Journal of Applied Toxicology最新文献

Ergothioneine (EGT) is a diet-derived natural sulfur-containing amino acid that exhibits strong anti-oxidant and anti-inflammation activities. Oxidative stress and chronic inflammatory injury are predominant pro-fibrogenic factors. Therefore, EGT may have therapeutic potential against liver fibrosis; however, its underlying mechanism is incompletely understood. This study aimed at investigating the protective effects of EGT on liver fibrosis based on metabonomics and network pharmacology. A mouse model of liver fibrosis was established by intraperitoneal injection with 40% CCl₄ solution (2 mL/kg, twice a week) and intragastric administration with EGT (5, 10 mg/kg/d) for six weeks. Results showed that EGT improved liver function by reducing serum levels of ALT (alanine aminotransferase), AST (aspartate aminotransferase), and TBIL (total bilirubin), and alleviated liver fibrosis by reducing LN (laminin) and HyP (hydroxyproline) levels, decreasing expressions of α-SMA (α-smooth muscle actin), Col-I (collagen type I), and Col-III (collagen type III), and improving pathological changes. EGT also significantly inhibited CCl₄-induced hepatic inflammation and TGF-β/Smads signaling pathway. Metabolomics identified six key metabolic pathways, such as purine metabolism, glycerophospholipid metabolism, and sphingolipid metabolism, and eight key metabolites, such as xanthine, guanine, ATP, phosphatidylcholine, and sphingosine. Network pharmacology analysis showed that IL-17, cAMP and NF-κB signaling pathways were potential key mechanisms. Integrated analysis revealed that PLA2G2A might be a potential target of EGT against liver fibrosis. EGT may inhibit the glycerophospholipid metabolism through PLA2G2A to inhibit the TGF-β/Smads signaling pathway, thereby alleviating fibrosis. The present study indicates that EGT may be considered a valid therapeutic strategy to regress liver fibrosis, and provides novel insights into the pharmacological mechanism of EGT against liver fibrosis.

Triclocarban (TCC) and triclosan (TCS) are antibacterial compounds used in household, veterinary, industrial and personal care products, which are known to be environmental pollutants and also toxic to organisms. The toxicological effects of these antibacterial chemicals on higher organisms have been studied in detail. But in lower invertebrates like hydra, it is still rare and yet to be explored. In this study, the toxicological effects of these two antibacterial compounds in Hydra vulgaris was performed to clearly understand the organismal, developmental, molecular and behavioural changes. Both TCC and TCS are toxic with respective LC₅₀ values of 0.09 and 0.25 mg/L, whereas TCC is comparatively more toxic than TCS. The structural damage of battery cell complexes (BCCs) on the tentacles was observed and ultimately made prey capturing difficult. It was evident that TCC and TCS exposure caused developmental toxicity by affecting reproduction and regeneration in H. vulgaris at higher sublethal doses (0.045 and 0.125 mg/L, respectively). TCC and TCS also caused DNA damage resulting in apoptosis. This study further reveals that these two antibacterial compounds are teratogenic and genotoxic in the organisms.

Total liver area is a traditional indicator in evaluating compound liver damage with zebrafish models. However, in some experiments, compounds changed zebrafish liver morphology but total liver area showed no significant difference, indicating it is inaccurate for evaluating compound effects on zebrafish liver damage. Therefore, in this study, transgenic zebrafish Tg(l-fabp:EGFP) labeled with liver cells using green fluorescent protein was used to evaluate compound effects on liver by the liver partition area ratio. The coefficient of variation of the total liver area and the liver partition area ratio of normal zebrafish at different development stages was calculated to determine the precision and dispersion of the liver partition area ratio. Three known hepatotoxic compounds (water extract of psoralea, alcohol, and α-naphthalene isothiocyanate) were used to treat zebrafish, and liver partition area ratio was calculated and verified by liver tissue pathological sections. The Pearson correlation coefficient was used to analyze the correlation between the liver partition area ratio, total liver area, and alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Results showed significant difference in liver partition area ratio between hepatotoxic compound treated group and control group, and it could accurately reflect liver morphology changes. There was a strong correlation between liver partition area ratio and ALT and AST level, whereas that between total liver area and ALT and AST level was low. Therefore, the change in zebrafish liver partition area ratio can be an evaluation indicator for rapid assessment of compound effects on zebrafish liver function damage, more sensitive and accurate than total liver area.

The association between the stress defense system and exposure to fine particulate matter (PM_2.5) is a hot topic in the field of environmental health. PM_2.5 pollution is an increasingly serious issue, and its impact on health cannot be ignored. The stress defense system is an important biological mechanism for maintaining cell and internal environment homeostasis, playing a crucial role in PM_2.5-induced damage and diseases. The association between PM_2.5 exposure and activation of the stress defense system has been reported. Moderate PM_2.5 exposure rapidly mobilizes the stress defense system, while excessive PM_2.5 exposure may exceed its compensatory and coping abilities, resulting in system imbalance and dysfunction that triggers pathological changes in cells and tissues, thereby increasing the risk of chronic diseases, such as respiratory diseases, cardiovascular diseases, and cancer. This detailed review focuses on the composition, function, and regulatory mechanisms of the antioxidant defense system, autophagy system, ubiquitin-proteasome system, and inflammatory response system, which are all components of the stress defiance system. In particular, the influence of PM_2.5 exposure on each of these defense systems and their roles in responding to PM_2.5-induced damage was investigated to provide an in-depth understanding of the pathogenesis of PM_2.5 exposure, accurately assess potential hazards, and formulate prevention and intervention strategies for health damage caused by PM_2.5 exposure.

Nitrogen dioxide (NO₂) is a pervasive gaseous air pollutant with well-documented hazardous effects on health, necessitating precise toxicological characterization. While prior research has primarily focused on lower airway structures, the upper airways, serving as the first line of defense against airborne substances, remain understudied. This study aimed to investigate the functional effects of NO₂ exposure alone or in combination with hypoxia as a secondary stimulus on nasal epithelium and elucidate its molecular mechanisms because hypoxia is considered a pathophysiological factor in the onset and persistence of chronic rhinosinusitis, a disease of the upper airways. Air-liquid interface cell cultures derived from primary nasal mucosa cells were utilized as an in vitro model, offering a high in vitro-in vivo correlation. Our findings demonstrate that NO₂ exposure induces malfunction of the epithelial barrier, as evidenced by decreased transepithelial electrical resistance and increased fluorescein isothiocyanate (FITC)-dextran permeability. mRNA expression analysis revealed a significant increase in IL-6 and IL-8 expressions following NO₂. Reduced mRNA expression of the tight junction component occludin was identified as a structural correlate of the damaged epithelial barrier. Notably, hypoxic conditions alone did not alter epithelial barrier integrity. These findings provide information on the harmful effects of NO₂ exposure on the human nasal epithelium, including compromised barrier integrity and induction of inflammatory responses. Overall, this study contributes to our understanding of pathophysiological mechanisms underlying also upper airway respiratory diseases associated with air pollution exposure and emphasizes the importance of mitigating NO₂ emissions to safeguard respiratory health.

Titanium dioxide nanoparticles (nano-TiO₂) can cause a reduction in sperm counts, and lactate production in Sertoli cells plays a key role in spermatogenesis. The aim of this study was to evaluate the effect of nano-TiO₂ on lactate production in mouse Sertoli cell line (TM4 cells) and to investigate whether the effect is mediated through the PI3K/AKT/HIF-1α pathway. After TM4 cells were treated with different concentrations of nano-TiO₂ for 48 h, cell viability, contents of glucose and lactate, and the expression levels of GLUT3 and key enzymes (HK1, HK2, PFKM, ENO1, LDH) during lactate production were detected. PI3K/AKT/HIF-1α pathway proteins were measured. In addition, PI3K agonist (IGF-1) was added to explore whether nano-TiO₂ regulates HIF-1α through PI3K/AKT pathway, thereby affecting the production of lactate in TM4 cells. The results showed that nano-TiO₂ significantly inhibited TM4 cell viability, increased glucose content, decreased lactate content, and downregulated the expression levels of GLUT3 and key enzymes during lactate production. Meanwhile, nano-TiO₂ decreased the expression of PI3K/AKT pathway phosphorylated proteins and HIF-1α, and IGF attenuated this effect of nano-TiO₂. Collectively, nano-TiO₂ downregulated the expression level of proteins and enzymes related to lactate production in TM4 cells by inhibiting PI3K/AKT/HIF-1α pathway, resulting in the decrease of lactate production in TM4 cells.

Depleted uranium (DU), as a heavy metal material extensively utilized in the industrial sector, poses potential health risks to humans through various exposure pathways, including inhalation, ingestion, and dermal contact. To comprehensively understand the toxicological hazards of DU, this study conducted a literature search in the Web of Science Core Collection database using "DU" and "toxicity" as keywords, covering the period from January 2000 to December 2023. A total of 65 papers related to human, animal, or cellular studies on DU were included. This review delves into the latest research advancements on the origin and toxicokinetics of DU, as well as its pulmonary toxicity, neurotoxicity, nephrotoxicity, immunotoxicity, hepatotoxicity, reproductive toxicity, cancer, bone toxicity, and hematological toxicity. The aim of this review is to gain a deeper understanding of the health hazards posed by DU, which is of significant importance for formulating corresponding protection strategies and measures.

To investigate the clinical characteristics of patients with membranous nephropathy (MN) and the therapeutic efficacy of Sodium Dimercaptosulphonate (DMPS), as well as the relationship between mercury (Hg) exposure and MN, we investigated the clinical manifestations and treatment outcomes of six patients with MN and searched the China National Knowledge Internet (CNKI), PubMed, Web Of Science, and Embase databases for relevant studies on Hg exposure and MN published from the inception of the databases to April 2024. Data analysis was performed using SPSS 26.0 and Stata 16.0. We found that (1) the clinical symptoms of MN patients were mainly characterized by proteinuria, edema, hypoproteinemia, and hyperlipidemia. Comparative analysis before and after DMPS treatment showed a decrease in 24-h urinary Hg, 24-h urinary protein, and total cholesterol levels, as well as an increase in serum albumin levels (p < 0.05). (2) Two MN patients received DMPS for sole Hg detoxification treatment, whereas four patients received Hg detoxification combined with hormone therapy, and all patients showed significant improvement in symptoms after treatment. (3) Among the 564 articles, four met the inclusion criteria. The results showed that Hg exposure increased the incidence of MN by 5.74 times (95% confidence interval [CI] = 2.57, 12.83). The clinical symptoms of MN patients are mostly manifested as proteinuria, edema, hypoproteinemia, and hyperlipidemia. DMPS Hg detoxification treatment is effective for Hg-induced MN. Hg exposure can increase the prevalence of MN, therefore making it necessary to take prudent measures to reduce the risk of Hg exposure.

Inorganic nanoparticles are nanomaterials with a central core composed of inorganic specimens, especially metals, which give them interesting applications but can impact the environment and human health. Their short- and long-term effects are not completely known and to investigate that, alternative models have been successfully used. Among these, the nematode Caenorhabditis elegans has been increasingly applied in nanotoxicology in recent years because of its many features and advantages for toxicological screening. This non-parasitic nematode may inhabit any environment where organic matter is available; therefore, it is interesting for ecotoxicological assessments. Moreover, this worm has a high genetic homology to humans, making the findings translatable. A notable number of published studies unraveled the level of toxicity of different nanoparticles, including the mechanisms by which their toxicity occurs. This narrative review collects and describes the most relevant toxicological data for inorganic nanoparticles obtained using C. elegans and also supports its application in safety assessments for regulatory purposes.

Nonalcoholic fatty liver disease (NAFLD) is one of the main causes of critical liver diseases leading to steatosis, steatohepatitis, fibrosis, and ultimately to liver cirrhosis and hepatic carcinoma. In this study, the effect of palmitic acid (PA), one of the most abundant dietary fatty acids, was investigated using an organ-on-a-chip (OoC) technology on hepatocyte-like cells derived from human-induced pluripotent stem cells (hiPSCs). After 1 week of hepatic maturation, followed by 1 week of exposure, the transcriptomic analysis showed lower liver transcription factor activity. It also revealed that 318 genes were differentially expressed between the control and 0.5-mM PA conditions. The 0.5-mM PA conditions were characterized by the downregulation of hepatic markers (liver transcription factors, phase I and phase II metabolism genes) of lipidic genes (metabolism and transport). In parallel, the 0.5-mM PA treatment upregulated several extracellular matrix genes (such as collagen genes). The physiopathological staining demonstrated no lipid accumulation in our model and confirmed the secretion of collagen in the 0.5-mM PA conditions. However, the production of albumin, the metabolic biotransformation by the cytochrome P450 enzymes, and the biliary acid concentrations were not altered by the PA treatments. Overall, our data illustrated the response to PA characterized by an early stage of dedifferentiation observed at the transcriptomic levels associated with a modification of the collagenic profile but without lipid accumulation. We believe that our model provides new insight of the onset of palmitic lipotoxicity in the early stage of NAFLD.