Ecotoxicology and Environmental Safety最新文献

{"title":"Membrane-translocated SO₂/₃-PRDX3 disrupts cystine uptake and GPX4 activity: A pivotal mechanism of boron-induced renal ferroptosis in broiler","authors":"Yuanxu Li ,&nbsp;Yumeng Li ,&nbsp;Mingyang Guo ,&nbsp;Yating Tian ,&nbsp;Mengran Wang ,&nbsp;Jiangli Huang ,&nbsp;Weiqian Su ,&nbsp;Zhonghua Liu ,&nbsp;Wenlan Yu","doi":"10.1016/j.ecoenv.2026.119969","DOIUrl":"10.1016/j.ecoenv.2026.119969","url":null,"abstract":"<div><div>Boron (B), a widely utilized non-metallic element in industrial, agricultural, and medical applications, has garnered significant attention due to its documented reproductive and developmental toxicity. Although the kidney plays a pivotal role in boron metabolism and excretion, the precise mechanisms underlying its nephrotoxicity remain incompletely elucidated. This study systematically investigated the toxic effects of boron exposure on chicken kidneys and its underlying molecular mechanisms, employing both in vivo chicken kidney tissues and an in vitro model of primary chicken renal tubular epithelial cells. Our findings demonstrate that boron exposure significantly impaired growth performance and renal function in broilers, induced histopathological alterations in kidney tissues, disrupted renal iron metabolism homeostasis, and triggered ferroptosis. Mechanistic exploration revealed that during boron-induced ferroptosis, peroxiredoxin 3 (PRDX3) underwent hyperoxidation (forming SO_2/3-PRDX3) and aberrantly translocated to the cell membrane. Intriguingly, the membrane localization of SO_2/3-PRDX3 impaired cellular cystine uptake, consequently inhibiting the synthesis of the critical antioxidant tripeptide glutathione (GSH), thereby exacerbating the ferroptosis process. Furthermore, dysfunctional SO_2/3-PRDX3 could affect the core antioxidant activity of glutathione peroxidase 4 (GPX4), weakening cellular defenses against lipid peroxidation. In conclusion, boron exposure induces renal damage in chickens by activating the ferroptosis pathway. This activation is mediated through PRDX3 hyperoxidation, its subsequent membrane translocation, and the resulting impairment of cysteine uptake and GSH biosynthesis. SO_2/3-PRDX3 dysfunction represents a critical molecular event in boron-induced nephrotoxicity in broiler chickens.</div></div>","PeriodicalId":303,"journal":{"name":"Ecotoxicology and Environmental Safety","volume":"312 ","pages":"Article 119969"},"PeriodicalIF":6.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147346904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physical exercise alleviates PM2.5-induced damage by repairing adipose mitochondria dysfunction in mice","authors":"Bingru Nan ,&nbsp;Kun Pan ,&nbsp;Chuan Xu ,&nbsp;Jinzhuo Zhao ,&nbsp;Jie Zhang","doi":"10.1016/j.ecoenv.2026.119896","DOIUrl":"10.1016/j.ecoenv.2026.119896","url":null,"abstract":"<div><div>Physical exercise (PE) can mitigate fine particulate matter (PM_2.5)-associated metabolic disorders, but its impacts on adipose mitochondrial health under PM_2.5 exposure remain unclear. Here, we performed a 4-month exposure study in C57BL/6 mice (filtered air, PM_2.5, and PM_2.5 plus PE) and evaluated systemic metabolic phenotypes (body and adipose weights, serum lipids, intraperitoneal glucose tolerance test, and intraperitoneal insulin tolerance test), adipose mitochondrial ultrastructure, and mitochondrial proteomes in brown adipose tissue (BAT) and epididymal white adipose tissue (eWAT). PM_2.5 exposure reduced mitochondrial number and area and caused ultrastructural injury in both adipose depots, accompanied by impaired glucose homeostasis. PE attenuated these phenotypic alterations but did not fully normalize them. Mitochondrial proteomics combined with an integrative stepwise analytical framework identified 6 candidate effector proteins in BAT and 18 in eWAT whose abundance patterns were consistent with PM_2.5 injury and partial PE restoration. Functional annotation suggested enrichment in pathways related to gene expression and protein homeostasis, membrane stability, and respiratory chain assembly in BAT, and protein sorting, post-translational modification, antioxidant activity, ion homeostasis, and energy metabolism in eWAT. These findings suggest that PE may alleviate PM_2.5-associated adipose mitochondrial dysfunction through coordinated changes across multiple pathways in a tissue-specific manner.</div></div>","PeriodicalId":303,"journal":{"name":"Ecotoxicology and Environmental Safety","volume":"312 ","pages":"Article 119896"},"PeriodicalIF":6.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146775803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acrylamide exposure induces neurotoxicity via the PI3K/Akt/NF-κB pathway: Evidence from network toxicology and experimental validation","authors":"Zhaoda Duan ,&nbsp;Chunjiao Yu ,&nbsp;Qiuxian Yu ,&nbsp;Wenjie Yang ,&nbsp;Rui Zhang ,&nbsp;Qiaoling Ruan ,&nbsp;Yongfang Zhao ,&nbsp;Shan Yan","doi":"10.1016/j.ecoenv.2026.119922","DOIUrl":"10.1016/j.ecoenv.2026.119922","url":null,"abstract":"<div><div>Acrylamide (ACR) is a chemical compound widely used in industrial production and food processing, the underlying mechanisms of its neurotoxicity have yet to be fully elucidated. Through the integration of network toxicology, molecular docking, and experimental validation, this study systematically explored the underlying molecular mechanisms of ACR-induced neurotoxicity. Through database analysis, 183 ACR-related targets and 2725 neurotoxicity-associated targets were identified, among which 100 overlapping genes were predominantly enriched in the PI3K/Akt signaling pathway and apoptosis-related biological processes. Molecular docking and molecular dynamics simulations suggested potential interactions between ACR and key target proteins. While causing minimal alterations in peripheral organs, ACR exposure <em>in vivo</em> resulted in hippocampal neuronal disorganization and Nissl body loss, indicating potential neurotoxicity. <em>In vitro</em> studies demonstrated that ACR not only decreased cell viability in PC12 and HT22 cells but also significantly enhanced apoptosis and inflammation, while markedly activating the PI3K/Akt and NF-κB signaling pathway. The significant attenuation of these effects was observed following treatment with the PI3K inhibitor LY294002. These findings suggest that ACR-induced neurotoxicity involves the coexistence and imbalance of survival and inflammatory–apoptotic signaling, providing mechanistic insight into its neurotoxic effects and a theoretical basis for potential preventive strategies.</div></div>","PeriodicalId":303,"journal":{"name":"Ecotoxicology and Environmental Safety","volume":"312 ","pages":"Article 119922"},"PeriodicalIF":6.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147281246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural and mechanistic insights into industrial phenolic compounds as potent inhibitors of human and rat 5α-reductase 1","authors":"Yixing Shi ,&nbsp;Yinghao Huang ,&nbsp;Chentao Ding ,&nbsp;Hao Lin ,&nbsp;Jiachen Lin ,&nbsp;Shaowei Wang ,&nbsp;Ren-shan Ge ,&nbsp;Wangning Shangguan","doi":"10.1016/j.ecoenv.2026.119914","DOIUrl":"10.1016/j.ecoenv.2026.119914","url":null,"abstract":"<div><div>This study identifies environmental chemicals 4-nonylphenol, 4-dodecylphenol, pentabromophenol, and popular anesthetics drug propofol as moderate to potent inhibitors of human and rat 5α-reductase type 1 (5α-R1), revealing novel endocrine-disrupting mechanisms in human brain cell and rat brain microsomes. Pentabromophenol exhibited the highest potency (IC₅₀ = 1.71 µM for human 5α-R1) with mixed/noncompetitive inhibition, supported by Surface Plasmon Resonance binding (<em>KD</em> = 1.22 µM). A 3D-QSAR pharmacophore model (Hypo1) highlighted critical structural features, including a hydrogen-bond acceptor and hydrophobic interactions, explaining pentabromophenol efficacy. Species differences emerged, with human 5α-R1 showing high pentabromophenol binding affinity (-6.80 kcal/mol via halogen bonds with Arg176). Inhibition may reduce neurosteroids (e.g., allopregnanolone) and androgens (e.g., dihydrotestosterone). These findings underscore industrial phenolic compound capacity to dysregulate neurosteroid homeostasis in a structure- and species-dependent manner, highlighting their endocrine-disrupting risks.</div></div>","PeriodicalId":303,"journal":{"name":"Ecotoxicology and Environmental Safety","volume":"312 ","pages":"Article 119914"},"PeriodicalIF":6.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147281385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations of prenatal exposure to bisphenols and phthalates with the fetoplacental ratio in the New York University Children’s Health and Environment Study (NYU CHES)","authors":"Ayushi Bommireddipalli ,&nbsp;Jacqueline A. Erler ,&nbsp;Duong Q. Nguyen ,&nbsp;Sara Hyman ,&nbsp;Emma Spring ,&nbsp;Eleanor A. Medley ,&nbsp;Kurunthachalam Kannan ,&nbsp;Shilpi S. Mehta-Lee ,&nbsp;Leonardo Trasande ,&nbsp;Whitney Cowell ,&nbsp;Linda G. Kahn","doi":"10.1016/j.ecoenv.2026.119925","DOIUrl":"10.1016/j.ecoenv.2026.119925","url":null,"abstract":"<div><div>Fetoplacental ratio (FPR), the ratio of birthweight (BW) to placental weight (PW), indicates placental efficiency. Changes in FPR are linked to poor pregnancy outcomes and child health risks. Bisphenols and phthalates are endocrine disruptors found in plastics and personal care products that can cross the placenta and have been linked to pregnancy complications and adverse child health outcomes. We examined prenatal exposure to these chemicals in relation to FPR as a possible explanation for these risks. Our analysis included 393 participants in the New York University Children’s Health and Environment Study with data on prenatal chemical exposure, BW, and PW from singleton live births. We calculated molar sums of bisphenols and of metabolites of low and high molecular weight (LMW, HMW) phthalates, diethylhexyl phthalate (DEHP), and antiandrogenic phthalates. Linear regression models were adjusted for maternal age, prepregnancy BMI, parity, gestational age at delivery, and fetal sex. Analyses were stratified by fetal sex. HMW were positively associated with FPR in the combined fetal sex sample (beta=0.26, [0.01, 0.50]) with a similar trend for DEHP and antiandrogenic phthalates (betas=0.21 [-0.04, 0.45] and 0.21 [-0.04, 0.45], respectively). Stratified analyses revealed that these results were driven by females, among whom LMW were also associated with higher FPR (beta=0.23 [0.003, 0.45]). No associations were observed between chemicals and BW in either combined or sex-stratified models. In contrast, HMW, LMW, DEHP, di-n-octylphthalate and bisphenols had negative associations with PW, suggesting placental growth as a target for phthalate-mediated endocrine disruption.</div></div>","PeriodicalId":303,"journal":{"name":"Ecotoxicology and Environmental Safety","volume":"312 ","pages":"Article 119925"},"PeriodicalIF":6.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147300553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute and sub-chronic exposure to bisphenol AF induces cardiac inflammatory response in zebrafish through lncRNA/circRNA-miRNA-mRNA regulatory networks","authors":"Qing Wei ,&nbsp;Junlang Liang ,&nbsp;Jianghui Zhu ,&nbsp;Yungu Zheng ,&nbsp;Chenyuan Pan ,&nbsp;Ming Yang ,&nbsp;Zhong Chen","doi":"10.1016/j.ecoenv.2026.119911","DOIUrl":"10.1016/j.ecoenv.2026.119911","url":null,"abstract":"<div><div>Bisphenol AF (BPAF) is a fluorinated derivative of bisphenol A and widely used as an alternative in industry. BPAF is often detected in various environmental media. The cardiovascular toxicity of bisphenols has been previously reported; however, how epigenetic regulation plays a role in bisphenol-induced cardiotoxicity remains unclear. Here, we aimed to assess the cardiovascular toxicity-related endpoints of BPAF. Using zebrafish as an experimental model, we combined an acute 120-h exposure to a series of BPAF concentrations (10, 100, and 1000 μg/L) with a sub-chronic (28 days) exposure of adults to an environmentally relevant concentration of BPAF at 10 μg/L. Acute BPAF exposure exerted dose-dependent impairment on cardiac development, morphology, and function in zebrafish embryos and larvae. Following 28-day exposure of adult zebrafish to an environmentally relevant concentration of BPAF, inflammatory infiltration was observed in both male and female zebrafish heart tissues. Whole-transcriptome sequencing revealed significant changes in the expression patterns of messenger RNAs (mRNAs), microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circulatory RNAs (circRNAs), and subsequent competing endogenous RNA (ceRNA) network analysis identified upstream regulators that differed between sexes. We also identified BPAF-disrupted key pathways (complement cascades, arachidonic acid metabolism, PPAR signaling) whose core genes (<em>fga</em>, <em>fgb</em>, <em>gpx3</em>, <em>ptgdsb</em>, <em>cd36</em>, <em>apoa1</em>) are potentially ncRNA-regulated. Paternal exposure had a more significant impact on the cardiac function of the next generation. These findings help to advance our understanding of the toxicity and action mechanisms of bisphenols, and provide scientific data for screening specific biomarkers for assessing bisphenol-induced cardiac toxicity.</div></div>","PeriodicalId":303,"journal":{"name":"Ecotoxicology and Environmental Safety","volume":"312 ","pages":"Article 119911"},"PeriodicalIF":6.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147281291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polystyrene nanoplastics trigger mitochondrial and metabolic reprogramming in cardiomyocytes: Evidence from integrated transcriptomic and metabolomic analysis","authors":"Haitao Zhang ,&nbsp;Huiting Cao ,&nbsp;Yu Luo ,&nbsp;Yunzhao Cao ,&nbsp;Xianze Meng ,&nbsp;Xinyu Wang ,&nbsp;Ruidong Du ,&nbsp;Xiwu Yan ,&nbsp;Yun Gao ,&nbsp;Zhuyuan Fang ,&nbsp;Ming Liu","doi":"10.1016/j.ecoenv.2026.119921","DOIUrl":"10.1016/j.ecoenv.2026.119921","url":null,"abstract":"<div><div>Nanoplastics (NPs) are emerging environmental pollutants that can cross biological barriers due to their small size. Although numerous studies have investigated their effects in animal and cell models, multi-omics evaluations of their potential cardiovascular toxicity are still limited. To address this gap, we conducted a comprehensive assessment of polystyrene NPs (PS-NPs) using both in vitro and in vivo models. Human AC16 cardiomyocytes were exposed to PS-NPs and analyzed using RNA-seq, untargeted metabolomics, and functional assays. Transcriptomics revealed enrichment of mitochondrial-related genes and response to lipids, with pathways involving mitochondrial translation, ribosome function, and oxidative phosphorylation (OXPHOS). Bioenergetic profiling showed reduced basal and maximal oxygen consumption and ATP-linked respiration, accompanied by increased intracellular and mitochondrial reactive oxygen species (ROS). Untargeted metabolomics indicated broad lipid remodeling, particularly in glycerophospholipids, and alterations in nucleotide metabolism, consistent with energy dysregulation. For in vivo validation, mice received repeated tail vein injections of PS-NPs every 3 days for 2 weeks. Electron microscopy showed PS-NPs accumulation in cardiomyocytes and mitochondrial cristae disruption. Echocardiography revealed interventricular septal thickening with preserved ejection fraction and fractional shortening, suggesting subclinical remodeling. Myocardial ATP content decreased, and western blotting showed downregulation of OXPHOS complexes III–V and Pgc-1α. Although the chemical and particulate effects could not be distinguished in this study due to the lack of a particulate control, these results indicate that PS-NPs impair mitochondrial function and energy homeostasis in cardiomyocytes, suggesting potential cardiovascular hazards and highlighting the need for exposure monitoring in risk assessment.</div></div>","PeriodicalId":303,"journal":{"name":"Ecotoxicology and Environmental Safety","volume":"312 ","pages":"Article 119921"},"PeriodicalIF":6.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147315849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exposure to per- and polyfluoroalkyl substance (PFAS) mixtures increases papillary thyroid cancer risk and clinicopathological aggressiveness: Findings from a case-control study and risk assessment","authors":"Yaling Yu,&nbsp;Yi Wang,&nbsp;Xuling Su,&nbsp;Qianqian Wang,&nbsp;Chenglong Wang,&nbsp;Zhenzhen Cai,&nbsp;Yiwei Zhao,&nbsp;Tonghui Zhang,&nbsp;Danjie Hu,&nbsp;Zhiyan Liu","doi":"10.1016/j.ecoenv.2026.119941","DOIUrl":"10.1016/j.ecoenv.2026.119941","url":null,"abstract":"<div><div>Per- and polyfluoroalkyl substances (PFAS) have been reported to possess endocrine-disrupting and tumor-promoting activity. However, the association between PFAS exposure and papillary thyroid carcinoma (PTC) remains poorly understood. This case-control study investigated whether PFAS exposure is associated with PTC risk, and if so, whether this association is mediated through thyroid hormone disruption and linked to specific clinicopathological and genetic features of the tumor. We recruited 60 PTC patients and 60 healthy controls from Shanghai, China. Serum levels of PFAS and thyroid hormones were measured. Multiple linear regression, weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) were used to analyze associations between PFAS mixtures and individual congeners with PTC risk and thyroid function. A chronic reference dose (CRfD) for PFOS was derived from animal studies using benchmark dose modeling. PTC patients had significantly elevated serum levels of several PFAS, including perfluorooctane sulfonate (PFOS), perfluorodecanoic acid (PFDA), and 8:2 chlorinated perfluoroalkyl ether sulfonic acid (8:2Cl-PFESA), compared to controls. WQS regression indicated a significant positive association between PFAS mixture exposure and PTC risk (OR = 2.01, <em>p</em> = 0.023), with 8:2CI-PFESA, PFDoDA, PFBS, and PFOS identified as the primary contributors. Furthermore, specific PFAS congeners were associated with more aggressive tumor features, including advanced TNM stage and with high-risk genetic alterations such as <em>TERT</em> mutation, and RAS&amp;TERT promoter co-mutations. In terms of hormonal effects, Furthermore, perfluorobutanesulfonic acid (PFBS) and 8:2Cl-PFESA showed significant negative dose-response relationships with FT3 levels in patients, suggesting a potential link between PFAS-induced thyroid disruption and carcinogenesis. The derived oral CRfD for PFOS, based on triiodothyronine reduction, was 40 ng/kg·bw/day. Our findings indicate that PFAS exposure is associated with an increased risk of PTC, potentially through mechanisms involving thyroid hormone disruption and the promotion of more aggressive tumor characteristics. These results underscore the need for stricter regulation of industrial PFAS emissions and enhanced thyroid function monitoring in high-risk populations.</div></div>","PeriodicalId":303,"journal":{"name":"Ecotoxicology and Environmental Safety","volume":"312 ","pages":"Article 119941"},"PeriodicalIF":6.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147300503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Benzo[a]pyrene promotes gastric cancer progression via activation of the Correa cascade through modulation of the STAT3-TP53-MMP9 molecular axis","authors":"Jiajia Tong ,&nbsp;ShiYu Liu ,&nbsp;Tingting Du ,&nbsp;Wangting Liu ,&nbsp;Ziyi Jin ,&nbsp;Wenqing Si ,&nbsp;Bingqian Zhang ,&nbsp;Guangxia Chen","doi":"10.1016/j.ecoenv.2026.119912","DOIUrl":"10.1016/j.ecoenv.2026.119912","url":null,"abstract":"<div><div>To investigate the role of Benzo[<em>a</em>]pyrene (BaP) in driving the Correa cascade during gastric cancer development, we employed an integrated strategy combining network toxicology, machine learning, and molecular dynamics (MD) simulations. We identified 301 co-expressed genes spanning the Correa sequence, from chronic inflammation to invasive carcinoma. A protein-protein interaction network was constructed using STRING, and CytoHubba analysis highlighted five hub genes: TNF, IL6, IFNG, IL1B, and STAT3. Using CHEMBL and SUPER-PRED, we predicted 846 potential BaP targets. Intersection with disease-related genes revealed 62 common targets. Among eight candidate hub genes, an integrated Stepglm[both] and Random Forest model identified STAT3, TP53, and MMP9 as core targets. Receiver operating characteristic analysis confirmed their strong diagnostic potential (AUC &gt; 0.78), while SHAP analysis ranked STAT3 as the most influential factor (SHAP = 0.241). Notably, these genes exhibited synergistic expression patterns in tumors (STAT3-TP53: ρ = 0.175; STAT3-MMP9: ρ = 0.261; TP53-MMP9: ρ = 0.216; all P &lt; 0.01) and showed a dose-dependent association with disease progression. Genomic profiling revealed frequent mutations and amplifications in STAT3, TP53, and MMP9, with TP53 exhibiting the highest mutation rate. Analysis using UALCAN demonstrated significant upregulation of their mRNA levels in tumor tissues compared to normal tissues (P &lt; 0.05). Clinically, high STAT3 and TP53 expression correlated with poorer survival, whereas elevated MMP9 levels were associated with improved outcomes. Mechanistic studies, including molecular docking and dynamics simulations, confirmed stable BaP-target interactions (e.g., STAT3 binding energy = −8.285 kcal/mol) mediated by non-covalent interactions, which disrupt the bidirectional STAT3-TP53 regulatory axis (STAT3 → MDM2 ⊣ TP53; TP53 → PIAS3 ⊣ STAT3). In summary, this study identifies STAT3, TP53, and MMP9 as central mediators of BaP-induced progression along the Correa cascade via a synergistic regulatory network. These findings provide new insights into environmental gastric carcinogenesis and highlight potential therapeutic strategies, including dual STAT3/MDM2 inhibition or MMP9 blockade.</div></div>","PeriodicalId":303,"journal":{"name":"Ecotoxicology and Environmental Safety","volume":"312 ","pages":"Article 119912"},"PeriodicalIF":6.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147353135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the phthalates-induced neurotoxicity mechanisms of neurodegenerative diseases via network toxicology, single-cell transcriptomics and molecular dynamic simulation","authors":"Jie Li ,&nbsp;Hongming Yin ,&nbsp;Zijie Qiu ,&nbsp;Yuan Fu ,&nbsp;Yao Luo ,&nbsp;Tianen Wu ,&nbsp;Zhenhua Zeng ,&nbsp;Zixiong Qiu ,&nbsp;Xu Deng ,&nbsp;Siyan Wu ,&nbsp;Yuhan Zhang ,&nbsp;Xiaojun Cui ,&nbsp;Mei Jiang","doi":"10.1016/j.ecoenv.2026.119954","DOIUrl":"10.1016/j.ecoenv.2026.119954","url":null,"abstract":"<div><div>Phthalates are considered to be a neurotoxicant, widely used in construction materials, packaging, and various medical products. Few studies have focused on the association between exposure to phthalates and risks on neurodegenerative diseases and thus this study delved into the potential mechanisms by which phthalates could cause neurodegenerative diseases. Firstly, using network toxicology, we discovered ten phthalates exert significant toxic effects on the blood-brain barrier (BBB), in which di(2-ethylhexyl) phthalate (DEHP) and diisobutyl phthalate (DiBP) also exhibit marked neurotoxicity, immunotoxicity, and ecotoxicity. Disease ontology (DO) analysis revealed that the impacts of these plasticizers on neurodegenerative diseases are primarily manifested in three major conditions, including Parkinson's disease (PD), Lewy body disease (LBD), and Alzheimer's disease (AD), and further demonstrated that phthalates may induce the pathogenesis of three neurodegenerative diseases via modulating cellular apoptosis and neuroinflammatory pathways, such as the PI3K-Akt and JAK-STAT pathways. Furthermore, we pinpointed the BCL2, BCL2L1, IL6, IL10 and CCND1 as hub genes through diagnostic models by utilizing sample data of PD patients' tissues. Interestingly, we found that BCL2 expressed in astrocytes plays a crucial role in the phthalates-induced neurotoxicity in single-cell analysis. Subsequently, molecular docking and dynamics simulations observed that ten phthalates form a stable interaction with BCL2, especially DEHP, and cellular experiments confirmed that both DEHP and its metabolite MEHP significantly decreased BCL2 level in MPP⁺ -induced cell model and induced the transformation of astrocytes from the neuroprotective A2 to the pro-inflammatory A1 subtype. Therefore, our study offers novel insights into the neurotoxic effects of environmental pollutants, thereby establishing a theoretical foundation for the prevention and treatment of neurodegenerative diseases.</div></div>","PeriodicalId":303,"journal":{"name":"Ecotoxicology and Environmental Safety","volume":"312 ","pages":"Article 119954"},"PeriodicalIF":6.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147353181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}