Toxicology Mechanisms and Methods最新文献

The harmful effects of PM_2.5 on human health, including an increased risk of chronic kidney disease (CKD), have raised a lot of attention, but the underlying mechanisms are unclear. We used the Shanghai Meteorological and Environmental Animal Exposure System (Shanghai-METAS) to simulate the inhalation of PM_2.5 in the real environment and established an animal model by exposing C57BL/6 mice to filtered air (FA) and Particulate Matter (PM_2.5) for 8 weeks. PM_2.5 impaired the renal function of the mice, and the renal tubules underwent destructive changes. Analysis of NHANES data showed a correlation between reduced kidney function and higher blood levels of PM_2.5 components, polychlorinated biphenyls (PCBs) and dioxins, which are Aryl hydrocarbon Receptor (AhR) ligands. PM_2.5 exposure induced higher levels of AhR and CYP1A1 and oxidative stress as evidenced by the higher levels of ROS, MDA, and GSSG in kidneys of mice. PM_2.5 exposure led to AhR overexpression and nuclear translocation in proximal renal tubular epithelial cells. Inhibition of AhR reduced CYP1A1 expression and PM_2.5-increased levels of ROS, MDA and GSSG. Our study suggested metformin can mitigate PM_2.5-induced oxidative stress by inhibiting the AhR/CYP1A1 pathway. These findings illuminated the role of AhR/CYP1A1 pathway in PM_2.5-induced kidney injury and the protective effect of metformin on PM_2.5-induced cellular damage, offering new insights for air pollution-related renal diseases.

Introduction: Heavy metals (HM) and polycyclic aromatic hydrocarbons (PAHs) exposition has been associated with health problems. Therefore, this research evaluated genotoxicity induced in male mice strain CD-1 exposed to benzo[a]anthracene (B[a]A) and benzo[a]pyrene (B[a]P) and their interaction with Fe, Pb, and Al.

Methods: Groups of animals were exposed intraperitoneally to HM, PAHs, and mixtures of both. Peripheral blood samples were taken from 0 to 96 h at 24 h intervals; genotoxicity was determined by micronucleus tests and comet assay. Additionally, toxicity and viability were evaluated.

Results: HM and PAHs individually were genotoxic. About toxicity, only Al altered polychromatic erythrocytes number and did not change leukocytes viability. Concerning mixtures, Fe + B[a]P, Fe + B[a]A, Pb + B[a]P increased genotoxicity. There were no changes with Pb + B[a]A. Finally, Al mixtures with both PAHs damage was decreased.

Conclusions: Exposure to HM and PAH caused genetic damage. Fe, Al, and B[a]A, established a genotoxic potential. Every metal can interact with PAHs in different ways. Also, the micronucleus test and the comet assay demonstrated their high capacity and reliability to determine the genotoxic potential of the compounds evaluated in this work.

Cooking oil fumes (COFs) are widely acknowledged as substantial contributors to indoor air pollution, having detrimental effects on human health. Despite the existence of commercialized in vitro aerosol exposure platforms, assessment risks of aerosol pollutants are primarily evaluated based on multiwell plate experiments by trapping and redissolving aerosols to conduct comprehensive in vitro immersion exposure manner. Therefore, an innovative real-time exposure system for COF aerosol was constructed, featuring a self-designed microfluidic chip as its focal component. The chip was used to assess toxicological effects of in vitro exposure to COF aerosol on cells cultured at the gas-liquid interface. Meanwhile, we used transcriptomics to analyze genes that exhibited differential expression in cells induced by COF aerosol. The findings indicated that the MAPK signaling pathway, known for its involvement in inflammatory response and oxidative stress, played a crucial role in the biological effects induced by COF aerosol. Biomarkers associated with inflammatory response and oxidative stress exhibited corresponding alterations. Furthermore, the concentration of COF aerosol exposure and post-exposure duration exert decisive effects on these biomarkers. Thus, the study suggests that COF can induce oxidative stress and inflammatory response in BEAS-2B cells, potentially exerting a discernible impact on human health.

Cyclosporine A (CsA) has shown efficacy against immunity-related diseases despite its toxicity in various organs, including the liver, emphasizing the need to elucidate its underlying hepatotoxicity mechanism. This study aimed to capture the alterations in genome-wide expression over time and the subsequent perturbations of corresponding pathways across species. Six data from humans, mice, and rats, including animal liver tissue, human liver microtissues, and two liver cell lines exposed to CsA toxic dose, were used. The microtissue exposed to CsA for 10 d was analyzed to obtain dynamically differentially expressed genes (DEGs). Single-time points data at 1, 3, 5, 7, and 28 d of different species were used to provide additional evidence. Using liver microtissue-based longitudinal design, DEGs that were consistently up- or down-regulated over time were captured, and the well-known mechanism involved in CsA toxicity was elucidated. Thirty DEGs that consistently changed in longitudinal data were also altered in 28-d rat in-house data with concordant expression. Some genes (e.g. TUBB2A, PLIN2, APOB) showed good concordance with identified DEGs in 1-d and 7-d mouse data. Pathway analysis revealed up-regulations of protein processing, asparagine N-linked glycosylation, and cargo concentration in the endoplasmic reticulum. Furthermore, the down-regulations of pathways related to biological oxidations and metabolite and lipid metabolism were elucidated. These pathways were also enriched in single-time-point data and conserved across species, implying their biological significance and generalizability. Overall, the human organoids-based longitudinal design coupled with cross-species validation provides temporal molecular change tracking, aiding mechanistic elucidation and biologically relevant biomarker discovery.

The fast-increasing use of chemicals led to large numbers of chemical compounds entering the aquatic environment, raising concerns about their potential effects on ecosystems. Therefore, assessment of the ecotoxicological features of organic compounds on aquatic organisms is very important. Daphnia magna and Fathead minnow are two aquatic species that are commonly tested as standard test organisms for aquatic risk assessment and are typically chosen as the biological model for the ecotoxicology investigations of chemical pollutants. Herein, global quantitative structure-toxicity relationship (QSTR) models have been developed to predict the toxicity (pEC(LC)50) of a large dataset comprising 2106 chemicals toward Daphnia magna and Fathead minnow. The optimal descriptor of correlation weights (DCWs) is calculated using the notation of simplified molecular input line entry system (SMILES) and is used to construct QSTR models. Three target functions, TF₁, TF₂, and TF₃ are utilized to generate 12 QSTR models from four splits, and their statistical characteristics are also compared. The designed QSTR models are validated using both internal and external validation criteria and are found to be reliable, robust, and excellently predictive. Among the models, those generated using the TF₃ demonstrate the best statistical quality with R² values ranging from 0.9467 to 0.9607, Q² values ranging from 0.9462 to 0.9603 and RMSE values ranging from 0.3764 to 0.4413 for the validation set. The applicability domain and the mechanistic interpretations of generated models were also discussed.

Professional painters represent an occupational population group that deserves attention for study in the field of occupational toxicology due to the wide range of complex chemical mixtures they are exposed to. It is imperative to underscore that the International Agency for Research on Cancer has classified commercial painting as a high-risk occupation for the development of cancer. Given this context, the primary objective of the present study was to conduct a systematic review aimed at addressing the following question: are car painters at occupational risk regarding potential genotoxicity? To address this question, a selection process was undertaken, with three reviewers carefully selecting, reading, and analyzing full manuscripts from 26 studies included in this review. The technical rigor of these studies underwent meticulous scrutiny, culminating in the classification of six studies as Strong, eight as Moderate, and 12 as Weak, predicated on the extent of confounders considered. Taken together, the findings suggest that chemical substances from paints may indeed pose a risk of genotoxicity for professionals in this field, as all studies indicated genotoxicity among professional painters through various tests.

The waterpipe works by placing tobacco in a bowl with holes at the bottom, which is connected to a tube leading to a water-filled container. Upon heating the tobacco product with hot charcoal placed atop it, the emanating smoke is inhaled by the user via a hose linked to the water receptacle. The aim of this literature review is to evaluate whether the use of waterpipes can indeed induce genotoxicity in mammalian cells in vivo. Additionally, the study aims to assess the quality of the included research articles on this topic to ensure the reliability of the findings. We performed comprehensive searches in PubMed, SCOPUS, and Web of Science to identify relevant articles published until July 2024. The findings confirmed that waterpipe smoke induces genetic damage. This assertion is supported by the fact that 11 studies (out of 15) received a Strong or Moderate assessment categorization, suggesting that the majority of studies adhered to most technical standards, thereby enhancing the reliability of the research findings. Regarding the types of DNA damage reported, DNA strand breaks, chromosome damage and oxidative DNA damage were found in this review. Taken together, this study holds significant importance in assessing the efficacy of genotoxicity assays in detecting DNA damage due to waterpipe smoke and the comet and micronucleus assays are suitable biomarkers for biomonitoring people who use waterpipe.

This study aimed to investigate the effects of copper (CuSO₄) and zinc (ZnSO₄) overload on male reproductive toxicity and the potential of a polysaccharide extracted from green alga Chaetomorpha linum (PS) in mitigating their toxicities. Adult male mice strain of 25 ± 2 g of weight was subdivided into eight groups. Group 1 served as control; group 2 received PS (200 mg/kg), and groups 3 and 4 received intraperitoneally zinc (60 mg/kg b.w) and copper (33 mg/kg b.w), respectively. Group 5 received both zinc (60 mg/kg b.w) and copper (33 mg/kg b.w), group 6 received zinc (60 mg/kg b.w) associated with PS (200 mg/kg), group 7 received copper (33 mg/kg b.w) associated with PS (200 mg/kg), and group 8 received zinc (60 mg/kg b.w) and copper (33 mg/kg b.w) associated with PS (200 mg/kg). Results suggested that ZnSO₄ and CuSO₄ significantly decreased the functional sperm parameters. Furthermore, extended exposure to these elements increased oxidative stress biomarkers, including malondialdehyde (MDA) as a measure of lipid peroxidation and advanced oxidation protein products (AOPP) indicating protein oxidative damage. This process also reduces the activity of antioxidant enzymes such as glutathione (GSH) and glutathione peroxidase (GPx), which neutralize and catalyze free radicals. Histopathological changes in mice testis were also studied. However, the co-treatments with PS significantly reduced these effects and promoted the reproductive parameters in male mice. In conclusion, PS exhibited protective effects against zinc and copper-induced reproductive toxicity, making it a potential adjuvant treatment for testicular toxicity.

The fenugreek plant (Trigonella foenum-graecum) is traditionally known for its anti-diabetic properties owing to its high content of furostanolic saponins, which can synergistically treat many human ailments. Non-enzymatic protein glycation leading to the formation of Advanced Glycation End products (AGE) is a common pathophysiology observed in diabetic or prediabetic individuals, which can initiate the development of neurodegenerative disorders. A potent cellular source of glycation is Methyl Glyoxal, a highly reactive dicarbonyl formed as a glycolytic byproduct. We demonstrate the in vitro glycation arresting potential of Fenfuro®, a novel patented formulation of Fenugreek seed extract with clinically proven anti-diabetic properties, in Methyl-Glyoxal (MGO) adducts of three abundant amyloidogenic cellular proteins, alpha-synuclein, Serum albumin, and Lysozyme. A 0.25% w/v Fenfuro^® was able to effectively arrest glycation by more than 50% in all three proteins, as evidenced by AGE fluorescence. Glycation-induced amyloid formation was also arrested by more than 36%, 14% and 15% for BSA, Alpha-synuclein and Lysozyme respectively. An increase in MW by attachment of MGO was also partially prevented by Fenfuro^® as confirmed by SDS-PAGE analysis. Glycation resulted in enhanced aggregation of the three proteins as revealed by Native PAGE and Dynamic Light Scattering. However, in the presence of Fenfuro^®, aggregation was arrested substantially, and the normal size distribution was restored. The results cumulatively indicated the lesser explored potential of direct inhibition of glycation by fenugreek seed in addition to its proven role in alleviating insulin resistance. Fenfuro^® boosts its therapeutic potential as an effective phytotherapeutic to arrest Type 2 diabetes.

The ability to assess cell proliferation and viability is essential for assessing new drug treatments, particularly in cancer drug discovery. This study describes a new method that uses a plate reader digital microscopy cell imaging and analysis system to assess cell proliferation and viability. This imaging system utilizes high throughput fluorescence microscopy with two fluorescent probes: cell membrane-impermeable SYTOX green and nuclear binding Hoechst-33342. Here we compare this technology to other known viability assays, namely: propidium iodide (PI)-based flow cytometry, and sulforhodamine B (SRB) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) based plate reader assays. These methods were assessed based on their effectiveness in detecting the cell numbers of two adherent cell lines and one suspension cell line. Automated cell imaging was most accurate at measuring cell number in both adherent and suspension cell lines. The PI-based flow cytometry method was more difficult to use with adherent cells, while the SRB and MTT assays had difficulties when monitoring cells in suspension. Despite these challenges, it was possible to obtain similar results when quantifying the effect of cytotoxic compounds. This study demonstrates that the digital microscopy automated cell imaging system is an effective method for assessing cell proliferation and the cytotoxic effect of compounds on both adherent and suspension cell lines.