Toxicology and applied pharmacology最新文献

{"title":"Targeting sonic hedgehog (shh) signaling pathways by the concentration–dependent topical resveratrol for protection from cyclophosphamide-induced alopecia in a mouse model","authors":"Aml A. El-Din,&nbsp;Dina M. Tahoon,&nbsp;Maaly A. Abd Elmaaboud,&nbsp;Fleur F. Abd Elmoniem,&nbsp;Amany A. Abdin","doi":"10.1016/j.taap.2025.117681","DOIUrl":"10.1016/j.taap.2025.117681","url":null,"abstract":"<div><h3>Background</h3><div>Chemotherapy-induced alopecia (CIA) is a common and inevitable side effect of systemic cancer treatment. There is an urgent need for novel therapies for cancer patients suffering from hair loss to improve their quality of life. This study aimed to investigate the potential protective effect of concentration-dependent topical resveratrol on hair follicles via targeting sonic hedgehog (Shh) signaling and its related downstream regulatory (Sirt-1), proliferative (Ki-67), and apoptotic status (caspase-3 and Bcl-2) pathways in cyclophosphamide-induced alopecia in female C57BL/6 mice model. Methods: All animals were subjected to depilation at the start of the experiment, then mice were divided into 5 equal groups as follows: Control group, cyclophosphamide (CPA)-untreated alopecia group, minoxidil (MXL) + CPA-alopecia, Resveratrol low concentration (RSV L10) + CPA-alopecia, Resveratrol high concentration (RSV H80) + CPA-alopecia. The effects of these drugs on hair coverage score, Shh signaling, Sirt-1, proliferation, and apoptosis were assessed. Results: Low concentration of topical RSV showed a significant increase in hair coverage score. Shh, Sirt-1, immunohistochemical expression levels of Ki-67, and Bcl-2 were significantly elevated, significantly decreasing caspase-3 expression in skin tissue. Moreover, the superiority extended to include histopathological findings and dermatoscopic skin monitoring compared to the groups that received either topical minoxidil 2 % or RSV at high concentration. Conclusion: Topical low-dose resveratrol protects against CIA by activating Shh signaling and modulating follicular proliferative and apoptotic pathways.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117681"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145726284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shionone ameliorates pulmonary fibrosis by activating mitophagy via PINK1-Parkin pathway","authors":"Yijia Su ,&nbsp;Qiang Fu ,&nbsp;Xilin Wu ,&nbsp;Xianhua Che ,&nbsp;Zhe Jiang ,&nbsp;Xuezheng Li","doi":"10.1016/j.taap.2025.117693","DOIUrl":"10.1016/j.taap.2025.117693","url":null,"abstract":"<div><div>Pulmonary fibrosis (PF) is a progressive and fatal interstitial lung disease with limited clinical treatment options. Shionone (SHI), a major active compound derived from <em>Ligularia fischeri</em> Turcz (LF), has shown pharmacological potential; however, its mechanism of action against PF remains unclear. This study investigates the anti-fibrotic effects and underlying pathways of SHI using a bleomycin (BLM)-induced PF mouse model and a Transforming Growth Factor-β (TGF-β)-stimulated A549 cell model. The results demonstrate that SHI treatment markedly alleviates BLM-induced alveolar damage, collagen accumulation, and inflammatory responses, while significantly improving survival rates in mice. At the molecular level, SHI activates the PTEN-induced putative kinase 1 (PINK1)-Parkin-mediated mitophagy pathway, leading to increased expression of autophagy-related proteins such as LC3II/LC3I and Beclin1, decreased levels of p62 and pro-fibrotic markers, enhanced clearance of dysfunctional mitochondria, restoration of mitochondrial membrane potential (MMP), and reduction of reactive oxygen species (ROS) accumulation. In vitro experiments further confirm that SHI inhibits fibrosis in TGF-β-challenged A549 cells through the same mechanism. This study is the first to elucidate that SHI mitigates PF by regulating mitophagy, offering a promising therapeutic target and potential drug candidate for PF. Future research may focus on optimizing the clinical application strategies of SHI.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117693"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145791017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of prenatal DINP exposure induced hepatic steatosis and underlying mechanism","authors":"Yahui Jin ,&nbsp;Junli Zhao ,&nbsp;Xinjing Wang ,&nbsp;Dan Li ,&nbsp;Meiqiong Wu ,&nbsp;Ben Li","doi":"10.1016/j.taap.2026.117707","DOIUrl":"10.1016/j.taap.2026.117707","url":null,"abstract":"<div><div>Prenatal exposure to diisononyl phthalate (DINP) exerts sex-specific effects on offspring liver lipid metabolism, yet the underlying mechanisms remain insufficiently defined. In this study, pregnant mice were administered DINP throughout gestation, and offspring were evaluated through growth assessment, liver histopathology, lipid profiling, hepatic gene expression, and fecal metabolomics to investigate potential gut–liver axis involvement. Maternal weight and food intake were unaffected, whereas offspring exhibited growth retardation and developmental delay. Male offspring showed elevated serum and hepatic triglycerides and total cholesterol, accompanied by marked hepatic steatosis, while females displayed milder lipid deposition.</div><div>Mechanistic analyses indicated that males exhibited impaired fatty acid oxidation, with upregulation of fatty acid binding protein (FABP) and perilipin 2 (PLIN2) and downregulation of peroxisome proliferator-activated receptor alpha (PPARα). In contrast, females maintained fatty acid β-oxidation through increased carnitine palmitoyltransferase-1a (CPT-1A) expression and lipid regulation mediated by peroxisome proliferator-activated receptor gamma (PPARγ). Fecal metabolomics revealed alterations in α-linolenic acid metabolism and ubiquinone biosynthesis in males, suggesting disrupted fatty acid utilization and mitochondrial function contributing to hepatic lipid accumulation. Female offspring primarily showed alterations in glycerophospholipid metabolism, which may facilitate membrane remodeling and lipid redistribution, thereby mitigating steatosis.</div><div>In summary, prenatal DINPexposure induces hepatic steatosis through sex-specific disruptions of the gut–liver metabolic axis. Males are more susceptible to lipid accumulation, whereas females exhibit compensatory adaptations that preserve metabolic balance. These findings provide mechanistic insight into the sex-dependent metabolic consequences of early-life DINP exposure and support a more comprehensive evaluation of its safety profile.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117707"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CYP genetic polymorphism, and CYP3A inducers and inhibitors regulate apatinib metabolism: Consequences for drug exposure and toxicity risks","authors":"Zhe Wang ,&nbsp;Le-hao Jin ,&nbsp;Ni-hong Pang ,&nbsp;Jun-er Xu ,&nbsp;Xiao-yu Xu ,&nbsp;Wei Sun ,&nbsp;Xiao-dan Zhang ,&nbsp;Jian-chang Qian","doi":"10.1016/j.taap.2025.117692","DOIUrl":"10.1016/j.taap.2025.117692","url":null,"abstract":"<div><div>Apatinib is a tyrosine kinase inhibitor metabolized by hepatic cytochromes P450 (CYPs). This study investigated how CYP genetic variations affect apatinib metabolism and response. We employed a multi-scale approach including enzyme kinetic studies with recombinant human CYP variants (<em>n</em> = 3), cellular proliferation assays in CYP3A4-overexpressing A549 cells (n = 3), and pharmacokinetic studies in rats treated with CYP3A modulators (<em>n</em> = 6 per group). CYP3A4*18, CYP2D6*10, and CYP2C9*3 variants showed markedly reduced metabolic activity. CYP3A4*18 overexpression enhanced apatinib's anti-proliferative effect in A549 cells. In rats, dexamethasone decreased apatinib exposure by inducing CYP3A expression, while ketoconazole increased exposure without altering CYP3A levels. Both CYP genetic polymorphisms and drug interactions significantly influence apatinib metabolism, highlighting the importance of personalized dosing strategies for optimizing therapy.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117692"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miR-207 mitigates silica-induced pulmonary fibrosis by suppressing fibroblast-to-Myofibroblast transition via multi-target modulation of the TGF-β1/SMADs signaling pathways in mice","authors":"Shu-ling Du ,&nbsp;Yuan-yuan Cui ,&nbsp;Xuan Zhou ,&nbsp;Wei-Lei Gong ,&nbsp;Zhao-qiang Zhang ,&nbsp;Gui-zhi Han","doi":"10.1016/j.taap.2025.117661","DOIUrl":"10.1016/j.taap.2025.117661","url":null,"abstract":"<div><div>TGF-β1/SMADs signaling pathway plays a vital role in development of silicosis, with SMADs serving as the core transducers. Accordingly, any fluctuation in SMAD abundance can decisively steer the disease trajectory. Our previous research revealed miR-207 suppresses the progression of silicosis fibrosis by targeting Smad3. Further bioinformatic analysis suggested that miR-207 could also bind to the sequences of genes of Smad2 and Smad7, raising the possibility that miR-207 functions as a coordinated rheostat of multiple SMADs. However, the specific regulatory mechanisms of miR-207 in silicosis remains unexplored. In this study, a mouse model of silicosis was established by administering a silica suspension (20 μg/μL, 80 μL) via nasal drip daily for 16 days. On day 17, the silica–dusted mice were transfected with either miR-207 mimics or inhibitors. Lungs samples were harvested on day 45 for histological assessment of injury. Then, the expression levels of miR-207, Smad2, and Smad7 were determined using RT-qPCR, and the levels of SMAD2 and 7, Collagen I and III, and indicators of fibroblast-to-myofibroblast transdifferentiation (FMT) (α-SMA, FAP-1, and Vimentin) were determined using Western blot. The results showed that miR-207 coordinately downregulated SMAD2 and upregulated SMAD7 at both the mRNA and protein levels in silica-exposed mice, with concomitant reductions in FMT indicators (α-SMA, FAP-1 and Vimentin) and collagen levels. Therefore, we concluded that miR-207 suppresses silicosis progression in mice by inhibiting FMT via modulation of the TGF-β1/SMADs signaling pathway by targeting SMADs.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117661"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145639846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resveratrol mitigates TOCP-induced spinal cord neurotoxicity by suppressing ferroptosis, a process mediated through the p62/Keap1/Nrf2 pathway","authors":"Sangping Li,&nbsp;Shule Tan,&nbsp;Xiangsheng Tian,&nbsp;Yiquan Ou,&nbsp;Shujuan Hu,&nbsp;Weichao Zhao,&nbsp;Dingxin Long","doi":"10.1016/j.taap.2025.117698","DOIUrl":"10.1016/j.taap.2025.117698","url":null,"abstract":"<div><div>This study investigated the protective effects of resveratrol (Res) against tri-o-cresyl phosphate (TOCP)-induced spinal cord neurotoxicity in adult hens, focusing on its modulation of ferroptosis via the p62/Keap1/Nrf2 pathway. Resveratrol is a classical neuroprotective compound with antioxidant properties and the ability to activate Nrf2. Adult hens were assigned to six groups: Control, TOCP, Ferrostatin-1 (Fer-1), Ferrostatin-1 + TOCP, Resveratrol, and Resveratrol + TOCP. Spinal cord tissues were analyzed using behavioral OPIDN scoring, histology (hematoxylin–eosin and Nissl staining), biochemical assays, and Western blotting for ferroptosis- and p62/Keap1/Nrf2-related proteins. TOCP exposure induced severe ultrastructural damage, including myelin sheath disruption and neuronal degeneration, along with increased malondialdehyde (MDA) and Fe²⁺ levels and decreased glutathione (GSH) and superoxide dismutase (SOD) activity. Western blot analysis demonstrated upregulation of NCOA4, ACSL4, Nrf2, P62, and LC3 II, with downregulation of GPX4, SLC7A11, FTH1, and Keap1. Resveratrol treatment significantly attenuated these molecular, biochemical, and histopathological alterations, mitigating oxidative stress and ferroptotic changes.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117698"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GKB7I-53: A novel anti-metastatic agent for colorectal cancer","authors":"Min Hee Yang ,&nbsp;Ducdat Le ,&nbsp;Thinhulinh Dang ,&nbsp;Vinhquang Truong ,&nbsp;In Jin Ha ,&nbsp;Mina Lee ,&nbsp;Kwang Seok Ahn","doi":"10.1016/j.taap.2026.117712","DOIUrl":"10.1016/j.taap.2026.117712","url":null,"abstract":"<div><div>Metastasis driven by epithelial-mesenchymal transition (EMT) remains a critical challenge in colorectal cancer treatment. This study investigated GKB7I-53, a saponin compound isolated through feature-based molecular networking, as a potential therapeutic agent targeting EMT pathways. GKB7I-53 demonstrated minimal cytotoxicity (&gt;90% cell viability at 50 μM) while effectively inhibiting metastatic processes. The compound downregulated mesenchymal markers (CXCR4, CXCR7) and upregulated epithelial markers (E-cadherin, occludin), suppressing EMT progression. In CXCL12-stimulated cells, GKB7I-53 significantly reduced cell migration and invasion while decreasing MMP-2/9 activity, key enzymes facilitating metastatic spread. Mechanistically, GKB7I-53 suppressed MnSOD-induced STAT3 activation, thereby blocking the JAK/STAT3 signaling pathway crucial for metastasis. Molecular docking studies confirmed strong binding affinity to target proteins involved in EMT and cancer progression. These findings suggest that GKB7I-53 may serve as a potential lead compound with anti-metastatic properties in colorectal cancer. Rather than inducing general cytotoxicity, GKB7I-53 selectively modulates EMT-related pathways, indicating a mechanistic basis for its anti-metastatic effects. However, further in vivo validation and preclinical studies are required to determine its therapeutic relevance.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117712"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145977776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Andrographolide-induced PANoptosis underlies its multiple organ toxicity in mice","authors":"Na Lu ,&nbsp;Yuan-wen Cai ,&nbsp;Qi-hai Cai ,&nbsp;Xiu-wen Liang ,&nbsp;Nuo Sun ,&nbsp;On-kei Chan ,&nbsp;Zi-jian Shi ,&nbsp;Bo Hu ,&nbsp;Xian-hui He ,&nbsp;Qing-bing Zha ,&nbsp;Dong-yun Ouyang","doi":"10.1016/j.taap.2025.117682","DOIUrl":"10.1016/j.taap.2025.117682","url":null,"abstract":"<div><div>Andrographolide (Andro), the major bioactive component of <em>Andrographis paniculata</em>, exhibits potent anti-inflammatory properties but has raised safety concerns due to reported organ toxicity. This study aimed to investigate the mechanisms underlying Andro's <em>in vitro</em> and <em>in vivo</em> toxicity. In mice, single dose (≤100 mg/kg) Andro administration showed no acute toxicity, with no overt histopathological organ injury. But repeated administration of the same dose of Andro triggered damage in lung, liver, uterus, and kidney, characterized by pulmonary alveolar disruption, renal tubular edema, and elevated serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT). Concurrent with systemic injury, PANoptosis was induced by Andro in these organs, as evidenced by the activation of caspase-1/−8/−3 (apoptosis), gasdermin D/E (GSDMD/E, pyroptosis), and MLKL (necroptosis), indicating the correlation between PANoptosis and organ toxicity. <em>In vitro</em>, Andro caused lytic cell death in macrophages and other cells in a time- and dose-dependent manner. During this process, Andro induced rapid activation of caspase-8, followed by caspase-1/−3 and GSDME cleavage and phosphorylation of MLKL (p-MLKL), indicative of the activation of the PANoptosis signaling pathway. Consistent with this, Andro induced lytic cell death was markedly attenuated by caspase-1 inhibitor VX-765, pan-caspase inhibitors (IDN-6556, <em>Z</em>-VAD-FMK) and GSDMD/E inhibitor (disulfiram). In addition, RIPK1 inhibition (by Nec-1) partially reduced cell death, confirming RIPK1-dependent necroptosis as a minor contributor. In conclusion, our data establish PANoptosis as an important mechanism of Andro-induced organ injury, providing a mechanistic framework for Andro's dichotomous bioactivity, informing evidence-based dosing strategies to maximize therapeutic efficacy while mitigating toxicity risks in clinical practice.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117682"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145726262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sinapic acid attenuates colistin-driven nephrotoxicity by targeting the miRNA-21/SIRT1/NF-κB pathway and facilitating tubular repair and inflammation in a rat model","authors":"Medine Akkan Öz ,&nbsp;Hasan Şimşek ,&nbsp;Selçuk Özdemir ,&nbsp;Özge Kandemir ,&nbsp;Sefa Küçükler ,&nbsp;Hüseyin Mutlu ,&nbsp;Ramiz Yazıcı ,&nbsp;Fatih Mehmet Kandemir","doi":"10.1016/j.taap.2026.117708","DOIUrl":"10.1016/j.taap.2026.117708","url":null,"abstract":"<div><div>The present study aimed to investigate the nephrotoxic effects of colistin (CS) in a rat model and to elucidate the potential renoprotective mechanisms of sinapic acid (SA) at biochemical, molecular, and metabolic levels. Colistin administration induced pronounced renal dysfunction, as evidenced by significant elevations in serum creatinine (Scr) and blood urea nitrogen (BUN), along with marked increases in kidney injury biomarkers, including KIM-1, NGAL, FABP, IL-18, MCP-1, and YKL-40. Metabolic disruption was further confirmed by reduced ATP levels and increased lactate dehydrogenase (LDH) and triacylglycerol (TAG) concentrations, indicating mitochondrial dysfunction and cytotoxicity. Serum proteomic profiling using proximity extension assay identified significant alterations in 22 of 43 proteins, with IL-1β, IL-2, CXCL2, CSF-1, CCL22, and IFN-α2 showing marked upregulation following CS exposure. These inflammatory and immune-related proteins were significantly attenuated by SA co-treatment. Molecular analyses revealed that CS activated the miR-21/NF-κB/CD68 axis while suppressing SIRT1 expression, reflecting enhanced inflammation and macrophage infiltration. Sinapic acid effectively normalized these molecular disturbances. Furthermore, CS significantly upregulated renal mRNA expression of Cst3, Timp2, Igfbp7, Hgf, IL9, and Dkk3—genes associated with renal stress, fibrosis, and inflammation—whereas SA treatment markedly reduced their expression. Collectively, these findings demonstrate that sinapic acid exerts renoprotective effects primarily through modulation of inflammatory signaling pathways, suppression of miR-21/NF-κB-mediated responses, restoration of SIRT1 activity, and improvement of metabolic homeostasis. The study confirms the therapeutic potential of SA against colistin-induced nephrotoxicity.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117708"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synergistic assault of DEHP and MPs: Unmasking the ER stress-triggered autophagic injury male fertility","authors":"Jiajun Guo ,&nbsp;Xiaoyan Feng ,&nbsp;Yuankun Zhou ,&nbsp;Tao You ,&nbsp;Hengyi Xu","doi":"10.1016/j.taap.2026.117710","DOIUrl":"10.1016/j.taap.2026.117710","url":null,"abstract":"<div><div>As an emerging category of environmental pollutants, microplastics (MPs) garner significant attention due to their exceptionally high exposure risk. Di(2-ethylhexyl) phthalate (DEHP), a ubiquitous plasticizer in the plastics industry, shares a similar trajectory of escalating risk as plastic pollution intensifies. MPs and DEHP are widely present in environments accessible to humans, exerting significant adverse effects on human health. The reproductive toxicity of both MPs and DEHP has been reported. However, their combined toxicity, particularly the damage to the male reproductive system, remains unclear. Here, we employed the C57BL/6 J mouse model for our experiments. The mice were continuously exposed to 10 mg/L MPs and 500 μg/L DEHP through free drinking water for two months to investigate the effects of these two pollutants on mouse testes. Our study found that mice co-exposed to MPs and DEHP experienced severe impairment of male reproductive system, manifested as disruption of testicular structure, decline in sperm quality, and dysregulation of sex hormone synthesis. Furthermore, the co-exposure to DEHP and MPs activated endoplasmic reticulum stress <em>via</em> the PERK-eIF2α-ATF4 pathway, and also induced excessive autophagy, contributing to reproductive damage. In summary, our findings highlight the significant risks of co-exposure to DEHP and MPs and provide new insights into their combined reproductive toxicity in male mammals.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117710"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}