Idiopathic pulmonary arterial hypertension (PAH) is a progressive cardiovascular disorder with high mortality. Although both genetic and environmental factors are implicated in its pathogenesis, the underlying mechanisms remain unclear. We integrated transcriptomic data from PAH lung tissue, GWAS summary statistics, and QTL data for DNA methylation, gene expression, and plasma protein. Core dysregulated genes were first identified via differential expression and protein-protein interaction network analysis. Using summary-data-based Mendelian randomization (SMR), we systematically evaluated potential potential genetic associations between methylation, expression, or protein levels of candidate genes and PAH risk, with the HEIDI test to distinguish causality from pleiotropy. Key findings were validated by examining gene expression trends in two independent cohorts. Finally, reverse network toxicology was applied: environmental pollutants targeting identified genes were screened using the CTD, their binding potential assessed via molecular docking, and effects of a candidate pollutant on gene expression and cell proliferation validated in vitro in human pulmonary artery smooth muscle cells (HPASMCs). We identified 254 differentially expressed genes in PAH. Among these, TAGLN2 exhibited a significant positive association with PAH risk at three molecular levels-DNA methylation, gene expression, and plasma protein, suggesting a pathogenic role. Specifically, increased TAGLN2 protein abundance (HR = 9.00, 95% CI: 1.52-53.16) and gene expression levels (HR = 9.00, 95% CI: 1.52-53.16) were associated with higher PAH risk, while its methylation sites (e.g., cg13892570, cg16107628) showed a negative association. Validation in two independent cohorts confirmed that TAGLN2 expression was upregulated in the lung tissue of PAH patients. Reverse toxicology predicted eight environmental pollutants as potential TAGLN2-targeting agents, including PFOS, dibutyl phthalate, bisphenols, and benzo[a]pyrene. Molecular docking indicated that all these compounds could bind stably to the TAGLN2 protein (binding free energy < -5.0 kcal/mol), with PFOS exhibiting the strongest binding affinity (-8.9 kcal/mol). In vitro experiments showed that PFOS upregulated TAGLN2 mRNA expression in HPASMCs and promoted cell proliferation in a dose-dependent manner, providing preliminary correlative evidence. This study prioritizes TAGLN2 as a genetically associated candidate gene for PAH and identifies environmental pollutants that may target TAGLN2. While the in vitro data show that PFOS upregulates TAGLN2 expression and promotes HPASMC proliferation, functional perturbation experiments are needed to establish a mechanistic requirement for TAGLN2. These findings provide hypothesis-generating insights into potential gene-environment interactions in PAH.
This study employs network toxicology to screen for toxicological targets of cadmium chloride-induced male infertility, and validates the mechanism of Yishen Tongluo Formula in treating cadmium-induced male infertility through animal experiments. Employing network toxicology to search for potential target molecules in the ChEMBL database, and STITCH databases using 'cadmium chloride' as the keyword to identify potential targets. Using "male infertility" as the keyword, we searched for male infertility-related targets in the OMIM, PharmGKB, and GeneCards databases. The primary components of the Yishen Tongluo Formula were then input into the SwissTargetPrediction and PharmMapper databases to identify potential targets. Cadmium chloride, Yishen Tongluo Formula component targets, and male infertility-related disease targets were imported into Venny 2.1.0 to construct a protein-protein interaction (PPI) network by identifying intersections. Cadmium chloride-induced male infertility-related targets were imported into Metascape for Gene Ontology (GO) and KEGG pathway enrichment analysis. Molecular docking validation was performed, and a 'compound-target-pathway' network was constructed for result visualisation. In animal experiments, 33 mice were randomly divided into three groups: a control group, a cadmium chloride-exposed group (Cd group), and a Yishen Tongluo Formula group, with 11 mice per group. Cadmium chloride was diluted in purified water to a working solution of 0.3 mg/ml. Except for the control group, the Cd group and Yishen Tongluo Formula group received cadmium chloride via gavage at 10 ml/kg for 70 days. After successful modeling, from day 31 onward, the cadmium-exposed group and the herbal intervention group received daily gavage of 10 ml/kg cadmium chloride working solution at 8:00 a.m. At 6:00 pm daily, the herbal intervention group received 10 ml/kg of the Yishen Tongluo Formula decoction solution via protective gastric lavage, The Yishen Tongluo Formula group received 1.2 g/ml of the decoction solution via gastric lavage, while the toxic exposure group received the same volume of deionised water. The control group received the same volume of deionised water at the same time points. All three groups underwent continuous gastric lavage for 40 days. Following organ collection, the following parameters were assessed: sperm DNA fragmentation index (DFI), testicular index, testicular superoxide dismutase (SOD), malondialdehyde (MDA), adenosine triphosphate (ATP), nitric oxide (NO), and serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone (T) were assessed. This study demonstrates that cadmium chloride induces male reproductive toxicity by targeting CFTR, SLC26A3, and SLC12A1 via the pancreatic secretion pathway, causing oxidative stress, endocrine disorders, sperm DNA damage, and testicular tissue injury. Yishen Tongluo Formula exerts therapeutic effects against cadmium-induced male infertility mainly by targeting TP53, which significantly improves testicular coefficient, reduces sperm DFI, enhances sperm quality, alleviates testicular oxidative stress, and restores the balance of reproductive hormones. These findings reveal the multi-target mechanism of Yishen Tongluo Formula in repairing cadmium-induced reproductive damage, provide a novel experimental basis for the treatment of heavy metal-related male infertility with traditional Chinese medicine, and suggest that further exploration of molecular mechanisms and clinical transformation will help develop safer and more effective intervention strategies for environmental toxin-induced reproductive dysfunction.
Metal and metalloid contamination from terrestrial and maritime human activities increasingly threatens coastal ecosystems, inducing ecotoxicological effects and potential risks to human health. Filter-feeding intertidal species such as Ruditapes spp. can bioaccumulate these contaminants and are therefore widely used for coastal environmental monitoring. For ecotoxicological purposes, seasonal and spatial concentrations of metals (Al, Cd, Cr, Co, Cu, Fe, Mn, Ni, Pb, V and Zn) and the metalloid As were analysed in sediments and clam tissues from the French English Channel and Atlantic coasts, using a multi-scale approach (local, regional and national). Spatial differences were mainly observed at local and regional scales, whereas no marked differences were detected at the national scale. Bioaccumulation in Ruditapes spp. was compared with Mytilus edulis and Crassostrea gigas, two other commonly used sentinel species. The species- and site-specific accumulation patterns suggested that employing multiple species could enhance environmental monitoring strategies. As showed the highest bioaccumulation values, followed by Zn, Cu, Ni and Co. Finally, environmental and human health risk assessments indicated that, among the studied elements, only As may raise concern in some sites, while risks associated with other metals remained low.
Environmental detection of antimicrobial resistance has expanded rapidly, but many programs still treat detection of antibiotic resistance genes (ARGs) or resistant bacteria as the primary endpoint. As a result, outputs are often only weakly linked to antibiotic exposure conditions and remain difficult to compare, interpret, and use consistently for follow-up decisions. This review examines how detection of antibiotics and ARG/ARB can be standardized for regulatory interpretation and qualitative concern tiering. It defines standardization across pre-analytical, analytical, data, and interpretive layers; proposes a minimum detection package; and describes how comparison-ready chemical and biological outputs can support integrated interpretation. It also reviews chromatographic, sequencing, biosensor, and other recognition-based platforms, arguing that platform choice should match screening, confirmation, quantification, or discovery roles. This review then outlines a four-tier framework for concern and decision priority, together with reporting and implementation elements needed to translate detection results into proportionate follow-up. Environmental AMR detection becomes more useful when antibiotic exposure, ARG/ARB evidence, and contextual information are standardized and interpreted together rather than handled as separate streams.
Benzo[a]pyrene (BaP) is a recognized mutagen and carcinogen, yet epidemiological links to breast cancer (BC) remain inconclusive. We integrated network toxicology, machine learning, and bioinformatics. BaP targets (ChEMBL, PharmMapper, SEA, GeneCards, OMIM) were intersected with BC genes, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Core regulatory genes were further screened using diverse machine-learning algorithms, and their expression levels, diagnostic performance, and associations with the tumor immune microenvironment were subsequently validated. Gene Set Variation Analysis (GSVA) was applied to assess pathway activity, and Cytoscape was used to construct a lncRNA-miRNA-mRNA multilevel regulatory network, thereby elucidating post-transcriptional control mechanisms. Finally, molecular docking and molecular dynamics simulations were performed to evaluate potential interactions between BaP and the core targets. A total of 216 overlapping BaP-breast cancer targets were initially identified, which were significantly enriched in processes such as the mitogen-activated protein kinase (MAPK) signaling pathway. Seven core genes were identified by machine-learning-based screening; among them, KIF11, INHBA, NEK2, and AURKA exhibited significantly higher expression in breast cancer tissues and were associated with worse patient prognosis and altered immune-cell infiltration. Based on pathway analyses, tumor progression was inferred to be promoted by these genes through regulation of the cell cycle, DNA replication, and cell-adhesion pathways. Molecular modeling indicated that BaP could form stable binding conformations with the proteins encoded by KIF11, AURKA, INHBA, and NEK2, suggesting possible direct interactions. This research provides new theoretical insights into the etiology of environmental pollutant-induced BC and offers potential molecular biomarkers for risk assessment and the formulation of targeted prevention strategies.
Arecoline, the major alkaloid of areca nut, is a common exposure in chewing products, but its relationship with prostate cancer (PCa) is unclear. We integrated network toxicology, bulk RNA machine learning, single-cell transcriptomics, molecular simulation, and in vitro validation to prioritize candidate molecular nodes potentially linking arecoline exposure to PCa-related alterations. Potential arecoline targets were intersected with PCa-related genes, followed by protein-protein interaction and enrichment analyses. Candidate genes were prioritized using TCGA-PRAD and external GEO cohorts, then refined in GWAS-relevant epithelial subpopulations from GSE141445. AR was further evaluated by the Human Protein Atlas, molecular docking, molecular dynamics, RT-qPCR, and Western blotting. We identified 97 overlapping targets enriched mainly in apoptosis-, p53-, and MAPK-related pathways. The optimal bulk RNA model showed good external performance (AUC = 0.956). Integrative analyses identified androgen receptor (AR) as the only consensus core gene. AR-high epithelial cells showed increased androgen response, mTORC1 signaling, and MYC targets. Molecular simulation provided computational support for structural compatibility between arecoline and AR, while in vitro experiments showed increased AR mRNA and protein expression after arecoline treatment in LNCaP cells. These findings suggest AR as a plausible candidate molecular node linking arecoline exposure to PCa-related molecular alterations and provide a hypothesis-generating framework for future mechanistic and exposure-focused studies.
Growing concerns regarding per- and polyfluoroalkyl substances (PFAS) as pervasive environmental contaminants have prompted increasing scrutiny regarding their potential contributions to pulmonary diseases. Therefore, this study specifically investigates their implications in lung adenocarcinoma (LUAD) pathogenesis. We utilized the Comparative Toxicogenomics Database (CTD), GeneCards, and OMIM databases to collect LUAD-related targets, while PFAS-related targets were independently predicted from ChEMBL, SwissTargetPrediction, and PharmMapper databases using stringent criteria. The intersecting targets were subjected to protein-protein interaction (PPI) network construction, functional enrichment analysis and molecular docking. We then integrated multi-omics data using ten clustering algorithms to identify the consensus LUAD subtypes, which were subsequently employed in three machine learning algorithms to develop a consensus per- and polyfluoroalkyl substance-related signature (CPFASRS) for LUAD patients. Consequently, we identified six hub toxicological targets: HSP90AA1, EGFR, AKT1, ALB, SRC, and ESR1, highlighting their potential central roles in PFAS-driven LUAD pathogenesis. These targets are enriched in PPAR signaling pathway, chemical carcinogenesis-receptor, and thyroid hormone signaling pathway. The PFAS-toxicity classifiers and CPFASRS prognostic model serve as valuable tools for clinical stratification and personalized management of LUAD patients. Molecular docking suggested that Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) bind tightly to core targets and weakly to other proteins, which may imply a potential role in PFAS-related LUAD toxicity. Therefore, this study clarifies how PFAS contribute to the development of LUAD and explores the molecular pathways involved, providing crucial insights into the toxicological effects of PFAS. Furthermore, it establishes a theoretical basis for devising preventive strategies and therapeutic approaches for pulmonary diseases related to PFAS exposure.
The contamination of wheat by aflatoxins, mainly resulting from fungal development during storage, represents a significant public health concern due to their well-documented carcinogenic effects. This study aimed to quantify aflatoxin contamination levels (AFB1, AFB2, AFG1, and AFG2) in Triticum durum wheat samples stored in four regions of Morocco, characterised by climatic conditions ranging from semi-arid to sub-humid. Aflatoxin B1 (AFB1) was detected in 27% of the analysed samples, with quantifiable concentrations ranging from 0.025 to 20.95 µg/kg. Among the AFB1-contaminated samples, 58% exceeded the regulatory limit. Traces of aflatoxin B2 (AFB2) and aflatoxin G2 (AFG2) were also detected in some samples. Aflatoxin occurrence appeared to be associated with regional climatic conditions, with higher contamination levels observed in humid coastal areas than in semi-arid regions. Molecular analysis of wheat samples corroborated the findings obtained by HPLC with fluorescence detection (HPLC-FLD) by revealing the presence of multiple Aspergillus species, including A. flavus (19.4%), A. aflatoxiformans (11.6%), A. versicolor (5.2%), A. nidulans (4.9%), and A. nomius (3.1%). Furthermore, the key genes involved in aflatoxin biosynthesis, aflR and omtA, were detected in all identified aflatoxigenic strains using multiplex PCR. Moreover, AFB1, the most toxic aflatoxin, was consistently detected in bread samples prepared from contaminated wheat grain. Although its concentration decreased by 40% to 70% during the baking process, the toxin remained present at concerning levels, underscoring the persistent health risk associated with aflatoxin contamination. These findings highlight the need for enhanced monitoring and control measures throughout the wheat production and storage chain to mitigate potential health hazards.
Hypersensitivity pneumonitis (HP) is an immune-mediated lung disease caused by repeated exposure to organic and inorganic antigens. Epidemiological studies suggest particulate matter (PM) exposure as a risk factor; however, the specific mechanisms underlying PM-induced injury remain uncharacterized. Here, we investigated whether repeated exposure to diesel exhaust particles (DEPs), a major component of PM2.5, could induce HP-like immune responses in mice. Mice received repeated intratracheal instillations of DEPs, and histopathological, immunological, and transcriptomic changes were evaluated across multiple points. Repeated DEP exposure showed features commonly used for the diagnosis of HP, including poorly formed non-caseating granulomatous inflammation and infiltration of mononuclear cells and lymphocytes. Transcriptomic and protein analyses demonstrated enhanced FcγR-associated immune complex-related phagocytic processes as well as antigen processing and presentation processes, consistent with immunological features bridging type Ⅲ and Ⅳ hypersensitivity responses. After 14 repeated DEP exposures, mouse lungs shared transcriptomic signatures with human HP lungs, including antigen presentation, humoral immune response, chemokine, and extracellular matrix-related pathways. Based on these findings, we constructed a putative adverse outcome pathway describing DEP-induced HP-like immunopathology. Collectively, these findings indicate that repeated DEP exposure results in key immunopathological features resembling HP and provide mechanistic insight into PM-associated immune-mediated lung disease.
The increasing global production of plastics has raised concerns about additive chemicals that can leach from polymer matrices and lead to widespread human and environmental exposure. While regulatory attention to endocrine-disrupting chemicals (EDCs) and their association with plastic additives has increased in recent years, hazard information for numerous plastic additives remains limited. Here, we applied an integrated new approach methodologies (NAMs)-based framework combining in silico molecular docking and in vivo Caenorhabditis elegans assays to efficiently screen the endocrine-disrupting potential of plastic additives. Molecular docking of 162 EU REACH-registered additives was performed against human estrogen and androgen receptors (ERα and AR), followed by cross-species docking using AlphaFold-predicted homology models of the C. elegans nuclear receptors (NHR-14 and NHR-69). Chemicals showing strong binding interactions across species were further examined through a systematic literature review focused on ER- and AR-mediated effects. By integrating evidence, 1,3-diphenylpropane-1,3-dione (DBM) and 2-(benzotriazol-2-yl)-4-methylphenol (UV-P) were identified as potential ER and AR disruptors and were subsequently validated through reproductive toxicity assays using C. elegans wild-type N2 and loss-of-function mutant strains (nhr-14 and nhr-69). This integrated approach provides a practical NAMs-based prioritization strategy by linking molecular interactions to phenotypic outcomes. By positioning C. elegans as a biological bridge between human toxicology and ecotoxicology, the framework supports cross-species hazard characterization within a One Health perspective.
As an endocrine-disrupting chemical, 4-nonylphenol (4-NP) has been found above safe limits in global water systems and associated with cancer progression. This multidisciplinary study systematically investigated the carcinogenic mechanisms of 4-NP by integrating network toxicology, machine learning, molecular docking simulations, single-cell RNA sequencing, and spatial transcriptomics. We identified oncogenic targets associated with 4-NP and performed pan-cancer expression profiling and prognostic analysis of 27 core genes, followed by machine learning algorithms to quantify the prognostic weights of these genes in different malignancies. Molecular docking identified six high-affinity 4-NP-binding targets (TNF, CDK2, PRKCA, ERBB2, CASP8, MAPK3); binding energies less than -7.0 (kcal/mol). Mechanistically, ERBB2, CDK2 and MAPK3 may be involved in the activation of the MAPK signaling pathway, and PRKCA plays a key regulatory role in this process, thus promoting oncogenic signaling. Meanwhile, TNF and CASP8 may lead to CD8⁺ T-cell exhaustion, thereby promoting the establishment of an immunosuppressive tumor microenvironment. Finally, we designed a 4-NP intervention model with concentrations ranging from 0.1 to 10 μmol/L, based on the upper concentration limits of polluted surface water and extreme upper values in heavily pollution, and validated its effect on promoting cell proliferation and CDK2 expression in two breast cancer cell lines. Our findings not only elucidate the potential role of 4-NP in tumorigenesis, but also establish a computational-experimental framework for environmental toxicant assessment. This work provides important insights for developing preventive strategies against pollutant-driven malignancies, bridging molecular toxicology and clinical cancer biology.
Azoxystrobin is a widely used strobilurin fungicide. Its environmental persistence and potential toxicity to aquatic organisms demand accurate trace-level quantification in biological tissues. However, its sensitive and specific determination in small tissue samples using conventional methods remains challenging. In this study, a novel high-sensitivity analytical method based on ultra-performance liquid chromatography coupled with triple-stage mass spectrometry (UPLC-MS3) was established for the trace determination of azoxystrobin in zebrafish liver tissues. Following protein precipitation extraction, chromatographic separation was performed on a C18 column using a gradient of 0.1% aqueous formic acid and acetonitrile. Detection relied on an optimized MS3 transition (m/z 404.0 → 371.9 → 344.2). The method exhibited excellent linearity (r > 0.9984) from 0.1 to 20 ng mL-1, with accuracy between -3.33% and 3.67% and precision (CV) between 5.57 and 10.19%. Consistent recoveries (94.93-106.64%) and minimal matrix effects (99.45-104.79%) were achieved across all tissue matrices. Compared to conventional MRM, MS3 scanning significantly enhanced specificity by reducing endogenous interference. The validated approach was successfully applied to tissue distribution studies in zebrafish, confirming its reliability for environmental toxicology research and providing a robust platform for investigating fungicide biodistribution in aquatic organisms.
Increasing public use of disinfectants and antiseptics (DAs) has raised concerns about their environmental contamination and adverse effects on non-target organisms, despite critical knowledge gaps in the ecological risks posed by DAs. This study adopted the risk quotient (RQ)-based assessment and a network pharmacology-based framework to screen potential ecological risks of 42 hydrophobic DAs. Among 27 RQ-available DAs, 19 DAs were predicted to pose high ecological risks, with chlorhexidine, dimethyldioctadecylammonium bromide, cetylpyridinium chloride, triclosan, and triclocarban exhibiting RQ > 100. Based on the screening criteria that the 50% effective concentrations for targets were equal to or below the predicted fish plasma concentrations, the final environmental risk-based network retained 140 targets and 214 DA-target interactions for 10 DAs. Functional analyses identified 8 core targets of the DA mixtures in fish, which were related to the behavior, endocrine, nervous system, digestive system, cardiovascular system, skeletal system, and eyes in exposed zebrafish.
Extremely premature infants are a highly vulnerable patient group that might be exposed to a vast number of dietary and environmental contaminants, which may impact their health trajectories. This study assessed xenobiotic exposures in 26 extremely premature infants, with a special focus on dietary mycotoxins, using a dual analytical approach combining four sensitive, targeted LC-MS/MS methods and one non-targeted high-resolution mass spectrometry (HR-MS) assay. A total of 187 matched biological samples comprising breast milk (n = 35), plasma (n = 48), urine (n = 52), and stool (n = 52) collected at 7 and 28 days post-partum were subjected to mycotoxin analysis by quantitative LC-MS/MS. In addition, the LC-HRMS workflow using data-dependent MS2 acquisition was applied to a small subset of 20 selected plasma samples to provide first insights into a broader chemical exposure characterization through suspect screening and non-targeted analysis (NTA). The targeted analyses revealed that most mycotoxin exposure biomarkers were absent in the samples. However, ochratoxin A was quantified in all breast milk and plasma samples (median values of 43 ng/L and 135 ng/L) and in 27% of urine samples (median: 20 ng/L). Citrinin was detected in 34% of breast milk and 6% of stool samples (median values of 10 ng/L and 2.5 ng/g). Alternariol monomethyl ether was detected in 94% of breast milk, 12% of stool, and 31% of tested urine specimens. In the non-targeted analysis, 356 features were annotated with confidence Levels 2a, 2b, and 3, while 20 compounds were identified at Level 1 with authentic reference standards. This included key toxicants like per- and polyfluorinated substances (PFAS), bisphenol A, cotinine, and phthalates. Albeit a small cohort, this study demonstrated that extremely premature infants were exposed to a mixture of dietary, environmental, and lifestyle-related exposures. While many of the analyzed mycotoxins, including the carcinogenic aflatoxins, were not detected and indicated low overall mycotoxin exposure, plastics- and industry-related chemicals were detected at comparatively high levels, warranting further investigation into their potential health implications.
In recent years, the zebrafish (Danio rerio) has become a prominent vertebrate model for toxicological and pharmacological research. Over 70% of its genome shares orthologous sequences with that of humans, establishing it as a genetically manipulable system that mirrors significant drug-target interactions and pathways associated with human diseases. While external fertilization and fast growth (organ function within 96-120 h) are made possible by transparent embryos and larvae, real-time, noninvasive monitoring of organogenesis and cellular processes is also made possible. Enable multi-well formats for high-throughput phenotypic screening. These characteristics, together with affordable housing expenses and adherence to the 3R ethical standards, make zebrafish an ethically and financially advantageous substitute for mammalian models. Its predictive value for developmental, neuro, and cardiotoxicity evaluations has been validated by comparative studies that show ≥ 80% concordance between zebrafish toxicity findings and mammalian data. Recent developments allow for exact dose-response modeling, metabolic profiling, and mechanistic dissection of oxidative stress, ER stress, inflammation, and apoptotic pathways by combining zebrafish tests with quantitative systems pharmacology. Additionally, zebrafish are being used more and more in environmental toxicology to examine the effects of pollutants on behaviors and neurodevelopment, bridging the gap between risk assessment for human health and the environment. The zebrafish model, when utilized in combination, provides significant experimental throughput and relevance for translation and accelerates safety pharmacology, toxicological mechanistic studies, and the process of drug development.
Heavy metal ions trigger hydrogen peroxide (H2O2) outbreak and sustained toxic damage, but current H2O2 fluorescent probes still suffer from critical limitations in revealing long-term oxidative stress under cadmium ion (Cd2+) and mercury ion (Hg2+) co-exposure, and are limited by narrow Stokes shift and insufficient sensitivity. Herein, an original donor-π-acceptor (D-π-A) push-pull electron transferring fluorescent probe, TQ-H2O2, was designed for clarifying the vague relationship between Cd2+/Hg2+-triggered up-regulated H2O2 overproduction, oxidative imbalance and cellular damage. Intrinsic fluorescence quenching was eliminated and the intramolecular charge transfer (ICT) mechanism restored upon addition of H2O2. The probe affords splendid responsive performance, including a large Stokes shift (119 nm), excellent sensitivity (LOD = 86.6 nM), distinctive specificity and decent biosecurity. TQ-H2O2 was employed to observe exogenous and endogenous H2O2 level fluctuations in RAW264.7 cells, HepG2 cells and zebrafish, and provided visual evidence of Cd2+/Hg2+-mediated H2O2 variation at the cellular level after exposure. Furthermore, the attenuation of the mitochondrial membrane potential (MMP) and the degree of cell damage under variant stimulation with Cd2+/Hg2+ were evaluated. This work establishes a reliable analytical method for visualizing H2O2 dynamics and clarifying the causal link between heavy metal-induced oxidative stress, mitochondrial dysfunction, and cellular damage, providing a powerful tool for environmental toxicology and risk assessment.
Hexafluoropropylene oxide dimer acid (HFPO-DA; GenX) is an environmentally persistent per- and polyfluoroalkyl substance (PFAS) alternative whose placental toxicity remains poorly understood. Pregnant Sprague-Dawley rats (n=20, 5 dams/group) received oral HFPO-DA at 0, 1, 10, or 100mg/kg·day from gestational day (GD) 0 to 19. Placental tissues collected on GD20 were analysed by targeted metabolomics, lipidomics, histopathology, immunohistochemistry (IHC), and immunofluorescence (IF). After false discovery rate (FDR) correction, three energy metabolites were significantly altered (q < 0.05): oxaloacetate and glutamate were downregulated, while pyruvate was dose-dependently upregulated, consistent with restricted TCA cycle entry. Lipidomics identified 148 nominally significant lipid species, with elevated ceramides and long-chain fatty acids alongside reduced triglycerides, a pattern suggestive of impaired mitochondrial β-oxidation capacity. Histopathology revealed dose-dependent villous hyperplasia, trophoblast disorganization, and vascular lesions at the high dose. Protein analysis showed decreased SDHB, increased HIF-1α and PDK1, and a non-significant rise in PDHA1, collectively consistent with a shift toward Warburg-like metabolic reprogramming. These findings suggest that gestational HFPO-DA exposure may disrupt placental energy and lipid homeostasis at supra-environmental doses, identifying placental metabolism as a potentially sensitive target of next-generation PFAS.
Metabolically dysfunction-associated steatotic liver disease (MASLD) is rising worldwide at a pace that cannot be fully explained by obesity, diet, or genetics alone. Emerging evidence supports a mechanistic dissection of how defined endocrine-disrupting chemicals (EDCs) rewire hepatic transcriptional and metabolic networks relevant to MASLD. This review focuses on the molecular interfaces through which major EDC families intersect with hepatic metabolic regulation. We propose the "hepato-exposome axis" as a receptor-centric framework that maps specific EDC classes to nuclear receptors (NRs) and key metabolic pathways that regulate lipid metabolism, glucose homeostasis, mitochondrial dysfunction and inflammatory signalling implicated in MASLD progression. We summarise key EDC groups linked to liver disease, including organochlorine pesticides, pyrethroids, bisphenols, phthalates, organophosphate esters, and per- and polyfluoroalkyl substances (PFAS). We then integrate current understanding of hepatic metabolic and xenobiotic pathways in homeostasis and MASLD, emphasising xenobiotic-sensing and metabolic NRs (AhR, PXR, CAR, PPARs, FXR, LXRs, RXR) as convergence points for EDC action. Drawing on in vivo and in vitro studies, we show that distinct EDC families imprint overlapping molecular signatures onto pathways that control de novo lipogenesis, β-oxidation, glucose handling, antioxidant defences, and inflammatory/immune signalling, collectively fostering a pro-steatotic and pro-inflammatory hepatic milieu. We further discuss vulnerable populations, critical windows of exposure, mixture effects, and sex-specific responses, positioning EDCs as environmental modifiers of the MASLD trajectory across the life course. Finally, we outline priorities for mechanistic and translational research, including mixture toxicology, multi-omics exposome profiling, and biomarker discovery, to better quantify and mitigate endocrine disruptors' contribution to the global MASLD burden.
Ulcerative colitis (UC) is a chronic, relapsing, immune-mediated inflammatory disease of the colonic mucosa that imposes a substantial and growing global health burden. The pathophysiological basis of UC encompasses a multifactorial interplay among genetic predisposition, dysregulated innate and adaptive immune responses, gut microbiome dysbiosis, epithelial barrier dysfunction, and environmental triggers. Despite considerable advances in therapeutic strategies over the past two decades ranging from aminosalicylates and corticosteroids to biologic agents targeting TNF-α, integrins, and the IL-12/23 axis, as well as small molecule modulators such as JAK inhibitors and sphingosine-1-phosphate receptor agonists-a substantial proportion of patients either fail to achieve remission or experience loss of response over time, underscoring the continued need for novel therapeutic approaches. This comprehensive review systematically addresses the definition, epidemiology, socioeconomic burden, and unmet clinical needs in UC. The molecular and cellular underpinnings of the disease are discussed in depth, including the roles of key signaling pathways, pattern recognition receptors, cytokine networks, and the gut-immune interface. Clinical features, diagnostic criteria, endoscopic and histological scoring systems, and validated disease activity indices are also described. Current pharmacological therapies are reviewed with regard to mechanisms of action, pivotal clinical trial data, and safety profiles. Emerging investigational strategies including precision biologic agents, next-generation small molecules, microbiome-based therapeutics, and cell and gene therapy approaches are evaluated within a translational framework. A curated synthesis of experimental models of UC induction in rodents is presented, followed by structured tabular summaries of selected naturally derived bioactive compounds and pharmacological drug candidates that have demonstrated protective efficacy in preclinical models of UC. Compounds were selected for tabular inclusion on the basis of three prespecified criteria: (i) availability of at least one peer-reviewed in vivo study conducted in a validated experimental colitis model (DSS, TNBS, and acetic acid); (ii) a clearly described and mechanistically plausible basis of action relevant to UC pathophysiology; and (iii) representation across the principal mechanistic clusters identified in this review. Application of these criteria to the studies included in the final review yielded 29 naturally derived bioactive compounds (Table 1) and 26 pharmacological drug candidates (Table 2) for structured synthesis.
Lead (Pb), a highly toxic heavy metal pollutant with a long biological half-life and environmental persistence, has posed serious threats to global health. However, efficient and safe detoxification methods for Pb poisoning remain lacking. In this study, Magnetospirillum magneticum AMB-1 containing magnetosomes (M-AMB-1) and magnetosome-deficient AMB-1 (NM-AMB-1) were selected to comparatively explore the detoxification efficacies of magnetotactic bacteria (MTB) against Pb(Ⅱ) and its related mechanisms. The results showed that both M-AMB-1 and NM-AMB-1 could significantly detoxify Pb(Ⅱ)-induced cytotoxicity. When the OD565 of bacteria was 1, M-AMB-1 and NM-AMB-1 increased the cell viability induced by Pb pretreatment for 6 h by 2.17 and 2.25-fold, respectively. Moreover, a series of biological endpoints including cell apoptosis, cell membrane damage, reactive oxygen species generation, and DNA damage confirmed the efficient antagonism of M-AMB-1 and NM-AMB-1 against Pb(Ⅱ)-induced cytotoxicity and genotoxicity. Both types of AMB-1 antagonized the toxicity of Pb(Ⅱ) by enriching Pb(Ⅱ) and reducing the cellular Pb(Ⅱ) accumulation. Interestingly, the presence or absence of magnetosomes determined the distinct enrichment pathways of Pb(Ⅱ) in AMB-1: M-AMB-1 primarily mediated surface adsorption of Pb(Ⅱ), whereas massive Pb(Ⅱ) could be internalized into NM-AMB-1 approximately through the iron-transport system. The different Pb(Ⅱ) enrichment mechanisms probably resulted from the content of iron in bacteria, which competitively inhibited the further uptake of Pb(Ⅱ). This study innovatively revealed the mechanistic differences between M-AMB-1 and NM-AMB-1 in Pb(Ⅱ) enrichment. These findings might not only offer novel intervention strategies for Pb(Ⅱ) poisoning but also expand the application of MTB in the field of environmental health.