditional Chinese medicine, valerian and its roots were used for the treatment of restlessness of the heart and mind, palpitation and insomnia caused by internal depression of emotions and moods. However, safety evaluation of valerian remains deeply unclear. AIM OF THE STUDY: This study aimed to evaluate the genotoxicity, 14-days acute oral toxicity test, 90-day subchronic oral toxicity test and teratogenicity test of aqueous extract of valerian root (AEVR). MATERIALS AND METHODS: The genotoxicity of AEVR was evaluated with bacterial reverse mutation, mouse erythrocyte micronucleus test and in vitro mammalian cell chromosome aberration test. In the 14-days acute toxicity study, Kunming mice were administered at a dosage of 96 g/kg body weigh by gavage. In the 90-day subchronic toxicity study, Sprague-Dawley rats received oral doses of 0, 3.5, 7 and 14 g/kg body weight of AEVR. In the teratogenicity study, pregnant Sprague-Dawley rats received a dose of 0, 3.5, 7 and 14 g/kg body weight of AEVR. RESULTS: AEVR did not show any genotoxicity based on the bacterial reverse mutation, mouse erythrocyte micronucleus test and in vitro mammalian cell chromosome aberration test. In the acute toxicity study, AEVR at a dose of 96 g/kg body weight did not cause death or abnormal behavior in male or female mice. In the subchronic toxicity study, at the doses of 0, 3.5, 7, 14 g/kg body weight, no dose-related effects on clinical observation, body weight, organ weight, hematology, serum biochemistry and urinalysis of AEVR were detected in male or female rats. Teratogenicity test shown that there were no significant toxicologically changes in embryonic formation, body weight of pregnant rats, external, skeletal and visceral examination observed in pregnant and fetal rats at the dosage of 0, 3.5, 7, 14 g/kg body weight. CONCLUSION: In vivo or in vitro assays demonstrated that AEVR does not exhibit genotoxicity. The LD50 of AEVR was greater than 96 g/kg body weight in both sex of mice according to acute oral toxicity study. Subchronic toxicity and teratogenicity tests showed that the no observed adverse effect level (NOAEL) of AEVR was no less than 14 g/kg body weight. This study established a non-toxic dose of AEVR, providing a foundation for the use of valerian as a new resource food in some countries and regions.
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Pruebas de Mutagenicidad , Extractos Vegetales , Raíces de Plantas , Ratas Sprague-Dawley , Pruebas de Toxicidad Aguda , Pruebas de Toxicidad Subcrónica , Valeriana , Animales , Masculino , Femenino , Extractos Vegetales/toxicidad , Extractos Vegetales/administración & dosificación , Valeriana/química , Ratones , Aberraciones Cromosómicas , Ratas , Pruebas de Micronúcleos , Relación Dosis-Respuesta a Droga , Cricetulus , Embarazo , Células CHO , Animales no ConsanguíneosRESUMEN
In the present study, the effects of levamlodipine benzenesulfonate on the development of fertile Sprague-Dawley (SD) rats, their embryos, and littermates were assessed using an embryo-fetal developmental toxicity test. Maternal body weight reduction was observed at a dose of 20â¯mg/kg, but it recovered after treatment cessation. The 20â¯mg/kg dose group showed a skewed sex ratio in fetal rats, with a higher proportion of males. While some effects on fetal sternum development were observed at 20â¯mg/kg, no skeletal malformations were observed. No significant gross morphological abnormalities were detected in the dams (mothers), no significant embryotoxicity or foetotoxicity in fetal rats and no significant effects on fetal length and weight development at doses of 5 and 10â¯mg/kg. Genotoxicity was evaluated using a combination of the Ames test, the Chinese hamster ovary (CHO) cell chromosome aberration assay, and the ICR mouse bone marrow micronucleus test. The Ames test results indicated substantial bacteriostatic effects at doses of 500 and 5000â¯mg/dish, with no mutagenicity observed at doses of 0.5, 5, and 50â¯mg/dish. No significant effect on the aberration rate of CHO cell chromosomes was found at doses of 2.8, 5.6, and 11.2â¯mg/mL. In the ICR mouse micronucleus test, no micronucleus-inducing effect was observed at doses of 3.125, 6.25, and 12.5â¯mg/kg in each treatment group. In conclusion, under the conditions of this experiment, the no-observed-adverse-effect level (NOAEL) for developmental toxicity of levamlodipine benzenesulfonate in fertile SD rats, their embryos, and littermates was established to be 10â¯mg/kg/day. Levamlodipine benzenesulfonate did not exhibit significant genotoxicity.
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Aberraciones Cromosómicas , Cricetulus , Pruebas de Mutagenicidad , Ratas Sprague-Dawley , Animales , Femenino , Masculino , Células CHO , Ratas , Cricetinae , Ratones , Embarazo , Aberraciones Cromosómicas/inducido químicamente , Ratones Endogámicos ICR , Pruebas de Micronúcleos , Relación Dosis-Respuesta a Droga , Desarrollo Embrionario/efectos de los fármacos , Desarrollo Fetal/efectos de los fármacos , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genética , Razón de Masculinidad , Peso Corporal/efectos de los fármacos , Mutágenos/toxicidadRESUMEN
Natural non-psychoactive cannabinoids such as cannabigerol (CBG), cannabidiol (CBD), cannabichromene (CBC), cannabidivarin (CBDV), and cannabinol (CBN) are increasingly consumed as constituents of dietary products because of the health benefits claims. Cannabinoids may reduce certain types of pain, nausea, and anxiety. Anti-inflammatory and even anti-carcinogenic properties have been discussed. However, there are insufficient data available regarding their potential (geno-)toxic effects. Therefore, we tested CBG, CBD, CBC, CBDV, and CBN for their genotoxic potential and effects on mitosis and cell cycle in human lymphoblastoid TK6 cells. The selected cannabinoids (except CBDV) induced increased micronuclei formation, which was reduced with the addition of a metabolic activation system (S9 mix). CBDV induced micronuclei only after metabolic activation. Mitotic disturbances were observed with all tested cannabinoids, while G1 phase accumulation of cells was observed for CBG, CBD and CBDV. The genotoxic effects occurred at about 1000-fold higher concentrations than are reported as blood levels from human consumption. However, the results clearly indicate a need for further research into the genotoxic effects of cannabinoids. The mechanism of the mitotic disturbance, the shape of the dose-response curves and the possible effects of mixtures of cannabinoids are aspects which need clarification.
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Cannabinoides , Linfocitos , Pruebas de Micronúcleos , Mitosis , Mutágenos , Humanos , Cannabinoides/toxicidad , Mitosis/efectos de los fármacos , Linfocitos/efectos de los fármacos , Línea Celular , Mutágenos/toxicidad , Ciclo Celular/efectos de los fármacos , Micronúcleos con Defecto Cromosómico/inducido químicamente , Relación Dosis-Respuesta a Droga , Daño del ADN/efectos de los fármacos , Pruebas de Mutagenicidad , Cannabidiol/toxicidadRESUMEN
Phillyrin is extracted from Forsythia suspensa (Thunb.) Vahl, is significantly higher in (unripe Forsythiae Fructus) Qing qiao than in (ripe Forsythiae Fructus) Lao qiao fruits of the plant. However, the toxicity of phillyrin has not been adequately investigated. The study investigates the genetic and teratogenic effects of phillyrin to determine its safety profile. Assessing the genotoxicity and teratogenicity of phillyrin involved various tests, such as the bacterial reverse mutation assay, mammalian erythrocyte micronucleus assay, spermatocyte chromosome aberration assay, and teratogenicity assay. The results demonstrated that phillyrin exhibited no discernible impact on the following: number of colonies that spontaneously revert for Salmonella typhimurium TA 97, TA98, TA100, TA102, and TA1535, frequency of bone marrow polychromatic erythrocytes, and the rate of chromosomal aberrations. In the teratogenicity test, the pregnant rats exhibited no signs of toxicity or abnormal changes, and the growth, embryonic development, and visual anatomy of each pup were normal. In comparison with the negative control group, there were no significant differences in fetal body weight, mortality, deformity rate, malformed nest rate, gravid uterus weight, average number of fetuses per litter, fetal body length, or visceral and skeletal development in each dose group. In conclusion, these findings provide evidence that phillyrin does not exhibit genotoxic or teratogenic effects, supporting its potential safety for pharmacological applications.
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Aberraciones Cromosómicas , Pruebas de Mutagenicidad , Teratógenos , Animales , Femenino , Masculino , Teratógenos/toxicidad , Ratas , Aberraciones Cromosómicas/inducido químicamente , Ratones , Pruebas de Micronúcleos , Embarazo , Ratas Sprague-Dawley , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genética , GlucósidosRESUMEN
Artemia is a brine shrimp genus adapted to extreme habitats like ranges salinity from 5-25 g/L and in temperatures from 9 to 35 °C. It is widely distributed and used as an environmental quality biomarker. Artemia franciscana and Artemia salina species are commonly used in ecotoxicological studies and genotoxicity assays due to their short life cycle, high fecundity rate, easy culture, and availability. Thus, considering the importance of these tests in ecotoxicological studies, the present study aimed to present Artemia genus as a biological model in genotoxicity research. To this end, we reviewed the literature, analyzing data published until July 2023 in the Web of Science, SCOPUS, Embase, and PubMed databases. After screening, we selected 34 studies in which the genotoxicity of Artemia for various substances. This review presents the variability of the experimental planning of assays and biomarkers in genotoxicity using Artemia genus as a biological model for ecotoxicological studies and show the possibility of monitoring biochemical alterations and genetic damage effects. Also highlight innovative technologies such as transcriptomic and metabolomic analysis, as well as studies over successive generations to identify changes in DNA and consequently in gene expression.
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Artemia , Ecotoxicología , Pruebas de Mutagenicidad , Artemia/efectos de los fármacos , Animales , Daño del ADN , Contaminantes Químicos del Agua/toxicidad , Mutágenos/toxicidadRESUMEN
In the present study, we investigated the genotoxicity of the active products formed from N-nitrosoproline (NPRO) dissolved in oleic acid following ultraviolet A (UVA) irradiation, bypassing the need for metabolic activation. We previously demonstrated the photomutagenicity of NPRO dissolved in a phosphate-buffered solution. It has been suggested that the association of the nitrosamine group with acid ions facilitates rapid photodissociation and photoactivation. We hypothesized that NPRO's inherent carboxyl group may mimic an acid, inducing photodissociation and photomutagenicity, even in a non-aqueous solvent lacking acidic ions. Following UVA irradiation, NPRO dissolved in oleic acid exhibited a dose-dependent mutagenic activity. Similar results were obtained when NPRO was dissolved in linoleic acid and triolein. Nitric oxide formation, which is dependent on NPRO concentration, is accompanied by mutagenic activity. The mutagenicity spectrum obtained in response to NPRO irradiation followed the absorption curve of NPRO dissolved in oleic acid. Irradiated NPRO in oleic acid displayed relative stability, retaining approximately 18, 36, and 63 % of initial mutagenicity after 10 days of storage at 25, 4, and -20 °C, respectively. Thus NPRO stored in a fatty environment undergoes photoactivation upon irradiation, leading to genotoxicity.
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Pruebas de Mutagenicidad , Ácido Oléico , Solventes , Rayos Ultravioleta , Ácido Oléico/química , Solventes/química , Mutágenos/química , Mutágenos/toxicidad , Óxido Nítrico/química , Óxido Nítrico/metabolismo , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genética , Salmonella typhimurium/efectos de la radiaciónRESUMEN
In vitro and in silico tests were used to assess the possible genotoxicity and mutagenicity of five impurities that may be present in levothyroxine, a drug used for thyroid hormone replacement therapy. Neither ToxTree nor VEGA (Virtual Models for evaluating the properties of chemicals within a global architecture) identified cause for concern for any of the impurities. Ames test results (doses up to 1â¯mg per plate), with or without metabolic activation, were negative. The micronucleus test with TK6 (human lymphoblastoid) cells, at doses up to 500 µg/mL, with or without metabolic activation, also gave negative results.
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Pruebas de Micronúcleos , Pruebas de Mutagenicidad , Tiroxina , Humanos , Pruebas de Micronúcleos/métodos , Pruebas de Mutagenicidad/métodos , Contaminación de Medicamentos , Mutágenos/toxicidad , Línea Celular , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genéticaRESUMEN
Nitrosamine drug substance related impurities or NDSRIs can be formed if an active pharmaceutical ingredient (API) has an intrinsic secondary amine that can undergo nitrosation. This is a concern as 1) nitrosamines are potentially highly potent carcinogens, 2) secondary amines in API are common, and 3) NDSRIs that might form from such secondary amines will be of unknown carcinogenic potency. Approaches for evaluating NDSRIs include read across, quantum mechanical modeling of reactivity, in vitro mutation data, and transgenic in vivo mutation data. These approaches were used here to assess NDSRIs that could potentially form from the drugs fluoxetine, duloxetine and atomoxetine. Based on a read across informed by modeling of physicochemical properties and mechanistic activation from quantum mechanical modeling, NDSRIs of fluoxetine, duloxetine, and atomoxetine were 10-100-fold less potent compared with highly potent nitrosamines such as NDMA or NDEA. While the NDSRIs were all confirmed to be mutagenic in vitro (Ames assay) and in vivo (TGR) studies, the latter data indicated that the potency of the mutation response was ≥4400 ng/day for all compounds-an order of magnitude higher than published regulatory limits for these NDSRIs. The approaches described herein can be used qualitatively to better categorize NDSRIs with respect to potency and inform whether they are in the ICH M7 (R2) designated Cohort of Concern.
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Clorhidrato de Atomoxetina , Clorhidrato de Duloxetina , Fluoxetina , Pruebas de Mutagenicidad , Clorhidrato de Duloxetina/toxicidad , Clorhidrato de Atomoxetina/toxicidad , Fluoxetina/toxicidad , Animales , Nitrosaminas/toxicidad , Mutágenos/toxicidad , Humanos , RatonesRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Cordyceps militaris, a traditional medicinal fungus, parasitizes the intestines of lepidopteron pupae or larvae, predominantly during the winter, and undergoes fruiting in the summer or autumn. Compounds extracted from C. militaris have demonstrated a broad spectrum of pharmacological effects, including antioxidant, anti-tumor, anti-metastatic, anti-inflammatory, antiviral, anti-diabetic, and various others. AIM OF THE STUDY: Herein, our study aimed at elucidating the acute, sub-acute toxicity, and genotoxicity profiles of C. militaris methanolic extract following oral administration in Swiss albino mice, representing the inaugural comprehensive exploration of the toxicological and safety profiles of C. militaris. MATERIALS AND METHODS: Prior studies have predominantly focused on its biological activities rather than its toxicity. Acute oral toxicity study was conducted at 500, 1000, and 2000 mg/Kg B.W. doses of C. militaris over a 14-day period. For sub-acute toxicity study, three groups of mice were administered 100, 300, and 600 mg/Kg B.W. of C. militaris extract for 28 consecutive days; one group served as a control. Mice were monitored for their body weight and behavioural changes once daily. Hematological, serum biochemical, histopathological, histomorphometric, seminal parameters, and mutagenic investigations were performed post-treatment period. RESULTS: Acute oral toxicity study at 2000 mg/Kg revealed no signs of toxicity, with an LD50 value surpassing 2000 mg/Kg. No occurrences of mortality observed, and no significant changes were noted in body weight, organ weight, or behaviour. Hematological analysis illustrated a marked upsurge in RBC, Hb, HCT, PLT, MPV, and PCT, alongside minor variations in differential leucocyte count post 28-day treatment. Liver enzyme tests indicated slight elevation in ALP, while renal enzyme tests showed alterations in CRE and BUN levels. Genotoxicity profile and histopathological assessments of the liver, spleen, testis, and ovary manifested no remarkable irregularities, except for mild renal toxicity. Seminal parameters including sperm concentration, motility and testosterone levels demonstrated a noteworthy increase. CONCLUSIONS: The study sheds light on the potential risks and safety considerations associated with C. militaris-based medicinal products. These findings establish a foundation for further investigations and the refinement of dosage optimization in the application of C. militaris, with the aim of mitigating any potential adverse effects.
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Cordyceps , Animales , Ratones , Masculino , Femenino , Metanol/química , Pruebas de Toxicidad Aguda , Pruebas de Micronúcleos , Pruebas de Toxicidad Subaguda , Daño del ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Pruebas de Mutagenicidad , Administración OralRESUMEN
The finding of N-nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA) in marketed drugs has led to implementation of risk assessment processes intended to limit exposures to the entire class of N-nitrosamines. A critical component of the risk assessment process is establishing exposure limits that are protective of human health. One approach to establishing exposure limits for novel N-nitrosamines is to conduct an in vivo transgenic rodent (TGR) mutation study. Existing regulatory guidance on N-nitrosamines provides decision making criteria based on interpreting in vivo TGR mutation studies as an overall positive or negative. However, point of departure metrics, such as benchmark dose (BMD), can be used to define potency and provide an opportunity to establish relevant exposure limits. This can be achieved through relative potency comparison of novel N-nitrosamines with model N-nitrosamines possessing robust in vivo mutagenicity and carcinogenicity data. The current work adds to the dataset of model N-nitrosamines by providing in vivo TGR mutation data for N-nitrosopiperidine (NPIP). In vivo TGR mutation data was also generated for a novel N-nitrosamine impurity identified in sitagliptin-containing products, 7-nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo-[4,3-a]pyrazine (NTTP). Using the relative potency comparison approach, we have demonstrated the safety of NTTP exposures at or above levels of 1500 ng/day.
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Contaminación de Medicamentos , Mutación , Nitrosaminas , Animales , Medición de Riesgo , Nitrosaminas/toxicidad , Mutación/efectos de los fármacos , Pruebas de Mutagenicidad/métodos , Mutágenos/toxicidad , Ratones , Relación Dosis-Respuesta a Droga , Dimetilnitrosamina/toxicidad , Animales Modificados Genéticamente , Dietilnitrosamina/toxicidad , Humanos , Carcinógenos/toxicidad , Ratas , MasculinoRESUMEN
The objective of the present study was to investigate some commonly detected halogenated textile pollutants for their bioavailability and hazardous properties. Release into artificial sweat and skin absorption in vitro were examined as well as mutagenic effects by Ames test, and skin-sensitizing properties from a peptide reactivity assay combined with a cell test. All investigated compounds were shown to migrate from the textile into sweat and be absorbed by the skin, although to a different extent. The experimental values for migration were found to be up to 390 times higher compared to literature values. Two of the studied compounds, 2,5-dinitrochlorobenzene and 3,5-dinitrobromobenzene, both exhibited mutagenic effects in the Ames test, while both 2,5-dinitrochlorobenzene and 2,6-dichlorobenzene-1,4-diamine were classified as skin sensitizers. The allergenic reactivity of the latter was found to be due to an oxidized transformation product. Risks for the induction of skin allergy and other non-carcinogenic effects from dermal exposure to the individual compounds were found low, even when considering clothing with the highest reported levels. However, the complex mixtures of chemicals often present in garments may still constitute a health risk, especially when considering the many hours of daily exposure. It is important to further study the toxicity of other frequently occurring chemicals as well as the synergistic effects of chemicals that co-occur in clothing.
Asunto(s)
Vestuario , Humanos , Piel/efectos de los fármacos , Piel/metabolismo , Hidrocarburos Halogenados/toxicidad , Medición de Riesgo , Textiles , Sudor/química , Absorción Cutánea , Pruebas de MutagenicidadRESUMEN
Tire and road wear particles (TRWP) contain complex mixtures of chemicals and release them to the environment, and potential toxic effects of these chemicals still need to be characterized. We used a standardized surrogate for TRWP, cryogenically milled tire tread (CMTT), to isolate and evaluate effects of tire-associated chemicals. We examined organic chemical mixtures extracted and leached from CMTT for the toxicity endpoints genotoxicity, estrogenicity, and inhibition of bacterial luminescence. The bioassays were performed after chromatographic separation on high-performance thin-layer chromatography (HPTLC) plates. Extracts of CMTT were active in all three HPTLC bioassays with two estrogenic zones, two genotoxic zones, and two zones inhibiting bacterial luminescence. Extracts of CMTT artificially aged with thermooxidation were equally bioactive in each HPTLC bioassay. Two types of aqueous leachates of unaged CMTT, simulating either digestion by fish or contact with sediment and water, contained estrogenic chemicals and inhibitors of bacterial luminescence with similar profiles to those of CMTT extracts. Of 11 tested tire-associated chemicals, two were estrogenic, three were genotoxic, and several inhibited bacterial luminescence. 1,3-Diphenylguanidine, transformation products of N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine, and benzothiazoles were especially implicated through comparison to HPTLC retention factors in the CMTT samples. Other bioactive bands in CMTT samples did not correspond to any target chemicals. Tire particles clearly contain and can leach complex mixtures of toxic chemicals to the environment. Although some known chemicals contribute to estrogenic, genotoxic, and antibacterial hazards, unidentified toxic chemicals are still present and deserve further investigation. Overall, our study expands the understanding of potential adverse effects from tire particles and helps improve the link between those effects and the responsible chemicals. Environ Toxicol Chem 2024;43:1962-1972. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.
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Antibacterianos , Estrógenos , Mutágenos , Antibacterianos/toxicidad , Antibacterianos/farmacología , Antibacterianos/química , Estrógenos/toxicidad , Mutágenos/toxicidad , Pruebas de MutagenicidadRESUMEN
Although the presence of nitro groups in chemicals can be recognized as structural alerts for mutagenicity and carcinogenicity, nitroaromatic compounds have attracted considerable interest as a class of agents that can serve as source of potential new anticancer agents. In the present study, the in vitro cytotoxicity, genotoxicity, and mutagenicity of three synthetic ortho-nitrobenzyl derivatives (named ON-1, ON-2 and ON-3) were evaluated by employing human breast and ovarian cancer cell lines. A series of biological assays was carried out with and without metabolic activation. Complementarily, computational predictions of the pharmacokinetic properties and druglikeness of the compounds were performed in the Swiss ADME platform. The MTT assay showed that the compounds selectively affected selectively the cell viability of cancer cells in comparison with a nontumoral cell line. Additionally, the metabolic activation enhanced cytotoxicity, and the compounds affected cell survival, as demonstrated by the clonogenic assay. The comet assay, the cytokinesis-block micronucleus assay, and the immunofluorescence of the γ-H2AX foci formation assay have that the compounds caused chromosomal damage to the cancer cells, with and without metabolic activation. The results obtained in the present study showed that the compounds assessed were genotoxic and mutagenic, inducing double-strand breaks in the DNA structure. The high selectivity indices observed for the compounds ON-2 and ON-3, especially after metabolic activation with the S9 fraction, must be highlighted. These experimental biological results, as well as the theoretical properties predicted for the compounds have shown that they are promising anticancer candidates to be exploited in additional studies.
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Activación Metabólica , Antineoplásicos , Supervivencia Celular , Daño del ADN , Humanos , Supervivencia Celular/efectos de los fármacos , Antineoplásicos/toxicidad , Antineoplásicos/farmacología , Antineoplásicos/química , Daño del ADN/efectos de los fármacos , Línea Celular Tumoral , Pruebas de Micronúcleos , Mutágenos/toxicidad , Ensayo Cometa , Pruebas de Mutagenicidad , Femenino , Nitrobencenos/toxicidad , Nitrobencenos/química , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/tratamiento farmacológico , Relación Dosis-Respuesta a DrogaRESUMEN
This study was carried out in the district of Taquaral de Minas, in the municipality of Itinga, located in Jequitinhonha Valley, state of Minas Gerais, which is considered one of the largest yolk-producing regions in Brazil. Miners in gem extraction areas are prone to severe oxidative damage due to their increased exposure to toxic metals, as well as chemical, physical, and biological agents, resulting in diseases such as silicosis. Thus, this work aimed to evaluate occupational exposure in prospectors through biomonitoring techniques using a variety of biomarkers for oxidative stress, genotoxicity, and mutagenicity. Twenty-two miners and seventeen workers who were not occupationally exposed were recruited, totaling thirty-nine participants. The study was approved by the Research Ethics Committee of the Federal University of the Jequitinhonha and Mucuri Valleys. In this study, the levels of total peroxides, catalase activity, and microelements in plasma were evaluated. Additionally, environmental analysis was carried out through the Ames and Allium cepa tests. The results of the lipoperoxidation assessment were significant, with increased frequencies in exposed individuals compared to controls (p < 0.05), as determined by the Mann-Whitney test. Micronutrients in the blood showed lower concentrations in the group exposed to Fe and Se than in individuals not exposed to these elements. The results of the Ames test and Allium cepa test were statistically significant compared to the controls (p < 0.05), as determined by the Mann-Whitney test for genotoxicity and cytotoxicity. Thus, the results of the present study indicate possible environmental contamination and a potential risk to the health of miners, which suggests that further studies are important in the region.
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Biomarcadores , Minería , Exposición Profesional , Estrés Oxidativo , Humanos , Brasil , Exposición Profesional/análisis , Exposición Profesional/efectos adversos , Adulto , Biomarcadores/sangre , Masculino , Persona de Mediana Edad , Monitoreo Biológico , Bertholletia/química , Pruebas de Mutagenicidad , Daño del ADNRESUMEN
Genotoxic substances widely exist in the environment and the food supply, posing serious health risks due to their potential to induce DNA damage and cancer. Traditional genotoxicity assays, while valuable, are limited by insufficient sensitivity, specificity, and efficiency, particularly when applied to complex food matrices. This study introduces a multiparametric high-content analysis (HCA) for the detection of genotoxic substances in complex food matrices. The developed assay measures three genotoxic biomarkers, including γ-H2AX, p-H3, and RAD51, which enhances the sensitivity and accuracy of genotoxicity screening. Moreover, the assay effectively distinguishes genotoxic compounds with different modes of action, which not only offers a more comprehensive assessment of DNA damage and the cellular response to genotoxic stress but also provides new insights into the exploration of genotoxicity mechanisms. Notably, the five tested food matrices, including coffee, tea, pak choi, spinach, and tomato, were found not to interfere with the detection of these biomarkers under proper dilution ratios, validating the robustness and reliability of the assay for the screening of genotoxic compounds in the food industry. The integration of multiple biomarkers with HCA provides an efficient method for detecting and assessing genotoxic substances in the food supply, with potential applications in toxicology research and food safety.