Current Research in Toxicology最新文献

Integrated approaches to testing and assessments (IATAs) have been proposed as a method to organise new approach methodologies in order to replace traditional animal testing for chemical safety assessments. To capture the mechanistic aspects of toxicity assessments, IATAs can be framed around the adverse outcome pathway (AOP) concept. To utilise AOPs fully in this context, a sufficient number of pathways need to be present to develop fit for purpose IATAs. In silico approaches can support IATA through the provision of predictive models and also through data integration to derive conclusions using a weight-of-evidence approach. To examine the maturity of a developmental and reproductive toxicity (DART) AOP network derived from the literature, an assessment of its coverage was performed against a novel toxicity dataset. A dataset of diverse compounds, with data from studies performed according to OECD test guidelines TG-421 and TG-422, was curated to test the performance of an in silico model based on the AOP network – allowing for the identification of knowledge gaps within the network. One such gap in the knowledge was filled through the development of an AOP stemming from the molecular initiating event ‘glutathione reaction with an electrophile’ leading to male fertility toxicity. The creation of the AOP provided the mechanistic rationale for the curation of pre-existing structural alerts to relevant key events. Integrating this new knowledge and associated alerts into the DART AOP network will improve its coverage of DART-relevant chemical space. In addition, broadening the coverage of AOPs for a particular regulatory endpoint may facilitate the development of, and confidence in, robust IATAs.

Several toxicological studies were conducted to evaluate the hepatoxicity of PBDEs using different animal models, congeners, duration of exposure, and other parameters. These variations in different animal models and conditions might have an impact on extrapolating experimental results to humans. Hence, by the meta-analysis, we aimed to clarify and elucidate the species differences in hepatoxicity induced by PBDE exposure in rats and mice across different conditions and moderators. Fourteen in vivo studies that utilized rats and mice models were identified, and data such as author names, year of publication, type of PBDE congeners, rodent species, life stage of exposure, dosage, duration, and hepatoxicity indicators were extracted. The pooled standard mean difference (SMD) with a 95% confidence interval (95% CI) was used to evaluate the association between hepatoxicity and PBDE exposure across multiple approaches of measurement. Subgroup analysis, meta-regression, and interaction analysis were utilized to elucidate the species-related differences among the results of the involved studies. The pooled SMD of hepatoxicity of PBDE exposure in the involved in vivo studies was 1.82 (p = 0.016), indicating exposure to PBDE congeners and mixtures is associated with a significant increase in liver toxicity in rodents. Moreover, findings showed that rats were more sensitive to PBDEs than mice with the BDE-209 had the highest SMD value. Among the life stages of exposure, embryonic stage was found to be the most sensitive to hepatoxicity induced by PBDE congeners. Positive relationships were found between the incidence of hepatoxicity with dosage and duration of exposure to PBDE. Interaction analyses showed significant interactions between rodent species (rats or mice), dosage, length of exposure, and hepatotoxicity endpoints. Rats demonstrated an increased susceptibility to variations in organ weight, histopathological changes, mitochondrial dysfunction, and oxidative stress markers. Conversely, mice showed pronounced lipid accumulation and modifications in liver enzyme expression levels. However, significant differences were not found in terms of endoplasmic reticular stress as a mechanistic endpoint for hepatotoxicity. In conclusion, this meta-analysis showed that there might be some species-related differences in hepatoxicity induced by PBDE exposure in rats and mice depending on the parameters used. This study highlights the importance of cross-species extrapolation of results from animal models to accurately assess the potential risks to human health from exposure to PBDEs.

Carapa guianensis (Andiroba, Meliaceae) is considered a multipurpose tree. In Brazil, Indigenous people have used it as insect repellent and in the treatment of various diseases. Most biological activities and popular uses are attributed to limonoids, which are highly oxygenated tetranortriterpenoids. More than 300 limonoids have been described in Meliaceae family. Limonoids from Andiroba oil have shown high anti-inflammatory and anti-allergic activities in vivo, by inhibiting platelet activating factors and many inflammatory mediators such as IL-5, IL-1β and TNF-α. It also reduced T lymphocytes, eosinophils and mast cells. In corroboration with the wide popular use of Andiroba oil, no significant cytotoxicity or genotoxicity in vivo was reported. This oil promotes apoptosis in a gastric cancer cell line (ACP02) at high concentrations, without showing mutagenic effects, and is suggested to increase the body's nonspecific resistance and adaptive capacity to stressors, exhibit some antioxidant activity, and protect against oxidative DNA damages. Recently, new methodologies of toxicological assays have been applied. They include in chemico, in vitro, in silico and ex vivo procedures, and take place to substitute the use of laboratory animals. Andiroba by-products have been used in sustainable oil production processes and as fertilizers and soil conditioners, raw material for soap production, biodegradable surfactants and an alternative natural source of biodegradable polymer in order to reduce environmental impacts. This review reinforces the relevance of Andiroba and highlights its ability to add value to its by-products and to minimize possible risks to the health of the Amazonian population.

Herbal medications have an extensive history of use in treating various diseases, attributed to their perceived efficacy and safety. Traditional medicine practitioners and contemporary healthcare providers have shown particular interest in herbal syrups, especially for respiratory illnesses associated with the SARS-CoV-2 virus. However, the current understanding of the pharmacokinetic and toxicological properties of phytochemicals in these herbal mixtures is limited. This study presents a comprehensive computational analysis utilizing novel approach methodologies (NAMs) to investigate the pharmacokinetic and toxicological profiles of phytochemicals in herbal syrup, leveraging in-silico techniques and prediction tools such as PubChem, SwissADME, and Molsoft's database. Although molecular dynamics, docking, and broader system-wide analyses were not considered, future studies hold potential for further investigation in these areas. By combining drug-likeness with molecular simulation, researchers identify diverse phytochemicals suitable for complex medication development examining their pharmacokinetic-toxicological profiles in phytopharmaceutical syrup. The study focuses on herbal solutions for respiratory infections, with the goal of adding to the pool of all-natural treatments for such ailments. This research has the potential to revolutionize environmental and alternative medicine by leveraging in-silico models and innovative analytical techniques to identify novel phytochemicals with enhanced therapeutic benefits and explore network-based and systems biology approaches for a deeper understanding of their interactions with biological systems. Overall, our study offers valuable insights into the computational analysis of the pharmacokinetic and toxicological profiles of herbal concoction. This paves the way for advancements in environmental and alternative medicine. However, we acknowledge the need for future studies to address the aforementioned topics that were not adequately covered in this research.

The liver is the most common target organ in toxicology studies. The development of chemical structural alerts for identifying hepatotoxicity will play an important role in in silico model prediction and help strengthen the identification of analogs used in structure activity relationship (SAR)- based read-across. The aim of the current study is development of an SAR-based expert-system decision tree for screening of hepatotoxicants across a wide range of chemistry space and proposed modes of action for clustering of chemicals using defined core chemical categories based on receptor-binding or bioactivation. The decision tree is based on ∼ 1180 different chemicals that were reviewed for hepatotoxicity information. Knowledge of chemical receptor binding, metabolism and mechanistic information were used to group these chemicals into 16 different categories and 102 subcategories: four categories describe binders to 9 different receptors, 11 categories are associated with possible reactive metabolites (RMs) and there is one miscellaneous category. Each chemical subcategory has been associated with possible modes of action (MOAs) or similar key structural features. This decision tree can help to screen potential liver toxicants associated with core structural alerts of receptor binding and/or RMs and be used as a component of weight of evidence decisions based on SAR read-across, and to fill data gaps.

Late-onset cardiomyopathy is becoming more common among cancer survivors, particularly those who received doxorubicin (DOXO) treatment. However, few clinically available cardiac biomarkers can predict an unfavorable cardiac outcome before cell death. Extracellular vesicles (EVs) are emerging as biomarkers for cardiovascular diseases and others. This study aimed to measure dynamic 4-hydroxynonenal (4HNE)-adducted protein levels in rats treated chronically with DOXO and examine their link with oxidative stress, antioxidant gene expression in cardiac tissues, and cardiac function. Twenty-two male Wistar rats were randomly assigned to receive intraperitoneal injection of normal saline (n = 8) or DOXO (3 mg/kg, 6 doses, n = 14). Before and after therapy, serum EVs and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were determined. Tunable resistive pulse sensing was used to measure EV size and concentration. ELISA was used to assess 4HNE-adducted protein in EVs and cardiac tissues. Differential-display reverse transcription-PCR was used to quantitate cardiac Cat and Gpx1 gene expression. Potential correlations between 4HNE-adducted protein levels in EVs, cardiac oxidative stress, antioxidant gene expression, and cardiac function were determined. DOXO-treated rats showed more serum EV 4HNE-adducted protein than NSS-treated rats at day 9 and later endpoints, whereas NT-proBNP levels were not different between groups. Moreover, on day 9, surviving rats' EVs had higher levels of 4HNE-adducted protein, and these correlated positively with concentrations of heart tissue 4HNE adduction and copy numbers of Cat and Gpx1, while at endpoint correlated negatively with cardiac functions. Therefore, 4HNE-adducted protein in serum EVs could be an early, minimally invasive biomarker of the oxidative response and cardiac function in DOXO-induced cardiomyopathy.

Diallyl trisulfide (DATS), an organosulfide compound derived from garlic, is renowned for its potent antioxidant properties, particularly in countering the generation of reactive oxygen species (ROS). It has also gained recognition as a potential agent for preventing heart-related conditions. Doxorubicin (Dox), a commonly used chemotherapeutic drug, is known to induce severe cardiac complications by promoting ROS production. Therefore, it was imperative to investigate whether DATS possesses cardioprotective capabilities against Dox-induced cardiac apoptosis and elucidate the underlying mechanisms. In this study, we observed that the intracellular ROS levels and cardiac apoptosis were heightened in H9c2 cells exposed to Dox (1 μM). However, treatment with 10 μM DATS effectively mitigated the Dox-induced ROS generation and apoptotic signaling, concurrently activating the PI3K/Akt pathway. Notably, the anti-apoptotic effects of DATS were attenuated when PI3K siRNA and the LY294002 PI3K inhibitor were employed. Furthermore, the TUNEL assay results demonstrated a significant reduction in Dox-induced apoptosis with DATS treatment. In summary, our findings indicate that DATS can activate the PI3K/Akt pathway, reducing ROS production in cardiac cells exposed to Dox, and subsequently rescue cardiac cells from apoptosis.

The presence of deoxynivalenol (DON), one of the most frequently occurring mycotoxin, in food and feed has been considered a risk factor to both human and animal health. Molecular mechanisms that regulate DON effects in tissues are still poorly understood. However, recent evidence suggests that nuclear factor erythroid 2-like 2 (Nrf2) may be a major target during mycotoxin-induced intestinal barrier dysfunction. Although quercetin, a plant-derived flavonoid, is known to induce the activation of Nrf2 signaling pathway, its potential to mitigate effects of DON and the implication of Nrf2 in its physiological effects is poorly understood. Therefore, this study was conducted to investigate the protective effects of quercetin in alleviating the DON-induced barrier loss and intestinal injuries in IPEC-J2 cells and weaned piglets and determine the potential role of Nrf2. Quercetin treatment dose-dependently increased mRNA expression of Nrf2 target gene, NQO-1, and concomitantly increased the expression of claudin-4 at both mRNA and protein levels. Quercetin supplementation also reversed the reduction of claudin-4 caused by DON exposure in vivo and in vitro. The decreased membrane presence of claudin-4 and ZO-1 induced by DON was also blocked by quercetin. Furthermore, quercetin attenuated the endocytosis and degradation of claudin-4 caused by DON exposure. The effects of quercetin also included the restoration of transepithelial electrical resistance (TEER) and reduction of FITC-dextran permeability that have been perturbed by DON. However, the protective effects of quercetin against DON exposure were abolished by a specific Nrf2 inhibitor (brusatol), confirming the importance of Nrf2 in the regulation of TJP expression and barrier function by quercetin. In vivo study in weaned pigs showed that DON exposure impaired villus-crypt morphology as indicated by diffuse apical villus necrosis, villus atrophy and fusion. Notably, intestinal injuries caused by DON administration were partly mitigated by quercetin supplementation. Collectively, this study shows that quercetin could be used to prevent the DON-induced gut barrier dysfunction in humans and animals and the protective effects of quercetin against DON-induced intestinal barrier disruption is partly through Nrf2-dependent signaling pathway.

The current study was designed to evaluate the protective effect of fenugreek seed powder against As-induced neurobehavioral and biochemical perturbations using a mouse model. Mice exposed to arsenic at 10 mg/kg body weight showed development of anxiety-like behavior and memory impairment compared to control mice in elevated plus maze and Morris water maze tests, respectively. A significantly decreased acetyl and butyrylcholinesterase, superoxide dismutase and glutathione reductase activities and brain-derived neurotrophic factor levels were found in the brain of arsenic-exposed mice compared to control mice. Interestingly, supplementation of fenugreek seed powder to arsenic-treated mice significantly restored the activity of cholinesterase and antioxidant enzymes (e.g. superoxide dismutase, glutathione reductase) as well as brain-derived neurotrophic factor levels in the brain tissue of arsenic-exposed mice. Consequently, reduced anxiety-like behavior, improved learning and memory were observed in fenugreek supplemented arsenic treated mice compared to only arsenic-exposed mice group. Thus, this study suggests that fenugreek seed powder reduces arsenic-induced neurotoxicity in mice.

Resveratrol is regarded as neutraceuticals with multiple health benefits. The introduction of prenyl can enhance the bioactivity. In this work, the cancer preventive activities and mechanisms of 18 prenylated reseveratrol and derivatives were investigated. The results showed that prenyl increased the antiproliferative activities of resveratrol, oxyresveratrol and piceatannol against cancer cells, and their antiproliferative activities were time- and dose-dependent. 4-C-prenylation was important for the antiproliferative activity of stilbenoids. The 4-C-prenyl stilbenoids showed better antiproliferative activities than other prenylated stilbenoids. 4-C-prenyl piceatannol showed the best antiproliferative activity. Human hepatoellular carcinomas (HepG₂) cell was more sensitive to prenylated stilbenoids than human MCF-7 breast carcinoma cell. 4-C-prenyl piceatannol had high affinities to Caspase-3, Caspase-9, CDK2 and Cyclin A2. The possible amino acids involved in binding 4-C-prenyl piceatannol were revealed. The expression of Caspase-3 and Caspase-9 were upregulated by 4-C-prenyl piceatannol and the expression of CDK2 and Cyclin A2 in HepG₂ cells were downregulated, which contributed to apoptosis. The above results eludicated the possible antiproliferative mechanisms of prenylated stilbenoids.