Toxicology最新文献

Microplastics (MPs), as the crucial environmental pollutants, can be easily transported into the human body and accumulate in the liver. However, current studies mainly focus on acute exposure to MPs, investigations on long-term interactions with MPs alone remain limited. Thereby, we examined noxious properties of MPs and selected the most common polystyrene (PS) MPs as the research object, including unmodified PS MPs (PS-MPs) and positive-charged PS MPs (PS-NH₂) at 10 mg/L employing oral drinking water methods in mice for six consecutive months in vivo. In vitro, we treated the human hepatocyte cells with MPs at 25 μg/mL to explore involved mechanisms. The results revealed that six-month MPs exposure led to nonalcoholic fatty liver disease (NAFLD) including impaired liver functions, extensive lipid depositions accompanied by abnormal levels of metabolic genes and PS-NH₂ MPs exerted a stronger effect than PS-MPs. Concurrently, mice treated with MPs revealed the accumulation of senescent hepatocytes, leading to increased secretions of senescent phenotypes in the liver. We also discovered that MPs initiated the HO-1/Nrf2 axis consequently inducing ferroptosis in vivo and in vitro, as shown by massive iron deposition, extensive lipid peroxidation along with significant protein expressions in ferroptosis-related markers. Additionally, targeting the HO-1/Nrf2 pathway to further alleviate ferroptosis with corresponding inhibitors could efficiently alleviate cell senescence. Therefore, our study reveals new evidence of the relationship between chronic exposure to MPs and NAFLD and furthers the understanding of how plastic pollution affects human health.

Drug-induced autoimmunity (DIA) is a non-IgE immune-related adverse drug reaction that poses substantial challenges in predictive toxicology due to its idiosyncratic nature, complex pathogenesis, and diverse clinical manifestations. To address these challenges, we developed InterDIA, an interpretable machine learning framework for predicting DIA toxicity based on molecular physicochemical properties. Multi-strategy feature selection and advanced ensemble resampling approaches were integrated to enhance prediction accuracy and overcome data imbalance. The optimized Easy Ensemble Classifier achieved robust performance in both 10-fold cross-validation (AUC value of 0.8836 and accuracy of 82.81%) and external validation (AUC value of 0.8930 and accuracy of 85.00%). Paired case studies of hydralazine/phthalazine and procainamide/N-acetylprocainamide demonstrated the model's capacity to discriminate between structurally similar compounds with distinct immunogenic potentials. Mechanistic interpretation through SHAP (SHapley Additive exPlanations) analysis revealed critical physicochemical determinants of DIA, including molecular lipophilicity, partial charge distribution, electronic states, polarizability, and topological features. These molecular signatures were mechanistically linked to key processes in DIA pathogenesis, such as membrane permeability and tissue distribution, metabolic bioactivation susceptibility, immune protein recognition and binding specificity. SHAP dependence plots analysis identified specific threshold values for key molecular features, providing novel insights into structure-toxicity relationships in DIA. To facilitate practical application, we developed an open-access web platform enabling batch prediction with real-time visualization of molecular feature contributions through SHAP waterfall plots. This integrated framework not only advances our mechanistic understanding of DIA pathogenesis from a molecular perspective but also provides a valuable tool for early assessment of autoimmune toxicity risk during drug development.

Understanding the potential impact of nanomaterials (NMs) on human health requires further investigation into the organ-specific nano-bio interplay at the cellular and molecular levels. We showed increased chromosomal damage in intestinal cells exposed to some of in vitro digested Titanium dioxide (TiO₂) NMs. The present study aimed to explore possible mechanisms linked to the uptake, epithelial barrier integrity, cellular trafficking, as well as activation of pro-inflammatory pathways, after exposure to three TiO₂-NMs (NM-102, NM-103, and NM-105). Using confocal microscopy, we show that all NMs, digested or not, were able to enter different types of intestinal cells. At the physiologically relevant concentration of 14µg/ml, the digested TiO₂-NMs did not compromise the transepithelial resistance, nor the levels of epithelial markers E-cadherin and Zonula occludens protein 1 (ZO-1), of polarized enterocyte monolayers. Nonetheless, all NMs were internalized by intestinal cells and, while NM-102 was retained in lysosomes, NM-103 and NM-105 were able to transverse the epithelial barrier through transcytosis. Moreover, 24h exposure of 14 and 1.4μg/mL digested NM-105, promoted interleukin IL-1β expression in activated M1 macrophages, indicating a potential pro-inflammatory action in the gut. Taken together, our findings shed light on the cell-specific nano-bio interplay of TiO₂-NMs in the context of the intestinal tract and highlight transcytosis as a potential gateway for their systemic distribution. The potential pro-inflammatory action of digested NM-105 emphasizes the importance of pursuing research into the potential impact of NMs on human health and contribute to the weight of evidence to limit their use in food.

Imidacloprid (IMI) and cadmium (Cd) have been shown to be harmful to mammals separately, but their combined toxicity to mammals remains largely unknown. In this study, biochemical analysis (oxidative stress and serum indicators of liver and kidney function), pathological sections and multiomics (metabolomics and transcriptomics) methods were used to investigate the changes and mechanisms of liver and kidney in mice coexposed to IMI and Cd. Biochemical analysis and pathological section results showed that oxidative stress, organ function, and cell damage were aggravated after the combination of the two methods. Omics results revealed the following mechanism: When mouse liver and kidney cells were threatened by the external environment, mitochondrial DNA was inhibited, which leads to changes in energy metabolism. In this process, lipid metabolism and amino acid metabolism were disordered, resulting in the inhibition of substances related to lipid metabolism and amino acid metabolism that protect the body from oxidative damage, and then showed more serious liver and kidney oxidative stress and liver and kidney function and cell damage. This research offers novel insights for the assessment of the safety profile associated with the concurrent exposure of the two chemicals in mammalian species.

Patients with benzene-induced leukemia undergo a continuous transformation from myelosuppression to malignant proliferation. However, the underlying mechanisms in this process remain unknown. Our previous studies have shown that the pathways involved in self-renewal capacity of bone marrow (BM) cells in Mll-Af9 mice exposed to benzene for life are significantly activated after severe blood toxicity. In order to investigate the hematotoxicity effects of benzene on the self-renewal capacity of HSCs, Mll-Af9 chimeric mice were exposed to benzene and hematological parameters were dynamically monitored after benzene exposure. Transcriptomic analysis were used to analyze different time points during benzene exposure and after competitive bone marrow transplantation (BMT). Results showed that despite severe hematotoxicity in mice, but the chimerism rate of Mll-Af9 cells in peripheral blood (PB) cells was significantly increased after 10 weeks benzene exposure (P < 0.001). After competitive BMT, the chimerism rate of Mll-Af9 cells from 10 weeks benzene-exposed mice was gradually increased and significantly surpassed that of the control at 26 weeks of bone marrow reconstruction (benzene group 86 % VS control group 78 %, P = 0.03). Transcriptome analysis revealed that the expression levels of self-renewal related genes, such as Hox genes (Hoxb4, Hoxa7, Hoxa10), Mecom and Ms4a in BM cells of 10 weeks benzene-exposed mice were relatively higher compared to those in the control group, but no significant difference were observed. Interestingly, Hoxa7, Hoxa10 and Mecom were significantly up-regulated at 26 weeks after bone marrow transplantation. In conclusion, our study suggests that abnormal expression of self-renewal-related genes may be potential early biomarkers for benzene-induced hematotoxicity. This hematotoxicity may contribute to the acquisition of evolutionary advantages by leukemic precursor cells and accelerate malignant transformation.

Cadmium is a heavy metal risk factor for various cardiovascular diseases, such as atherosclerosis. In atherosclerotic lesions, hyaluronan, a glycosaminoglycan consisting of β4-glucuronic acid-β3-N-acetylglucosamine disaccharides repeats, is highly accumulated, regulating signal transduction, cell migration, and angiogenesis. Hyaluronan is synthesized by hyaluronan synthase (HAS)1-3 in the plasma membrane and secreted into the extracellular space. Hyaluronan derived from HAS3 promotes inflammatory responses. Recently, we found that cadmium elongates chondroitin/dermatan sulfate chains in vascular endothelial cells and that glycosaminoglycan sugar chains are potential targets for the vascular toxicity of cadmium. Therefore, hyaluronan, a glycosaminoglycan sugar chain, may also affected by cadmium; however, this has not yet been clarified. In this study, we aimed to analyze the effect of cadmium on hyaluronan synthesis using cultured aortic endothelial cells. Cadmium at a concentration of 2 µM upregulated hyaluronan synthesis in the medium and specifically induced HAS3 mRNA and protein expression. However, cadmium-mediated HAS3 induction was abolished by the inhibition of the c-Jun N-terminal kinase (JNK)-c-Jun pathway. Moreover, JNK inhibition prevented the increase in hyaluronan levels in the medium. These results revealed that the JNK-c-Jun pathway was involved in HAS3-mediated hyaluronan synthesis by cadmium in vascular endothelial cells, suggesting that endothelial HAS3 induction contributes to atherosclerotic lesion formation by promoting inflammatory responses.

Breast cancer is a major public health problem, and distant metastases are the main cause of morbidity and mortality. Chlorpyrifos is an organophosphate that promotes Epithelial-Mesenchymal Transition-like phenotype in breast cancer cell lines and modulates the Breast Cancer Stem Cells activating two key processes related to the metastatic cascade. Here, we investigated whether Chlorpyrifos may induce distant metastases in an in vivo triple negative tumor model. Also, we studied the expression of Breast Cancer Stem Cell and Epithelial-Mesenchymal Transition activation-markers in Triple Negative Breast Cancer mice tumors and human cells. We demonstrate that Chlorpyrifos modulates stem cell plasticity as a function of growth conditions in monolayer or three-dimensional culture. Furthermore, Chlorpyrifos decreased the doubling period, increased tumor volume, stimulated the infiltration of adjacent muscle fibers and induced lung and lymphatic node metastases in mice. Finally, Chlorpyrifos modulated the expression of Epithelial-Mesenchymal Transition and Breast Cancer Stem Cell markers in mice exposed to the pesticide. All our findings confirm that Chlorpyrifos promotes breast cancer progression, enhances stemness and Epithelial-Mesenchymal Transition marker expression and generates lung metastases in an in vivo model induced in mice.

Acetaminophen (APAP) stands as one of the most prevalent triggers of drug-induced acute liver injury (ALI). The intricate modulation of immune system activation and inflammatory cascades by hepatic immune cells is paramount in managing liver injury and subsequent restoration. In this study, we employed an integrative approach that fused our proprietary flow cytometry analyses across various time points post-APAP injury with publicly available single-cell RNA sequencing (scRNA-seq) datasets, encompassing time-series data from liver tissue of mice subjected to APAP intoxication. This allowed us to delve into the dynamics of T cell profiles during APAP-induced ALI. Our comprehensive analyses unveiled the intricate temporal shifts in intrahepatic T cell populations across different phases following APAP-induced ALI. Notably, we observed a persistent augmentation of intrahepatic CD4⁺ T cells post-APAP injury. Amongst these, a distinct population of restorative Cxcr3⁺ tissue-resident CD4⁺ T cells emerged. Inhibition of CXCR3 using a neutralizing antibody exacerbated APAP-induced liver function impairment and hepatocyte death. Furthermore, we identified that the Cxcr3⁺ tissue-resident CD4⁺ T cells were tightly regulated by intrahepatic ''Lgals9-Cd45'' and 'CXCL13-Cxcr3' signaling pathways. These discoveries underscore the novel protective function of CXCR3, a vital biological macromolecule, in mitigating APAP-induced ALI, and may shed lights on new therapeutic strategies targeting this condition.

Household chemicals used daily are often combined, leading to inhalation exposure to mixtures. However, methods for assessing their toxic effects are limited. This study proposes an in vitro assay strategy for evaluating household chemical mixtures using benzalkonium chloride (BKC) and didecyldimethylammonium chloride (DDAC), a common disinfectant. Our approach utilizes the mode of action (MOA) of chemicals by applying toxicity units (TU) to assess the key events related to lung disease, such as reactive oxygen species (ROS) production and cell death. The TU (EC₅₀) values for BKC and DDAC were 3.97 µg/mL and 1.89 µg/mL, respectively, from cytotoxicity results. The TU value of the mixture (5:5 ratio of BKC to DDAC) was calculated as 2.56 µg/mL. Using the OpenMRA platform, the TU values were predicted as 2.37 µg/mL with the concentration addition (CA) model and 11.26 µg/mL with the independent action (IA) model, indicating that the mixture effects were additive and closer to that predicted using the CA model. Both BKC and DDAC induced apoptosis and ROS production in human epithelial cells in a dose-dependent manner, suggesting similar modes of action in promoting cell death. Our results suggested that BKC and DDAC exhibited additive toxicity when combined. Our results demonstrate the utility of the TU-based approach, which combines cytotoxicity, ROS induction, and apoptosis measurements to evaluate mixture toxicity. This approach may be beneficial for assessing early key events relevant to lung diseases and offers a practical strategy for evaluating the inhalation toxicity of household chemical mixtures.

Aflatoxin B1 (AFB1) has been reported to synergize with hepatitis B virus (HBV) to induce development of hepatocellular carcinoma (HCC). Precise daily exposure to AFB1 and its contribution to liver injury have not been quantified and have even been disregarded due to lack of convenient detection, and the strong species specificity of HBV infection has restricted research on their synergistic harm. Hence, our objective was to investigate the molecular mechanisms by which AFB1 exacerbates HBV-related injury. We constructed tree shrew models with 400 μg HBV plasmid and 4 mg/kg AFB1 co-exposure for 4-6 days. Injury and molecule expression resulting from HBV and AFB1 toxicity were observed in vivo and in vitro. Expression datasets of tree shrew livers, human HCC, and pregnane X receptor (PXR) activation were employed to screen vital pathways and target genes. The oncogenic hepatitis B virus x (HBx) protein, HBV-related histopathological damage, metabolic dysregulation, and several cancer-related signaling pathways were enriched in injured tree shrew livers, and PXR signaling was inhibited after co-exposure to HBV and AFB1. Furthermore, in human HCC and HBV-integrated Hep3B and HepG2.215 cells, FTCD Antisense RNA 1 (FTCD-AS1), PXR and mannose-binding lectin-associated serine protease 1 (MASP1) exhibited strong correlation. Overexpression of FTCD-AS1 and PXR alleviated cell damage in exposure to 5 μM AFB1 for 48 h. In summary, inactivation of the FTCD-AS1-PXR-MASP1 axis was pinpointed as the key event in AFB1-enhanced HBV infection, metabolic dysregulation and carcinogenic injury.