The objective of this study was to investigate the protective effects and underlying mechanisms of Astragalus polysaccharide (APS) against benzene-induced DNA damage and hematopoietic toxicity. A mouse model was established through subcutaneous injection of benzene (150 mg/kg/d), while APS (100 mg/kg/d) was administered intraperitoneally for 15 days. The results indicated significant improvements in haematotoxicity: APS markedly elevated the levels of white blood cell (WBC, restored to 68 % of normal) and platelets (Plt, 67 %) in benzene-exposed mice (p < 0.05). Additionally, it alleviated femoral bone marrow luminal fibrosis and reduced haematopoietic cell counts. Furthermore, DNA damage repair was observed: Western blotting (WB) and immunohistochemistry analyses demonstrated that APS decreased the expression levels of gamma-H2AX induced by benzene (p < 0.05) as well as p21 expression (p < 0.05/p < 0.0001), thereby ameliorating DNA damage in bone marrow cells. In a model involving K562 cells subjected to damage from the benzene metabolite 1,4-BQ, APS significantly down-regulated gamma-H2AX levels (p < 0.001/p < 0.05) and p21 levels (p < 0.0001/p < 0.01). Moreover, comet assay results revealed an 86 % reduction in DNA breaks due to APS treatment (p < 0.001). Through network pharmacological analysis, it was predicted that APS exerts its protective effects against DNA damage and hematopoietic toxicity by inhibiting oxidative stress while regulating gene expressions such as TNF-alpha, STAT3, and HSP90AA1; these findings were further validated using RT-qPCR along with MDA, GSH, and GSH-Px assays. In conclusion, this study demonstrates that APS has considerable potential to mitigate benzotoxicity while providing theoretical foundations for effective therapeutic strategies or interventions aimed at addressing benzotoxicity.

Perfluorooctane sulfonate (PFOS), a widely used persistent organic pollutant, has been implicated in multiple toxicities. However, its nephrotoxic mechanisms remain unclear. Chronic kidney disease (CKD) is a growing global health concern. We adopted a multidisciplinary approach combining epidemiological analysis, network toxicology, molecular docking, and animal experiments to investigate PFOS-induced kidney injury using CKD as a model. NHANES data (n = 9119) were analyzed to examine the association between serum PFOS levels and CKD prevalence. Network toxicology identified PFOS-related target genes, which were further refined through protein-protein interaction (PPI) analysis and validated using the GSE32591 dataset. A diagnostic model was constructed, and molecular docking and in vivo studies were performed to verify gene-compound interactions and biological effects. Coremine Medical was used to identify traditional Chinese medicine (TCM) candidates targeting key genes. Serum PFOS levels were significantly associated with CKD, showing a U-shaped dose-response. Four hub genes-ALB, PTGS2, AKT1, and IGF1-were identified and used to develop a diagnostic model with excellent accuracy (AUC = 0.96). Molecular docking confirmed stable PFOS-protein interactions. PFOS exposure in mice led to dose-dependent renal tubular injury, elevated NGAL and KIM-1 levels, and PI3K-AKT pathway activation. Astragalus membranaceus, identified through TCM screening, exhibited strong binding to the target proteins and may have therapeutic potential. This study reveals key molecular targets and pathways involved in PFOS-induced nephrotoxicity and proposes a TCM-based therapeutic strategy. Our findings offer new perspectives for risk assessment and intervention in PFOS-related kidney disease.

The novel pollutant, N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6-PPDQ) leaked out of the tire and has attracted extensive concerns due to its high lethal toxicity of salmon. However, the potential hepatotoxicity of 6-PPDQ exposure and its mechanisms are unknown. As a novel 3D cell culture, liver organoids (LOs) are more similar to real organ invitro in structure and function, which showed great potential for toxicity assessment. Herein, stable LOs were generated and their applicability on hepatotoxicity assessment was evaluated with four hepatotoxic compounds. The negative effect of 6-PPDQ was explored in LOs, live/dead staining visually demonstrated the damage to the liver, and the changes of ATP, LDH, ALT, and AST effectively reflected its hepatotoxicity. Meanwhile, machine learning-based quantitative assessments of LOs morphology changes provided objective data on area, circularity, and luminance changes, enabling sensitive detection of 6-PPDQ-induced hepatotoxicity. Furthermore, transcriptomic analysis revealed that the pathways related to DNA replication and repairment, cancers, and inflammation were significantly involved in the process of 6-PPDQ-induced liver injury; Disease enrichment analysis highlighted an increased risk of chronic liver diseases, and biliary atresia were validated by Cholyl-Lys-Fluorescein (CLF). Moreover, molecular docking analysis identified potential molecular targets of 6-PPDQ, including Slc6a9, Yes1, and Nos2. This study underscored the potential of LOs for toxicological studies and highlighted the toxic effects of 6-PPDQ on the liver, suggesting the need for further investigations to understand its long-term impact on human health.

Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) have become first-line therapies for advanced non-small cell lung cancer (NSCLC) with ALK rearrangements. This study investigates ALK-TKI-associated adverse events (AEs), focusing on identifying hepatotoxicity signals and previously undocumented safety concerns. Using disproportionality analysis of 56,864 reports from the FDA Adverse Event Reporting System (FAERS) database, we systematically classified AEs via the Medical Dictionary for Regulatory Activities (MedDRA). At the System Organ Class (SOC) level, crizotinib exhibited a significantly stronger signal for eye disorders, ceritinib was uniquely linked to gastrointestinal disorders, and loratinib was predominantly associated with metabolism and nutrition disorders. Several AEs previously undocumented in drug labels were identified, including pericardial effusion, elevated C-reactive protein, hemolytic anemia, hemoptysis, and decreased hemoglobin. Furthermore, crizotinib, ceritinib, and alectinib were significantly associated with hepatotoxicity, marked by elevated alanine aminotransferase, aspartate aminotransferase, and hepatic enzyme levels. These findings highlight the need for vigilant monitoring of unlabeled AEs and potential label updates, particularly for hepatotoxicity risks associated with crizotinib, ceritinib, and alectinib.

Noise-induced hearing loss (NIHL) is an occupational-related disease characterized by progressive sensorineural hearing impairment. Autophagy is thought as a key pathway mediated by highly conserved autophagy-related genes (ATGs) and plays a critical role in maintaining the homeostasis of cells, tissue and organisms. However, the potential molecular mechanism linking ATGs with NIHL are still relatively unclear. Here, we conducted a case-control study on 688 NIHL-afflicted cases and 667 normal hearing controls to investigate the relationship of single nucleotide polymorphisms (SNPs) in ATG4C, ATG5 and ATG7 genes with the susceptibility to NIHL. We found that ATG5 rs510432 CT/TT genotypes significantly diminished the risk of NIHL compared to the CC genotype. Individuals with rs510432 CT/TT genotypes had significantly elevated mRNA and plasma levels of ATG5 than those with the CC genotype. Human plasma with the rs510432 CT/TT genotypes expressed obviously higher SOD, GSH-Px and Bcl-2 than that with the CC genotype, while opposite trends were observed for Caspase-3. Mechanistically, rs510432 could regulate the transcription of ATG5 by affecting the binding of C/EBPβ in the promoter region. Of note, C/EBPβ knockdown promoted the expression of ATG5 and LC3-II and simultaneously inhibited p62 expression to induce autophagy in HEI-OC1 cells. Moreover, C/EBPβ knockdown could increase the Bcl-2 expression, but decrease the expressions of Caspase-3, Bax and PARP in HEI-OC1 cells. In summation, our study provides initial evidence that ATG5 rs510432 is associated with the susceptibility to NIHL by altering the binding efficiency of C/EBPβ to ATG5 promoter in a specific allelic manner and it may act as a promising biomarker for NIHL susceptibility.

The ubiquitous environmental presence of nanoplastics (NPs) necessitates urgent investigation into their biological impacts. As the primary target organ for accumulated NPs, the liver faces substantial health risks, but the differential hepatotoxic effects of different exposure routes remain unknown. In this study, a four-week exposure experiment in mice using polystyrene nanoplastics (PS-NPs) through oral and inhalation routes were conducted. Multidimensional assessments revealed exposure route-specific pathological patterns: oral administration primarily caused histopathological damage, whereas inhalation exposure induced more severe hepatic synthetic impairment and systemic inflammatory responses. Transcriptomic profiling identified 739 and 1350 differentially expressed genes (DEGs) for oral and inhalation routes respectively, with merely 17% overlap (228 DEGs), demonstrating fundamentally distinct molecular responses. Pathway enrichment analysis further indicated substantial disruption of lipid metabolism processes. Lipidomic analysis revealed that PS-NPs caused wide hepatic lipid profile alterations, 693 and 882 lipids were significantly changed after oral and inhalation exposure, mainly focused on Glycerophospholipids (GPs) and Glycerolipids (GLs). Further integrated multi-omics approaches revealed route-dependent metabolic reprogramming: oral exposure decreased Diacylglycerols (DG) and Phosphatidic acids (PA) through enhanced lipid hydrolysis and suppressed PA biosynthesis, while inhalation exposure remarkably elevated these lipid species. Notably, inhaled PS-NPs significantly increased polyunsaturated fatty acid (PUFA) levels, showing strong correlation with lipid peroxidation markers. This study provides the first experimental evidence of exposure route-dependent hepatotoxicity mechanisms for PS-NPs, elucidating distinct molecular pathways in nanoplastic-induced liver injury and revealing route-specific lipid metabolic disturbances, thereby offering crucial insights for environmental risk assessment and targeted preventive strategies.

Bacterial degradation is one important Microcystin (MC) removal method in the natural environment. The traditional MC-degrading pathway was proposed based on the functions of individual recombinant Mlr enzymes and the structures of the main MC-degrading products. However, the actual MC-degrading mechanism by Mlr enzymes in wild-type bacteria remains unclear. In this study, bioinformatic analysis, heterologous expression, and knockout mutation were performed to elaborate the MC-degrading mechanism by Mlr enzymes in Sphingopyxis sp. m6. The results showed that mlr gene cluster was initially acquired by horizontal gene transfer, followed by vertical inheritance within Alphaproteobacteria. Mlr enzymes exhibit distinct subcellular localizations and possess diverse conserved catalytic domains. The enzymatic cascade MlrA/MlrB/MlrC sequentially cleaves Microcystin-LR (MC-LR) via Adda-Arg, Ala-Leu, and Adda-Glu bonds, generating characteristic intermediates (linearized MC-LR, tetrapeptide, and Adda). Notably, recombinant MlrC demonstrated dual-targeting degrading capability (linearized MC-LR and tetrapeptide), while tetrapeptide specificity in endogenous processing of Sphingopyxis sp. m6. Marker-free knockout mutants of mlr genes were first constructed in MC-degrading bacteria, unveiling that mlrA was indispensable in initial MC cleavage, whereas mlrB/mlrC/mlrD displayed functional compensation through other enzymes with similar functions. This study promotes the mechanistic understanding of MC bacterial degradation and offers a theoretical basis for a bioremediation strategy targeting cyanotoxin pollution.

AI image processing techniques hold promise for clinical applications by enabling analysis of complex status information from cells. Importantly, real-time brightfield imaging has advantages of informativeness, non-destructive nature, and low cost over fluorescence imaging. Currently, human liver organoids (HLOs) offer an alternative to animal models due to their excellent physiological recapitulation including basic functions and drug metabolism. Here we show a drug-induced liver injury (DILI) level prediction model using HLO brightfield images (DILITracer) considering that DILI is the major causes of drug withdrawals. Specifically, we utilize BEiT-V2 model, pretrained on 700,000 cell images, to enhance 3D feature extraction. A total of 30 compounds from FDA DILIrank are selected (classified into Most-, Less-, and No-DILI) to activate HLOs and corresponding brightfield images are collected at different time series and z-axis. Our computer vision model based on image-spatial-temporal coding layer excavates fully spatiotemporal information of continuously captured images, links HLO morphology with DILI severity, and final output DILI level of compounds. DILITracer achieves an overall accuracy of 82.34%. To our knowledge, this is the first model to output ternary classification of hepatotoxicity. Overall, DILITracer, using clinical data as an endpoint categorization label, offers a rapid and effective approach for screening hepatotoxic compounds.

Polystyrene nanoplastics (PS-NPs) are omnipresent in the air and can be inhaled by humans. However, their long-term adverse implications and toxicological mechanisms for human respiratory health are unclear. Therefore, this study aims to provide new insights into the pulmonary toxicity of PS-NPs using mice and organoid models. After subacute and subchronic inhalation of PS-NPs, mice showed pronounced lung injury characterized by respiratory rate changes, altered hematology, and histological evidence of tissue damage and oxidative stress. Similarly, repeated PS-NPs exposure also restricted organoid growth and cause oxidative damage. Notably, through BisqueRNA analysis for a single-cell dataset and canonical markers verification, it was found that PS-NPs induced the emergence and accumulation of transitional cells, suggesting impaired alveolar epithelial repair processes. Sequencing analyses revealed dynamic alterations in non-coding RNA (ncRNA) profiles, including circRNAs and lncRNAs, in response to PS-NPs exposure. Moreover, temporal profiling highlighted distinct sets of ncRNAs as early and progression-associated biomarkers of PS-NP-induced lung injury. These biomarkers correlated with aberrant transitional cells, implicating their roles in disrupted cellular differen tiation and repair mechanisms. Overall, this study observed the multifaceted toxicological responses of PS-NPs to the respiratory system, emphasizing the critical involvement of ncRNAs in mediating PS-NP-induce transitional cells, which was crucial for elucidating the pathophysiology of nanoplastic-induced lung injury and developing targeted therapeutic strategies.

Background: Levofloxacin (LVX), a widely used fluoroquinolone antibiotic, is generally considered to have low hepatotoxic potential compared to its analog trovafloxacin (TVX). Although considered relatively safe, LVX has been implicated in Drug-induced liver injury (DILI) cases, prompting the need for a comprehensive mechanistic assessment. Methods: This study employed an integrated strategy combining real-world pharmacovigilance analysis based on FDA Adverse Event Reporting System (FAERS), human liver organoid modeling, and extracellular vesicle (EV) proteomics to systematically assess LVX-associated DILI risks and mechanisms. Results: A total of 1671 LVX-related DILI cases were identified in FAERS, with a predominance in males and individuals aged 45-65. Disproportionality analysis revealed statistically significant signals indicative of cholestatic liver injury phenotypes, including mixed liver injury, cholestasis, and conjugated hyperbilirubinemia, etc. Furthermore, liver organoid assays revealed that LVX induced moderate hepatocellular injury, which was less severe than that caused by TVX. EV proteomic analysis from LVX-exposed organoids identified glycolysis as the most significantly enriched pathway, with notable upregulation of phosphoglycerate kinase 1 (PGK1), lactate dehydrogenase A (LDHA), and fructose-bisphosphate aldolase A (ALDOA). The expression of these three key glycolysis-related targets was further validated by RT-qPCR and proteomic analysis, and molecular docking demonstrated strong binding affinities between LVX and these proteins. Collectively, these findings suggest that glycolytic reprogramming may contribute to the pathogenesis of LVX-induced liver injury. Conclusions: This study presents a multidimensional strategy to investigate LVX-induced liver injury by integrating real-world pharmacovigilance data with a human liver organoid model. Together, these findings provide a translational framework for elucidating DILI.

Toxicological assessment of chemicals is crucial for safeguarding human health and the environment. However, traditional animal experiments are associated with ethical, technical, and predictive limitations in assessing the toxicity of chemicals to the skin. With the recent development of bioengineering and tissue engineering, three-dimensional (3D) skin models have been commonly used as an alternative for toxicological studies. The skin consists of the subcutaneous, dermis, and epidermis. All these layers have crucial functions such as physical and biological protection and thermoregulation. The epidermis is the shallowest layer protecting against external substances and media. Because the skin is the first contact point for many substances, this organ is very significant for assessing local toxicity following skin exposure. According to the classification of the United Nations Global Harmonized System, skin irritation is a major potentially hazardous characteristic of chemicals, and this characteristic must be accurately assessed and classified for enhancing chemical safety management and preventing and reducing chemical accidents. This review discusses the research progress of 3D skin models and introduces their application in assessing chemical skin irritation.

Defective erythropoiesis is one of the causes of anemia and leukemia. However, the mechanisms underlying defective erythropoiesis under a low-dose environment of benzene are poorly understood. In the present study, multiple omics (transcriptomics and metabolomics) and methods from epidemiology to experimental biology (e.g., benzene-induced (WT and HIF-1α + ) mouse, hiPSC-derived HSPCs) were used. Here, we showed that erythropoiesis is more easily impacted than other blood cells, and the process is reversible, which involves HIF-1 and NF-kB signaling pathways in low-level benzene exposure workers. Decreased HIF-1α expression in benzene-induced mouse bone marrow resulted in DNA damage, senescence, and apoptosis in BMCs and HSCs, causing disturbances in iron homeostasis and erythropoiesis. We further revealed that HIF-1α mediates CCL3/macrophage-related immunosurveillance against benzene-induced senescent and damaged cells and contributes to iron homeostasis. Mechanistically, we showed that m6A modification is essential in this process. Benzene-induced depletion of m6A promotes the mRNA stability of gene NFKBIA and regulates the NF-κB/CCL3 pathway, which is regulated by HIF-1α/METTL3/YTHDF2. Overall, our results identified an unidentified role for HIF-1α, m6A, and the NF-kB signaling machinery in erythroid progenitor cells, suggesting that HIF-1α/METTL3/YTHDF2-m6A/NF-κB/CCL3 axis may be a potential prevention and therapeutic target for chronic exposure of humans to benzene-associated anemia and leukemia.

Benzene is a common environmental and occupational pollutant, benzene exposure causes damage to hematopoietic system. ZMAT3 is a zinc finger protein which has important biological functions. In this study, benzene-exposed mouse model and ZMAT3 overexpression and low expression hematopoietic stem cells (HSCs) models were constructed to explore the mechanism of ZMAT3 in benzene-induced hematopoietic toxicity. The results showed that benzene increased the expression of ZMAT3 in mouse bone marrow (BM) cells, HSCs and peripheral blood (PB) leukocyte, and the changes in HSCs were more sensitive than BM and PB cells. In addition, overexpression of ZMAT3 decreased the self-renewal ability of HSCs and reduced the HSCs differentiation into myeloid hematopoietic cells, while low expression has the opposite effect. Besides, over and low expression of ZMAT3 both increased the HSCs differentiation into lymphoid progenitor cells. Moreover, bioinformatics analysis suggested that ZMAT3 was associated with TNF-α signaling pathway, and the correlation was confirmed in mouse model. Meanwhile, the results indicated that ZMAT3 promoted TNF-α mRNA processing by binding to the ARE structural domain on TNF-α and interacting with hnRNP A2/B1 and hnRNP A1 proteins, ultimately activating the NF-κB signaling pathway. This study provides a new mechanism for the study of benzene toxicity.

Nanoplastics are widely distributed in indoor and outdoor air and can be easily inhaled into human lungs. However, limited studies have investigated the impact of nanoplastics on inhalation toxicities, especially on the initiation and progression of chronic obstructive pulmonary disease (COPD). To fill the gap, the present study used oronasal aspiration to develop mice models. Mice were exposed to polystyrene nanoplastics (PS-NPs) at three concentrations, as well as the corresponding controls, for acute, subacute, and subchronic exposure. As a result, PS-NPs could accumulate in exposed mice lungs and influence lung organ coefficient. Besides, PS-NPs induced local and systemic oxidative stress, inflammation, and protease-antiprotease imbalance, resulting in decreased respiratory function and COPD-like lesions. Meanwhile, PS-NPs could trigger the subcellular mechanism to promote COPD development by causing mitochondrial dysfunctions and endoplasmic reticulum (ER) stress. Mechanistically, ferroptosis played an important role in the COPD-like lung injury induced by PS-NPs. In summary, the present study comprehensively and systematically indicates that PS-NPs can damage human respiratory health and increase the risk for COPD.

Copper, a vital mineral nutrient, possesses redox qualities that make it both beneficial and toxic to organisms. Excessive environmental copper exposure can result in neurological damage and cognitive decline in humans. Astrocytes, the predominant glial cells in the brain, are particularly vulnerable to pollutants, but the mechanism of copper-induced damage to astrocytes remains elusive. The aim of this study was to determine the role of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway in initiating NLRP3 inflammasome-induced astrocyte pyroptosis and chronic inflammation under conditions of copper overload. Our findings indicated that copper exposure elevated mitochondrial ROS (mtROS) levels, resulting in mitochondrial damage in astrocytes. This damage caused the release of mitochondrial DNA (mtDNA) into the cytoplasm, which subsequently activated the cGAS-STING pathway. This activation resulted in interactions between STING and NLRP3 proteins, facilitating the assembly of the NLRP3 inflammasome and inducing pyroptosis. Furthermore, depletion of mtROS mitigated copper-induced mitochondrial damage in astrocytes and reduced mtDNA leakage. Pharmacological inhibition of STING or STING transfection further reversed copper-induced pyroptosis and the inflammatory response. In conclusion, this study demonstrated that the leakage of mtDNA into the cytoplasm and the subsequent activation of the cGAS-STING-NLRP3 pathway may be potential mechanisms underlying copper-induced pyroptosis in astrocytes. These findings provided new insights into the toxicity of copper.

Exposure to micro- and nanoplastics (MNPs) has been implicated in potential cardiotoxicity. However, in vitro models based on cardiomyocyte cell lines lack crucial cardiac characteristics, while interspecies differences in animal models compromise the reliability of the conclusions. In addition, current research has predominantly focused on single-time point exposures to MNPs, neglecting comparative analyses of cardiac injury across early and late stages. Moreover, there remains a large gap in understanding the susceptibility to MNPs under pathological conditions. To address these limitations, this study integrated cardiac organoids (COs) and organ-on-a-chip (OoC) technology to develop the cardiac organoid-on-a-chip (COoC), which was validated for cardiotoxicity evaluation through multiple dimensions. Based on COoC, we conducted a dynamic observation of the cardiac damage caused by short- and long-term exposure to polystyrene nanoplastics (PS-NPs). Oxidative stress, inflammation, disruption of calcium ion homeostasis, and mitochondrial dysfunction were confirmed as the potential mechanisms of PS-NP-induced cardiotoxicity and the crucial events in the early stages, while cardiac fibrosis emerged as a prominent feature in late stages. Notably, low-dose exposure exacerbated myocardial infarction symptoms under pathological states, despite no significant cardiotoxicity shown in healthy models. In conclusion, these findings further deepened our understanding of PS-NP-induced cardiotoxic effects and introduced a promising in vitro platform for assessing cardiotoxicity.

An increasing number of harmful environmental factors are causing serious impacts on human health, and there is an urgent need to accurately identify the toxic effects and mechanisms of these harmful environmental factors. However, traditional toxicity test methods (e.g., animal models and cell lines) often fail to provide accurate results. Fortunately, organoids differentiated from stem cells can more accurately, sensitively and specifically reflect the effects of harmful environmental factors on the human body. They are also suitable for specific studies and are frequently used in environmental toxicology nowadays. As a combination of organoids and organ-on-a-chip technology, organoids-on-a-chip has great potential in environmental toxicology. It is more controllable to the physicochemical microenvironment and is not easy to be contaminated. It has higher homogeneity in the size and shape of organoids. In addition, it can achieve vascularization and exchange the nutrients and metabolic wastes in time. Multi-organoids-chip can also simulate the interactions of different organs. These advantages can facilitate better function and maturity of organoids, which can also make up for the shortcomings of common organoids to a certain extent. This review firstly discussed the limitations of traditional toxicology testing platforms, leading to the introduction of new platforms: organoids and organoids-on-a-chip. Next, the applications of different organoids and organoids-on-a-chip in environmental toxicology were summarized and prospected. Since the advantages of the new platforms have not been sufficiently considered in previous literature, we particularly emphasized them. Finally, this review also summarized the opportunities and challenges faced by organoids and organoids-on-a-chip, with the expectation that readers will gain a deeper understanding of their value in the field of environmental toxicology.

LncRNA TUG1 plays pivotal roles in various diseases. However, its exact roles in benzene - induced hematotoxicity remain unclear. Herein, we aimed to investigate the role and mechanism of TUG1 in hematoxic injuries caused by benzene. In the current study, TUG1 was found dramatically decreased in WBCs of benzene exposure workers and negatively correlated with benzene exposure duration and urine SPMA. In vitro assays demonstrated that TUG1 overexpression attenuated 1,4-BQ-caused suppression of cell viability and proliferation, and promotion of ROS generation and apoptosis via PI3K/AKT/mTOR pathway. Bioinformatic prediction and molecular assay validated miR-34a-5p was negatively regulated by TUG1. The miR-34a-5p was upregulated in 1,4-BQ treated cells and downregulated in TUG1 overexpression cells. Moreover, miR-34a-5p upregulation partially reversed the protective effects of TUG1 overexpression on 1,4-BQ - caused cytotoxicity. Furthermore, SIRT6 was a downstream target gene of miR-34a-5p, whose expression was reduced in miR-34a-5p upregulation cells and elevated in TUG1 overexpression cells. Upregulated SIRT6 could counteract accelerated cytotoxicity mediated by miR-34a-5p upregulation after 1,4-BQ treatment. Taken together, our study revealed that the critical role of the TUG1/miR-34a-5p/SIRT6 axis in benzene-caused hematotoxicity, and provided scientific basis for further understanding the epigenetic regulatory mechanisms underlying benzene hematotoxicity.

Conventional plastics are inherently difficult to degrade, causing serious plastic pollution. With the development of society, biodegradable plastics (BPs) are considered as an alternative to traditional plastics. However, current research indicated that BPs do not undergo complete degradation in natural environments. Instead, they may convert into biodegradable microplastics (BMPs) at an accelerated rate, thereby posing a significant threat to environment. In this paper, the definition, application, distribution, degradation behaviors, bioaccumulation and biomagnification of BPs were reviewed. And the impacts of BMPs on soil and marine ecosystems, in terms of physicochemical property, nutrient cycling, microorganisms, plants and animals were comprehensively summarized. The effects of combined exposure of BMPs with other pollutants, and the mechanism of ecotoxicity induced by BMPs were also addressed. It was found that BMPs reduced pH, increased DOC content, and disrupted the nitrification of nitrogen cycle in soil ecosystem. The shoot dry weight, pod number and root growth of soil plants, and reproduction and body length of soil animals were inhibited by BMPs. Furthermore, the growth of marine plants, and locomotion, body length and survival of marine animals were suppressed by BMPs. Additionally, the ecotoxicity of combined exposure of BMPs with other pollutants has not been uniformly concluded. Exposure to BMPs induced several types of toxicity, including neurotoxicity, gastrointestinal toxicity, reproductive toxicity, immunotoxicity and genotoxicity. The future calls for heightened attention towards the regulation of the degradation of BPs in the environment, and pursuit of interventions aimed at mitigating their ecotoxicity and potential health risks to human.

The emerging contaminant nanoplastics (NPs) have received considerable attention. Due to their tiny size and unique colloidal properties, NPs could more easily enter the body and cross biological barriers with inhalation exposure. While NPs -induced hepatotoxicity has been reported, the hepatic impact of inhaled NPs was still unknown. To close this gap, a 40 nm polystyrene NPs (PS -NPs) inhalation exposure mice model was developed to explore the hepatotoxicity during acute (1 week), subacute (4 weeks), and subchronic period (12 weeks), with four exposure doses (0, 16, 40, and 100 mu g/day). Results showed that inhaled PS -NPs caused a remarkable increase of ALT, AST, and ALP with a decrease of CHE, indicating liver dysfunction. Various histological abnormalities and significantly higher levels of inflammation in a dose- and time -dependent manner were observed. Moreover, after 4 weeks and 12 weeks of exposure, Masson staining and upregulated expression of TGF-beta, alpha-SMA, and Col1a1 identified that inhaled PS -NPs exposure triggered the progression of liver fibrosis with the exposure time prolonged. From the mechanistic perspective, transcriptome analysis revealed that ferroptosis was involved in PS -NPs -induced liver hepatotoxicity, and key features of ferroptosis were detected, including persistent oxidative stress, iron overload, increased LPO, mitochondria damage, and the expression changes of GPX4, TFRC, and Ferritin. And in vitro and in vivo recovery tests showed that ferroptosis inhibitor Fer-1 treatment alleviated liver injury and fibrosis. The above results confirmed the critical role of ferroptosis in PS -NPs -induced hepatotoxicity. Furthermore, to better conclude our findings and understand the mechanistic causality within it, an adverse outcome pathway (AOP) framework was established. In total, this present study conducted the first experimental assessment of inhalation exposure to PS -NPs on the liver, identified that continuous inhaled PS -NPs could cause liver injury and fibrosis, and PS -NPs- ferroptosis provided a novel mechanistic explanation.