Microplastics (MPs) have emerged as pervasive environmental contaminants in aquatic, terrestrial, and atmospheric ecosystems. Once released into the environment, MPs are rapidly colonized by microorganisms, leading to the formation of complex biofilm communities collectively termed the "plastisphere." These biofilms significantly alter the physicochemical properties, transport behavior, ecological interactions, and toxicity of microplastics. This review synthesizes recent findings on the mechanisms of biofilm formation on microplastics, including the roles of polymer type, surface aging, eco-corona formation, and environmental factors such as salinity, temperature, nutrient availability, and hydrodynamics. The composition and ecological functions of plastisphere communities, including bacteria, archaea, fungi, algae, and protists, are discussed with emphasis on extracellular polymeric substances (EPS), quorum sensing, metabolic interactions, and horizontal gene transfer. The review further evaluates the role of biofilm-coated microplastics as vectors for pollutants, antibiotic resistance genes, and pathogenic microorganisms across marine, freshwater, wastewater, soil, and agricultural systems. In addition, the interactions between microplastics and co-contaminants such as heavy metals, pharmaceuticals, PFAS, and organic pollutants are examined in the context of ecotoxicological risks. Current methodological approaches, environmental implications, and regulatory challenges are also addressed. Overall, this review emphasizes the importance of adopting a biofilm-centered perspective for understanding the environmental fate and ecological impacts of microplastics, delves deeper into microplastic-associated biofilms across diverse ecosystems, including marine and freshwater environments, wastewater and urban water systems, and soils and agricultural lands, while only briefly considering less-studied compartments such as the atmosphere, integrating pathogen-specific food safety evidence, nanoplastic-EPS interactions, AMR/HGT mechanisms, and co-contaminant-derived risks, identifying the impacts of microplastics/biofilms themselves or the pathogens they carry on human health, and identifies critical knowledge gaps that require future investigation.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental pollutant linked to metabolic disorders, but its role in non-alcoholic fatty liver disease (NAFLD) remains unclear. This study integrated network toxicology, transcriptomics, and in vitro experiments to investigate the molecular mechanisms linking TCDD exposure to NAFLD. Using multi-source databases (CTD, PubChem, STITCH, SwissTargetPrediction) and two liver transcriptome datasets (GSE126848, GSE213621), we identified 176 common targets between TCDD and NAFLD, enriched in lipid metabolism, oxidative stress, inflammation, and PPAR/AhR pathways. Protein‑protein interaction network and cytoHubba algorithms prioritized ten hub genes, including PPARA, NFE2L2, IL6, and CYP1A1. Molecular docking predicted strong binding affinities of TCDD to PPARA (- 8.5 kcal/mol) and NFE2L2 (- 8.1 kcal/mol). In vitro experiments using HepG2 cells showed that TCDD dose‑dependently downregulated PPARA, NFE2L2, and their downstream targets CPT1A and NQO1, while upregulating IL6. TCDD also increased malondialdehyde (MDA) and triglyceride (TG) levels, indicating oxidative stress and lipid accumulation. These experimental results are consistent with the computational predictions. We propose a mechanistic framework in which TCDD may impair PPARA‑mediated fatty acid oxidation and NFE2L2‑mediated antioxidant defense, while promoting inflammation, thereby contributing to NAFLD. This study provides a systematic understanding of TCDD‑induced NAFLD and suggests PPARA and NFE2L2 as potential key targets for environmental risk assessment and therapeutic intervention.
Environmental exposure to endocrine-disrupting chemicals has been increasingly implicated in cardiovascular disease, yet the causal molecular mechanisms linking such exposures to atherosclerosis remain incompletely defined. Benzyl butyl phthalate (BBP), a widely used plasticizer, has been associated with vascular dysfunction, but its mechanistic contribution to atherogenesis is unclear. Here, we employed an integrative systems biology framework combining network toxicology, transcriptomic profiling, protein-protein interaction network analysis, molecular docking, molecular dynamics simulations, and summary-data-based Mendelian randomization to systematically elucidate BBP-associated atherosclerotic mechanisms. A total of 114 overlapping targets were identified between BBP-related and atherosclerosis-associated datasets, with MMP9 emerging as a central hub across network topology, transcriptomic validation, and structural analyses. Molecular docking and molecular dynamics simulations demonstrated stable and high-affinity binding between BBP and MMP9, supporting the concept that BBP may act as an exogenous modulator of protease function. Functional enrichment and gene set enrichment analyses consistently revealed immune activation and leukocyte recruitment as dominant biological processes across independent datasets. Furthermore, Mendelian randomization analysis provided genetic evidence supporting causal involvement of immune-related genes, particularly CXCR2, a key regulator of leukocyte trafficking. Integrative multi-level evidence and functional in vitro assays point toward an MMP9-associated, CXCR2-related inflammatory recruitment mechanism, in which BBP-induced modulation of MMP9 may alter chemokine processing, which subsequently enhances neutrophil chemotaxis and potentially contributes to vascular inflammation and atherosclerosis. Collectively, these findings suggest that BBP exposure is associated with alterations in vascular inflammatory processes involving MMP9 and CXCR2. By integrating computational analyses with experimental validation, our study provides evidence supporting an inflammatory recruitment mechanism involving MMP9 and CXCR2 in BBP-associated vascular responses and offers a framework for future investigation into the contribution of environmental pollutants to atherosclerosis.
Aluminum causes learning and memory impairments, and is an environmental and occupational toxicant. This in vivo and in vitro study assessed the implications of Lnc_000151 on aluminum-induced neurotoxicity through competitive binding to miR-96-5p. Fifty-six male SpragueDawley rats were randomly divided into eight groups: untreated, sham-operated, saline + sham-operated, Al(mal)₃ + sham-operated, saline + AAV-NC, Al(mal)₃ + AAV-NC, saline + AAV-Lnc_000151 shRNA, and Al(mal)₃ + AAV-Lnc_000151 shRNA. PC12 cells were separated into groups of 0, 100, 200, and 400 µM Al (mal)₃, and transfection groups including Lnc_000151 NC/siRNA, miR-96-5p NC/inhibitor, and IRS1 NC/siRNA. The learning and memory functions of rats were assessed via Morris water maze. Hippocampal CA1 neuronal count and synaptic structure were detected with hematoxylin-eosin staining and transmission electron microscopy. Cell apoptosis was measured using flow cytometry. Relative expression of Lnc_000151, miR-96-5p, and the IRS1/AKT/GSK3β pathway was determined using RT-PCR and Western blotting. The dual-luciferase assay confirmed targeted binding of Lnc_000151 to miR-96-5p and miR-96-5p to IRS1. In vivo and in vitro experiments demonstrated that under aluminum exposure, inhibition of Lnc_000151 expression exacerbated learning and memory impairments, neuronal loss, synaptic damage, increased Tau and p-Tau (Ser396) expression, and cell apoptosis. In vitro experiments further verified that under aluminum exposure and Lnc_000151 inhibition, suppressing miR-96-5p expression reduced Tau and p-Tau (Ser396) expression and cell apoptosis, while activating the IRS1/AKT/GSK3β pathway. However, further inhibition of IRS1 expression abrogated these ameliorative effects. In conclusion, this study demonstrates that Lnc_000151 can competitively bind to miR-96-5p in a competing endogenous RNA (ceRNA)-dependent manner, thereby regulating IRS1 expression, modulating the AKT/GSK3β pathway, and affecting aluminum-induced neurotoxicity.
Intelligence quotient (IQ) plays a significant role in assessing neurodevelopment. However, the effects of prenatal exposure to bisphenols or air pollution on intelligence quotient in preschool children remain unclear. A total of 231 mother-child pairs were from Guangxi Zhuang Birth Cohort. Single- and multiple-pollution methods were performed to examine the effects of prenatal exposure to bisphenols and air pollutants on IQ in preschool children, including generalized linear models, restricted cubic spline (RCS), principal component analysis (PCA), quantile G-computation (Qgcomp), and Bayesian kernel machine regression (BKMR). In generalized linear model, prenatal exposure to bisphenol A (BPA) (β=-3.55; 95%CI: -7.04, -0.06) and bisphenol F (BPF) (β=-12.68; 95%CI: -21.31, -4.05) was negatively associated with working memory index (WMI) in preschool children. Similarly, prenatal tetrabromobisphenol A (TBBPA) exposure was associated with lower verbal comprehension index (VCI) (β=-4.23; 95%CI: -7.90, -0.57), FRI (β=-5.59; 95%CI: -9.88, -1.30), WMI (β=-5.40; 95%CI: -9.47, -1.32), processing speed index (PSI) (β=-4.79; 95%CI: -9.25, -0.33), and full-scale IQ (FSIQ) (β=-4.38; 95%CI: -7.92, -0.84). Among air pollution, higher O3 exposure was correlated with lower VCI (β=-138.44; 95%CI: -198.55, -78.34), visuospatial index (VSI) (β=-64.41; 95%CI: -126.53, -2.29), WMI (β=-93.59; 95%CI: -162.67, -24.50), and FSIQ (β=-114.85; 95%CI: -173.79, -55.92). Furthermore, prenatal exposure to PM2.5 and PM10 was correlated with decreased VCI (PM2.5: β=-45.64; 95%CI: -82.77, -8.51 and PM10: -61.85; 95%CI: -107.36, -16.35) and FSIQ (PM2.5: β=-49.76; 95%CI: -85.57,-13.95 and PM10: β=-60.23; 95%CI: -104.28, -16.19). After gender stratification, the above effects were more significant in boys. In Bayesian kernel machine regression, prenatal exposure to the mixtures of 10 pollutants (5 bisphenols and 5 air pollutants) or 5 air pollution components was associated with less VCI, VSI, WMI, and FSIQ, and an inverted U-shaped association was found between these mixtures and FRI. Prenatal exposure to both single and mixed bisphenols and air pollutants may decrease the IQ of preschool children. These adverse effects appear to be more pronounced in boys and exhibit a nonlinear exposure-response relationship. This work offers epidemiological support for public health interventions that reduce co-exposure to multiple pollutants during pregnancy.
Nitro-aromatic compounds (NACs) are pervasive environmental pollutants with recognized pulmonary toxicity, yet their mechanistic involvement in pulmonary fibrosis remains incompletely understood. We applied an integrative framework combining network toxicology, transcriptomic analysis, prognostic modeling, immune infiltration profiling, molecular docking, and molecular dynamics (MD) simulations to investigate the fibrogenic effects of two representative NACs, 1-nitropyrene (1-NP) and nitrobenzene (NB). Identification and evaluation of NACs-related targets and their clinical relevance using the idiopathic pulmonary fibrosis (IPF) GEO dataset. Network analysis using eight topological algorithms identified ten key genes occupying central positions in the NACs-associated fibrosis-related candidate network. Among these, BCL2L1 and MYC exhibit significant prognostic significance in IPF.Risk models based on hub genes effectively stratify patient survival rates and are closely associated with immune dysregulation, characterized by macrophage aggregation and CD8⁺ T cell exhaustion. Molecular docking analysis indicates that 1-NP and NB exhibit strong binding affinity with the anti-apoptotic protein BCL2L1. Notably, 100-ns MD simulations revealed that NACs binding was associated with significant conformational destabilization and partial unfolding of BCL2L1, as evidenced by sustained increases in Root mean square deviation (RMSD), radius of gyration (Rg), and solvent-accessible surface area (SASA). These findings support a non-classical mechanism of structural toxicity, wherein NACs exert their effects by disrupting protein stability rather than acting as classical enzyme inhibitors. This study suggests a potential mechanism by which environmental NACs may contribute to fibrotic progression by disrupting the structural stability of BCL2L1 and reshaping the immune microenvironment. Our findings elucidate a potential molecular association between environmental exposure and fibrosis progression, suggesting that BCL2L1-mediated structural toxicity may serve as a potential biomarker and therapeutic target for pollution-related pulmonary fibrosis.
Fipronil (FIP), a widely used phenylpyrazole insecticide, biotransforms into metabolites (FIP-desulfinyl, FIP-sulfone, FIP-sulfide) with enhanced toxicity, persistence, and bioaccumulation potential that pose substantial human health risks. However, their hepatotoxic mechanisms and targeted interventions remain poorly elucidated. This study clarifies FIP metabolites' hepatic pathogenic effects and identifies mitigation strategies. Using mouse primary hepatocytes (MPHs) as an in vitro hepatic model, we combined transcriptomic profiling, Connectivity Map (CMap) analysis, molecular docking, molecular dynamics simulations, and functional validation assays to systematically investigate the mechanisms and intervention targets of FIP metabolite-induced hepatotoxicity. High-throughput transcriptomics showed FIP metabolites induce dexamethasone (DEX)-like phenotypes with enhanced gluconeogenesis and suppressed innate immunity in MPHs. CMap screening identified the natural phytochemical parthenolide (PTL) as a modulator reversing these effects. Mechanistically, molecular docking, molecular dynamics simulations, and functional assays confirmed the androgen receptor (AR) as a common direct target. Importantly, FIP metabolites stabilize AR and promote its accumulation, while PTL competitively binds AR with higher affinity, accelerates its degradation, and abrogates FIP metabolites' detrimental effects. Functionally, PTL dose-dependently inhibits FIP metabolites-induced G6pc upregulation and glucose output, and restores Isg15 mRNA expression and IFN-β levels in MPHs. Collectively, FIP metabolites act as environmental endocrine disruptors via AR stabilization, inducing DEX-like metabolic and immunological dysfunctions. PTL is a promising targeted agent for mitigating FIP metabolites-induced hepatotoxicity, offering insights into FIP metabolites' toxicity mechanisms and related health risk interventions.
Arsenic (As) contamination is a major environmental constraint that impairs wheat growth and productivity by disrupting cellular redox homeostasis, photosynthesis, and metabolic processes. Melatonin (MT), a multifunctional plant signaling molecule, has emerged as a promising regulator of plant tolerance to abiotic stresses; however, its role in mitigating As toxicity in wheat remains insufficiently understood. Wheat seedlings of three cultivars (Anaj-17, Galaxy-13, and Nayab-11) were grown in pots containing dried sand and exposed to As stress (20 mg L⁻¹) with or without MT supplementation (75 and 150 µM). Arsenic stress markedly increased As accumulation in grains, malondialdehyde (MDA), hydrogen peroxide (H₂O₂), and electrolyte leakage (EL%), while significantly reducing biomass, chlorophyll content, and gas exchange parameters. In contrast, MT application, particularly at 150 µM, effectively alleviated As-induced oxidative damage by enhancing the activities of catalase (CAT), peroxidase (POD), and superoxide dismutase (SOD). Melatonin also promoted the accumulation of glycine betaine, proline, total soluble sugars, total soluble proteins, and phenolic compounds, contributing to improved physiological performance and stress tolerance. Among the tested cultivars, Anaj-17 exhibited the greatest resilience to As stress and the strongest response to MT treatment, followed by Galaxy-13 and Nayab-11, indicating considerable genotypic variation in As tolerance. These findings demonstrate that melatonin enhances wheat tolerance to arsenic toxicity by strengthening antioxidant defenses, improving osmotic adjustment, and promoting the accumulation of protective metabolites, highlighting its potential as an effective strategy for enhancing heavy-metal stress resilience in wheat and other crop species.
The influence of environmentally relevant concentrations of aryl hydrocarbon receptor (AhR)-active pollutants on low-pathogenic avian influenza virus (LPAIV) replication remains poorly resolved, particularly under realistic co-exposure scenarios. Here, we quantified how single and mixed AhR agonists modulate replication of multiple LPAIV subtypes in avian fibroblasts at field-relevant concentrations. Chicken (DF-1) and duck (CCL-141) fibroblasts were exposed to 9-chlorophenanthrene (0.1-50 nM), PCB126 (0.01-10 nM), and TCDD (0.001-1 nM), with or without the endogenous AhR ligand 6-formylindolo[3,2-b]carbazole (FICZ), and subsequently infected with four LPAIV subtypes (H16N3, H9N2, H7N3, H5N3). Viral replication was quantified by qPCR (ΔCt). Factorial models emphasized host lineage × virus subtype interactions and mixture-versus-single comparisons across a shared concentration window. Host lineage × virus subtype interactions explained the largest share of variance. Single-agent effects were highly context-dependent; statistically supported antiviral activity was observed only for PCB126 in DF-1 cells infected with H7N3 (q = 0.006). In contrast, a three-compound pollutant mixture significantly enhanced replication in CCL-141 cells infected with H7N3 (q = 3.8 × 10^-4), whereas this supported trend was not observed with FICZ co-exposure. Within the tested environmentally plausible concentration window, concentration-matched Highest Single Agent comparisons more often yielded mixture responses below the strongest matched single-agent response among the evaluated comparisons. Within the tested concentration window, responses were graded and lacked clear thresholds. Overall, AhR-active xenobiotics can tune LPAIV replication in a host- and subtype-specific manner, highlighting the need for mixture-aware, context-dependent ecological infection-risk assessment.
Environmental exposure is increasingly recognized as an important contributor to the onset and progression of inflammatory bowel disease (IBD). Although the benzotriazole ultraviolet stabilizer UV-328 is widely present in environmental matrixes and biological samples, and exhibits broad toxicity across multiple organisms, its intestinal toxicity remains unclear. In this study, we investigated the effects of UV-328 on colitis progression and the underlying mechanisms using a dextran sulfate sodium (DSS)-induced chronic colitis mouse model combined with colonic epithelial NCM460 cells. UV-328 markedly exacerbated DSS-induced colitis, as evidenced by colon shortening, weight loss, increased disease activity, altered goblet cell numbers and tight junction-related markers, aggravated histopathological damage, and enhanced inflammatory responses. Transcriptomic analysis suggested altered cholesterol metabolism following UV-328 exposure. Treatment with the liver X receptor (LXR) agonist GW3965 alleviated inflammatory responses and colonic injury in the DSS + UV-328 group. Our findings suggest that altered cholesterol metabolism, potentially involving LXR signaling, may contribute to the intestinal toxicity of UV-328 and provide new evidence for evaluating the potential health risks associated with long-term exposure to this persistent organic pollutant, particularly in susceptible populations with impaired intestinal homeostasis.
Di-(2-ethylhexyl) phthalate (DEHP) is a widespread environmental obesogen; however, its immune-proinflammatory mechanisms in the progression of metabolic dysfunction-associated steatohepatitis (MASH) remain incompletely elucidated. This study aims to comprehensively characterize the core targets and molecular mechanisms by which DEHP disrupts the hepatic microenvironment and drives disease progression through multi-omics integration and experimental analysis. Real-world clinical transcriptomic cohorts were integrated and combined with LASSO and SVM-RFE machine learning algorithms to screen for core pathogenic genes intersecting MASH and DEHP exposure. Single-cell RNA sequencing (scRNA-seq) and virtual knockout (scTenifoldKnk) technologies were utilized to decipher the cell-type-specific expression of target genes and their downstream regulatory networks. The binding mode between the small molecule and the protein was evaluated using CB-Dock2. Furthermore, siRNA interference, Western blotting, real-time quantitative PCR, and Transwell assays were comprehensively applied in HepG2 and THP-1 cell models to systematically verify the biological functions of the "DEHP-target gene-chemokine" regulatory cascade. Machine learning algorithms accurately identified the transcription factor FOS as the core hub gene for DEHP-mediated MASH regulation, which showed promising diagnostic potential. Following resampling validation in a small independent cohort, FOS yielded an adjusted AUC of 0.964, though future validation in larger populations is warranted. Single-cell mapping revealed a significant downregulation of FOS expression within the MASH hepatic immune microenvironment, particularly in monocyte and NK cell subpopulations; systematic virtual knockout simulation predicted that FOS suppression potentially leads to substantial activation of chemokine signaling pathways. In vitro cellular experiments corroborated that DEHP induces hepatic lipid accumulation and biochemical injury in a dose-dependent manner, while targeted FOS knockdown further exacerbates this lipotoxic phenotype. Molecular docking studies suggested that DEHP potentially interacts with the binding pocket of the FOS protein through a multiple-hydrogen-bond network, thereby suppressing its transcription and translation. The suppression of FOS expression abolishes its physiological negative regulation of downstream chemokines, resulting in the high-level release of CCL3 and CCL4, which subsequently drives the transmembrane chemotaxis and infiltration of peripheral monocytes into the liver. This study suggests a potential mechanism by which DEHP exposure may promote monocyte infiltration and exacerbate MASH pathogenesis, potentially by interacting with and inhibiting the core regulatory protein FOS, thereby relieving its suppressive effect on CCL3/CCL4. These findings deepen our understanding of the "multiple-hit" mechanism by which environmental endocrine disruptors participate in liver diseases, highlighting FOS as a potential biomarker for environment-related metabolic diseases that warrants further thorough in vivo validation before considering it as a clinical intervention target.
Microplastics (MPs), as widespread and increasingly prevalent environmental pollutants, pose a persistent threat to aquatic organisms and mammals, including humans. Sodium humate (HNa), a naturally derived humate salt that is widely available, low-cost, and has a favorable safety profile, exhibits multiple biological activities, including antimicrobial, anti-inflammatory, and antioxidant properties. This study was designed to evaluate whether HNa could protect against intestinal and hepatic injury caused by polystyrene microplastics (PS-MPs) exposure in mice and to clarify the involvement of the gut-liver axis. HNa intervention alleviated impairment of body weight gain and colonic pathological injury following PS-MPs exposure. HNa enhanced intestinal antioxidant capacity, suppressed pro-inflammatory mediator expression, and promoted anti-inflammatory factor expression. Furthermore, HNa upregulated the expression of mucins and adherens junction and tight junction proteins, thereby restoring intestinal barrier function and limiting endotoxin translocation. In the liver, HNa ameliorated histopathological lesions, improved biochemical injury markers, attenuated inflammatory responses, and suppressed excessive activation of the TLR4/NF-κB pathway. Collectively, HNa mitigated gut-liver axis injury following PS-MPs exposure in mice through coordinated protection of intestinal barrier integrity and attenuation of hepatic inflammatory signaling. This study provides the first experimental evidence that HNa mitigates PS-MPs toxicity by protecting the gut-liver axis, supporting its potential as a practical intervention strategy against MPs-related digestive system injury.
Triclosan (TCS), a compound ubiquitous in personal care products, is now a prevalent environmental contaminant across various ecosystems and has been detected in human tissue samples. Despite its prevalence and strong association with female infertility, the mechanisms by which TCS induces ovarian toxicity have not been thoroughly studied. This study employed an integrated approach combining network toxicology, molecular docking, transcriptomics, and cell experiments to systematically investigate the molecular mechanisms linking TCS to two core ovarian dysfunction diseases: polycystic ovary syndrome (PCOS) and premature ovarian insufficiency (POI). The physicochemical properties and multi-organ toxicity of TCS were predicted using ADMETlab 3.0 and SwissADME. Following the retrieval of TCS, PCOS, and POI-associated targets from public databases, a PPI network was built to pinpoint central hubs. Subsequently, GO and KEGG enrichment analyses were conducted to delineate implicated biological pathways. Molecular docking was conducted to evaluate the binding affinity of TCS to core proteins. Transcriptomic analysis was performed on the ovarian granulosa cell line KGN exposed to 10 μM TCS, a concentration close to human exposure levels. Cell biology experiments were further employed to validate the findings. The network toxicology results indicated that TCS induces ovarian toxicity primarily by promoting apoptosis and triggering inflammatory responses. Key targets identified included AKT1, EGFR, TNF, IL6, and CASP3, which exhibited strong binding affinities, suggesting direct interactions. Transcriptomic analyses further confirmed disruptions in cytokine receptor binding and apoptosis pathways. Cell experiments confirmed that TCS exposure significantly promotes apoptosis and increases the production of inflammatory cytokines in two types of ovarian granulosa cell lines, SVOG and KGN. Overall, this study provides a conceptual framework for TCS-induced ovarian dysfunction and offers new insights for future research on the mechanisms underlying the ovarian toxicity of TCS.
As a widely utilized plasticizer, di(2-ethylhexyl) phthalate (DEHP) is recognized as a classic environmental endocrine-disrupting chemical. Although DEHP has been implicated in multi-organ toxicity, its ototoxic effects and underlying mechanisms remain poorly understood. This study aimed to investigate DEHP-induced ototoxicity and elucidate the associated molecular mechanisms. First, network toxicology and molecular docking approaches were employed to predict potential targets and signaling pathways of DEHP. By integrating multiple databases, 55 potential gene targets related to DEHP-induced hearing impairment were identified, with the PI3K/AKT/FOXO signaling pathway being significantly enriched. Molecular docking further revealed strong binding affinities between DEHP and the core targets AKT1, EGFR, and TP53. In vivo and in vitro assays were carried out to confirm these results. C57BL/6 J mice were administered DEHP via gavage for 30 consecutive days. Auditory function was assessed using auditory brainstem response tests, and cochlear hair cell morphology was examined by histology and IF. Results showed that DEHP exposure significantly elevated ABR thresholds and induced structural damage to cochlear hair cells. IF analyses confirmed that DEHP modulated the PI3K/AKT/FOXO pathway in cochlear tissues. In vitro, DEHP treatment in HEI-OC1 cells reduced cell viability and promoted apoptosis. Taken together, these findings demonstrate that DEHP exposure induces auditory dysfunction and cochlear hair cell damage through modulation of the PI3K/AKT/FOXO signaling pathway and subsequent activation of apoptotic cascades. This study provides the first mechanistic evidence linking DEHP exposure to hearing loss and identifies potential molecular targets for therapeutic intervention.
Pesticides are major environmental pollutants, and the swim bladder is highly sensitive to chemical stressors. However, the effects of spirodiclofen on swim bladder and the underlying mechanisms remain poorly understood despite its widespread environmental detection. In this study, zebrafish embroys were exposed to spirodiclofen to evaluate its impacts on the swim bladder. At 120 hpf, complete failure of swim bladder inflation was observed in the 0.146 mg/L and 0.300 mg/L treatment groups. Swim bladder area decreased by 40.3% and 52.8% (p < 0.01), and locomotor activity was markedly impaired, with total distance reduced by 87.4% and 95.5%, respectively (p < 0.01). RT-qPCR analysis revealed downregulate genes in Hedgehog and Wnt signaling pathways, as well as key developmental markers of swim bladder formation. Spirodiclofen also disrupted the prolactin pathway and significantly reduce Na⁺/K⁺-ATPase activity (p < 0.05), suggesting impaired ion regulation during inflation. Integrative GGE biplot analysis, molecular docking, and molecular dynamics simulations identified Wnt5b, Atp1b2, and Elovl1a as potential toxicity targets. Environmental monitoring further revealed that the risk quotients (RQ)> 1 at most sampling sites, underscoring the ecological relevance of these findings. Overall, this study provides mechanistic evidence for spirodiclofen-induced swim bladder toxicity and supports ecological risk assessment and the design of safer alternatives.
The distribution of environmental pollutants and their associated metabolic perturbations within tissues is essential for understanding toxicological mechanisms. However, whether hexafluoropropylene oxide tetramer acid (HFPO-TeA), an emerging alternative to legacy PFASs, induces spatially heterogeneous metabolic disruption in aquatic organisms remains unclear. Here, adult zebrafish were exposed to HFPO-TeA to investigate hepatic phospholipid spatial distribution and gut microbial dysfunction. Matrix-assisted laser desorption/ionization quadrupole time-of-flight mass spectrometry imaging (MALDI-QTOF-MSI) revealed marked spatial perturbation of 14 putatively annotated lipid features, mainly including phosphatidylcholines (PCs), phosphatidylglycerols (PGs), phosphatidylethanolamines (PEs), diacylglycerols (DAGs), and phosphatidylinositols (PIs). Notably, these phospholipids exhibited region-specific down- or up-regulation, suggesting localized phospholipid remodeling within hepatic microdomains rather than spatially uniform disruption. These spatially resolved phospholipid alterations provide mechanistically relevant evidence for HFPO-TeA-induced hepatotoxicity and phospholipids with annotated spatial perturbation as candidate lipid-feature biomarkers for future validation. Moreover, HFPO-TeA reduced gut microbial diversity and reshaped the intestinal community, including decreases in Firmicutes at the phylum level and increases in Shewanella and Aeromonas at the genus level, taxa linked to lipid metabolism and phospholipid remodeling. Functional prediction further indicated suppressed microbial metabolic potential, with relative enrichment of genetic information processing and cellular maintenance functions. Together, the microbiome shift toward phospholipid remodeling-associated taxa and the spatially resolved hepatic perturbation of specific phospholipids provide convergent evidence that targeted phospholipid metabolic remodeling within tissue microregions may underlie HFPO-TeA-induced metabolic toxicity. This study provides a spatially resolved perspective on the multilevel metabolic toxicity of HFPO-TeA and demonstrates significant potential for revealing the health impacts of emerging PFAS alternatives.
The concentrations of iron (Fe), zinc (Zn), copper (Cu), manganese (Mn) and cadmium (Cd) were analyzed in muscle, liver, kidney and lung tissue samples, and stable carbon and nitrogen isotopes were measured in the muscle tissue samples from 10 Kogia breviceps (Kb), 3 Steno bredanensis (Sb), 14 Tursiops truncatus (Tt) and 4 Tursiops aduncus (Ta), collected from waters around Taiwan from 2003 to 2020.The results indicated that Kb and Sb primarily inhabit deeper and offshore regions, while Tt and Ta are found in shallower, nearshore areas. Kb primarily feed on deep-sea cephalopods, whereas the other three consume fish and a variety of marine invertebrates. In Kb, kidney Fe concentrations increased with body length, suggesting enhanced deep-diving capabilities as they mature-a trend not observed in the other species. Elevated Zn concentrations in muscle and Mn concentrations in kidney tissues of young Kogiids and Delphinids likely reflect physiological demands during early development. Furthermore, the high mean Cd concentrations detected in the muscle and kidney tissues of Tt and Sb indicate a rising trend in Cd pollution in the north-western Pacific Ocean over the past two to three decades.
Climate change and childhood obesity are major global health threats that share common upstream determinants. However, evidence on the associations between ambient temperature and childhood obesity remains limited. This study aimed to investigate the associations between temperature exposure and childhood obesity using longitudinal datasets from The Early Prevention of Obesity in CHildren (EPOCH) Collaboration. The analysis included four trials involving 2372 mother-child dyads from five cities in Australia and New Zealand (2007-2016). Anthropometric outcomes were assessed at ages 1, 2, 3.5, and 5 years, with overweight and obesity defined according to World Health Organization standards. Exposures to minimum, maximum temperatures, and extreme heat (>95th percentile of the maximum temperature) were assigned using residential postcode proximity to meteorological stations. Site-specific associations between temperature metrics and repeated anthropometric outcomes were estimated using Generalized Estimating Equations, adjusting for maternal and child socioeconomic factors. Random-effects meta-analyses were used to assess consistency across sites. Despite site-specific variation, meta-analyses showed that extreme heat was negatively associated with overweight in 3-month (RR =0.98, 95% CI: 0.97-0.99) and 6-month exposure windows. Obesity risk was increased with longer exposure (12-month) to elevated daily minimum temperature (RR =1.97, 95% CI:1.35-2.88) and maximum temperature. These findings suggest that short-term extreme heat may be associated with a lower risk of overweight, whereas long-term exposures to higher temperatures may be associated with a higher risk of childhood obesity. Early-life temperature exposures may be considered in obesity prevention under climate change.
Anticoagulant rodenticides (ARs) are globally used for rodent control, posing significant risks to non-target predators and scavengers through secondary poisoning. ARs act by inhibiting the vitamin K epoxide reductase complex (VKOR), impairing coagulation. While chemical analyses have extensively documented AR exposure in wildlife, sublethal effects remain understudied. The vkorc1 and vkorc1l1 genes encode components of VKOR. This study investigates the expression of these genes and its potential association to AR exposure in a population of free-ranging Eurasian eagle owls (Bubo bubo). Blood samples (0.3-0.5 mL) collected in 2022 from 72 nestlings were analysed for vkorc1 and vkorc1l1 mRNA levels using RT-qPCR. Additionally, Canonical Correlation Analysis allowed exploring relationships between environmental variables and gene expression. Results revealed that vkorc1 is predominantly expressed in eagle owl blood (median = 4.22 RU), while vkorc1l1 exhibits lower expression levels (median = 2.25 RU). Nevertheless, in one-third of the samples vkorc1l1 was predominant. Probably, vkorc1l1 expression acts as a compensatory mechanism, increasing in response to recent AR exposure. This pattern was evident in anthropogenic environments, such as urban areas and landfills. Conversely, vkorc1 appears to respond adaptively over time, with higher expression associated with natural watercourses and livestock farms. To our knowledge, this is the first study reporting vkorc1 and vkorc1l1 gene expression in a raptor species. The integration of molecular and environmental data provided valuable insights into AR exposure dynamics in apex predators, informing management strategies to reduce risks on wildlife and ecosystem functioning.
Cadmium (Cd) is a toxic heavy metal for plants, and although its mechanisms of toxicity are well characterized, the regulatory networks underlying plant responses remain incompletely understood. This study investigated membrane-associated molecular responses linked to RBOHC and RBOHF during Cd stress through a label-free proteomics of root microsomal membrane fractions from Arabidopsis thaliana wild-type (WT), rbohC and rbohF plants. Proteomic analysis revealed pronounced genotype-dependent responses, with most Cd-responsive differentially expressed proteins (DEPs) being genotype-specific. The rbohF mutant displayed broader proteomic reprogramming than rbohC, whereas rbohC exhibited a comparatively attenuated response. Functional analyses indicated that Cd stress altered proteins associated with detoxification, ion transport, membrane trafficking, redox regulation and stress signaling. WT plants showed coordinated accumulation of glutathione S-transferases (GSTs), MATE/DTX transporters, ABC transporters and Ca²⁺-related proteins, whereas rbohC lacked GST accumulation and showed reduced abundance of the IRT1-CIPK23 module. In contrast, rbohF exhibited enhanced accumulation of several GSTs together with altered abundance of proteins associated with redox regulation, Casparian strip organization and ion homeostasis, including SBP1, CASP1 and PER64. Physiological analyses further revealed increased superoxide accumulation in rbohC roots under Cd stress, while GST activity differed among genotypes, supporting distinct antioxidant responses. Together with previous physiological evidence, these findings identify membrane-associated proteins and pathways associated with the contrasting Cd responses of rbohC and rbohF mutants. Overall, this work provides new insights into membrane-associated molecular responses linked to RBOHC and RBOHF during Cd stress and identifies candidate proteins for future functional studies on Cd tolerance.