Toxicology Mechanisms and Methods最新文献

{"title":"Aloe-emodin upregulates DUSP1 to alleviate aristolochic acid-induced renal tubular epithelial cell damage.","authors":"Huifang Cui, Wei Jiang","doi":"10.1080/15376516.2025.2515071","DOIUrl":"10.1080/15376516.2025.2515071","url":null,"abstract":"<p><p>To explore aloe-emodin (AE)'s effects on aristolochic acid I (AAI)-induced toxicity in renal tubular epithelial cells and particularly through its regulation of dual-specificity phosphatase 1 (DUSP1). Human renal proximal tubular epithelial cells (HK-2 cells were treated with different concentrations of AE and then exposed to AAI to induce cell damage. The experimental groups included the control group, AAI group, AAI + AE 10 μM group, AAI + AE 50 μM group, AAI + AE + shNC group, AAI + AE + sh-DUSP1 group, AAI + AE + oe-DUSP1 group, and AAI + AE + oe-NC group. Cell viability was assessed using the MTT assay, and apoptosis was detected by the TUNEL assay. Levels of pro-inflammatory cytokines were measured by ELISA. Mitochondrial function was evaluated. In addition, qRT-PCR and Western blot were used to analyze the expression of DUSP1 and apoptosis-related proteins. AE significantly increased the viability of HK-2 cells after AAI treatment and inhibited apoptosis. In the AAI-treated group, cell viability was significantly reduced, apoptosis increased, levels of pro-inflammatory cytokines were elevated, and mitochondrial function was impaired. In DUSP1 knockdown HK-2 cells, the protective effect of AE was significantly weakened, with decreased cell viability, increased apoptosis, aggravated inflammation, and impaired mitochondrial function. In the DUSP1 overexpression group, the protective effect of AE was further enhanced, indicating that DUSP1 plays a key role in the protective effects mediated by AE. AE can enhance AAI-induced HK-2 cell viability, inhibit cell apoptosis, and reduce inflammation and oxidative stress. The mechanism of AE may be related to the up-regulation of DUSP1 expression.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1074-1088"},"PeriodicalIF":2.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zebrafish larvae locomotion bioassay: application on nanofractionated <i>Naja nigricollis</i> venom.","authors":"Gregorio Calderoni, Haifeng Xu, Hugo Nelck, Julien Slagboom, Michael K Richardson, Jeroen Kool, Christian Tudorache","doi":"10.1080/15376516.2025.2509740","DOIUrl":"10.1080/15376516.2025.2509740","url":null,"abstract":"<p><p>Snakebite envenoming remains a major global health issue, particularly in underserved regions. To better understand venom composition and toxic effects, crude snake venoms can be fractionated into distinct toxin groups using high-throughput nanofractionation analytics. These fractions can then be assessed using venomics to identify specific toxins, in conjunction with bioassays to evaluate their bioactivity. Traditional <i>in vivo</i> testing in rodents is limited by legal and ethical concerns, the high number of fractions, and the small quantities of toxins in each. In this study, zebrafish larvae were introduced as an efficient alternative model for <i>in vivo</i> analysis of toxins that impair locomotion. A behavioral bioassay was developed using a light-dark challenge to assess locomotion in 5-day post-fertilization (dpf) larvae. A Locomotion Index was created to compare movement during the dark phase between venom-exposed and control groups. Using venom from the spitting cobra <i>Naja nigricollis</i>, two fractions were found to reduce locomotor activity significantly. Microscopic screening also revealed three tissue-toxic fractions, one of which caused bradycardia. Dose-response testing was performed for each toxic fraction. Furthermore, oxygen consumption assays were conducted with venom fractions from <i>N. nigricollis, N.haje, N. siamensis,</i> and <i>N. subfulva</i>, identifying two fractions that elevated oxygen consumption. High-throughput venomics linked these toxic effects to three-finger toxins and phospholipases A₂. This integrative approach offers a scalable, efficient method for <i>in vivo</i> toxicity screening of venom components and shows promise for broader applications in the discovery and profiling of diverse bioactive compounds.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1057-1073"},"PeriodicalIF":2.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144286543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronological activation of the NLRP3 inflammasome/pyroptosis pathway in the progression from metabolic dysfunction-associated fatty liver disease to hepatocellular carcinoma.","authors":"Linda Vanessa Márquez-Quiroga, Eduardo E Vargas-Pozada, Irina Cardoso-Lezama, Erika Ramos-Tovar, Verónica Rocío Vásquez-Garzón, Carolina Piña-Vázquez, Saúl Villa-Treviño, Jaime Arellanes-Robledo, Pablo Muriel","doi":"10.1080/15376516.2025.2524749","DOIUrl":"10.1080/15376516.2025.2524749","url":null,"abstract":"<p><p>Metabolic dysfunction-associated fatty liver disease (MAFLD) is a risk factor for hepatocellular carcinoma (HCC). Evidence links the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome/pyroptosis pathway to MAFLD-related fibrosis; however, its role in MAFLD progression to HCC remains poorly understood. This study investigates the temporal activation of the NLRP3 inflammasome/pyroptosis pathway in MAFLD-associated HCC. Rats were assigned to a control group, who received a standard diet with intraperitoneal injections of liquid petrolatum and water, or to experimental groups, subjected to a hepatopathogenic diet, CCl₄, and diethylnitrosamine. Serum liver enzymes, inflammatory cytokines, NLRP3 inflammasome/pyroptosis pathway, fibrosis, and HCC markers were assessed. Hepatosteatosis and serum liver enzymes increased after 3 weeks. Hepatosteatosis was associated with elevated levels of ALT (<i>p</i> = 0.0051), GGT (<i>p</i> < 0.0001), IL-6 (<i>p</i> = 0.0499), TNF-α (<i>p</i> = 0.0020), and IL-1β (<i>p <</i> 0.0001), and the NLRP3 inflammasome/pyroptosis pathway activators (NLRP3, <i>p</i> = 0.0246; ASC, <i>p =</i> 0.0003, caspase-1, <i>p</i> = 0.0003, and GSDMD <i>p</i> = 0.0111). Levels of fibrosis markers, including TGF-β (<i>p</i> < 0.0001), α-SMA (<i>p</i> = 0.0035), and collagen (<i>p</i> < 0.0001), increased after 7 weeks, while those of HCC markers PTGR1 and KRT19 increased 13 weeks onwards (both <i>p</i> < 0.0001). These findings provide the first evidence of the NLRP3 inflammasome/pyroptosis pathway's involvement in MAFLD-associated HCC development. The data strongly suggest that metabolic dysregulation and NLRP3-driven inflammation lead to pyroptosis, triggering ongoing cycles of cellular damage and regeneration and accelerating the transition from MAFLD to HCC.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1103-1117"},"PeriodicalIF":2.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144544978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isothiazolinones as preservatives: physicochemical characteristics, biological activity, and safety assessment.","authors":"Wiktoria Omachel, Barbara Kreczmer, Anna Barbasz","doi":"10.1080/15376516.2025.2510531","DOIUrl":"10.1080/15376516.2025.2510531","url":null,"abstract":"<p><p>Isothiazolinones are heterocyclic compounds with potent broad-spectrum antimicrobial properties, commonly used as preservatives in cosmetics, pharmaceuticals, and industrial products. Their antimicrobial efficacy results from interference with microbial protein and nucleic acid synthesis. However, their limited water solubility and instability under alkaline conditions, elevated temperatures, and UV exposure constrain their formulation and use. Despite regulatory restrictions, especially in the EU, due to their allergenic and toxic potential, exposure remains widespread, particularly through industrial and household products. Studies indicate that isothiazolinones can penetrate the skin, bind to cellular components, and induce oxidative stress, apoptosis, and immune responses. Furthermore, emerging data suggest possible endocrine-disrupting and neurotoxic effects. The mechanisms driving these toxicities are still not fully understood. This review examines the physicochemical characteristics, antimicrobial mechanisms, applications, exposure routes, cytotoxic effects, and molecular interactions of isothiazolinones. Deeper mechanistic insight is needed to support the development of safer alternatives and to inform more stringent regulatory frameworks.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"919-942"},"PeriodicalIF":2.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of Ca²⁺ signaling induced by the flavonoid diosmin in glioblastoma cells and its potential implications in the treatment using the Ca²⁺ chelating agent BAPTA-AM.","authors":"Lyh-Jyh Hao, Chiang-Ting Chou, Yen-Hui Lin, Tzu-Ying Sung, Wei-Zhe Liang","doi":"10.1080/15376516.2025.2501251","DOIUrl":"10.1080/15376516.2025.2501251","url":null,"abstract":"<p><p>Flavonoids, found in fruits and vegetables, can potentially prevent brain diseases. Diosmin (diosmetin-7-O-rutinoside), a flavonoid, exhibits various pharmacological activities, but its impact on calcium ion (Ca²⁺) signaling and the associated mechanisms in human glioblastoma cells remain unclear. This study investigated the effect of diosmin on intracellular Ca²⁺ levels ([Ca²⁺]_i), cell viability, and the participation of Ca²⁺-related pathways in DBTRG-05MG human glioblastoma cells. It also investigated the connection between Ca²⁺ signaling and toxicity in cells treated with diosmin and the Ca²⁺ chelator BAPTA-AM. Research indicates that diosmin (20-60 μM) caused an increase in [Ca²⁺]_i and induced cytotoxicity in a concentration-dependent manner. Furthermore, pre-treating the cells with the BAPTA-AM can intensify the cytotoxic effect. The removal of extracellular Ca²⁺ suppressed the entry of Ca²⁺. Agents that modulate store-operated Ca²⁺ channels, SKF96365 and 2-APB, can inhibit the entry of Ca²⁺ induced by diosmin. Treatment with the endoplasmic reticulum Ca²⁺ pump inhibitor thapsigargin in a Ca²⁺-free environment inhibited the increase in [Ca²⁺]_i caused by diosmin; conversely, treatment with diosmin reduced the increase in [Ca²⁺]_i caused by thapsigargin. Moreover, inhibiting phospholipase C (PLC) with U73122 eliminated the increase in [Ca²⁺]_i triggered by diosmin. In DBTRG-05MG cells, diosmin-induced cell death is associated with Ca²⁺, a process involving the entry of Ca²⁺ through store-operated Ca²⁺ channels and the release of Ca²⁺ from the endoplasmic reticulum, which relies on the PLC. Additionally, BAPTA-AM, a compound with Ca²⁺-chelating properties, shows promise in enhancing diosmin-induced cytotoxicity, and this could represent a significant development in glioblastoma research.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"982-992"},"PeriodicalIF":2.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144970525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of micro- and nanoplastic exposure on macrophages: a review of molecular and cellular mechanisms.","authors":"Parisa Ahmadi, David Doyle, Negin Mojarad, Soroush Taherkhani, Atousa Janzadeh, Maryam Honardoost, Mitra Gholami","doi":"10.1080/15376516.2025.2500546","DOIUrl":"10.1080/15376516.2025.2500546","url":null,"abstract":"<p><p>Micro- and nanoplastics (MNPs), pervasive environmental pollutants, contaminate water, soil, air, and the food chain and ultimately accumulate in living organisms. Macrophages are the main immune cells that gather around MNPs and engulf them through the process of phagocytosis. This internalization triggers M1 polarization and the secretion of inflammatory cytokines, including IL-1, IL-18, IL-12, TNF-α, and IFN-γ. Furthermore, MNPs damage mitochondria and lysosomes, causing overactivation of iNOS and excessive production of ROS. This results in cellular stress and induce apoptosis, necroptosis, and, in some cases, metosis in macrophages. The internalization of MNPs also increases the expression of receptors, involving CD36, SR-A, LOX-1, and the macrophage receptor with a collagenous structure (MARCO) while decreasing ABCA-1 and ABCG-1. MNPs in adipose tissue macrophages trigger proinflammatory cytokine secretion, causing adipogenesis, lipid accumulation, insulin resistance, and the secretion of inflammatory cytokines in adipocytes. Various factors influence the rate of MNP internalization by macrophages, including size, charge, and concentration, which affect internalization through passive diffusion. Receptor-mediated phagocytosis of MNPs occurs directly <i>via</i> receptors like T-cell immunoglobulin and mucin domain containing 4 (TIM-4) and MARCO. The attachment of biomolecules, including proteins, antibodies, opsonins, or microbes to MNPs (forming corona structures) promotes indirect receptor-mediated endocytosis, as macrophages possess receptors like TLRs and FcγRIII. MNPs also cause gut dysbiosis, a risk factor for proinflammatory microenvironment and M1 polarization. Here, we review the mechanisms and consequences of MNP macrophage exposure, which is linked to autoimmunity, inflammation, and cardiometabolic syndrome manifestations, including atherosclerosis and obesity, highlighting the immunotoxicity of MNPs.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"823-846"},"PeriodicalIF":2.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Implications of plastic-derived endocrine disruptors on human health.","authors":"Adebola Busola Ojo, Oluwatobi Deborah Agbeye, Theophilus Oghenenyoreme Ogwa, Damilola Adedoyin, Damilare Emmanuel Rotimi, Oluwafemi Adeleke Ojo","doi":"10.1080/15376516.2025.2510525","DOIUrl":"10.1080/15376516.2025.2510525","url":null,"abstract":"<p><p>Endocrine-disrupting chemicals (EDCs), such as bisphenol A (BPA), bisphenol S (BPS), phthalates, and micro- and nanoplastics, present substantial environmental and health hazards because of their potential to disrupt hormonal systems. Micro- and nanoplastics can release EDCs that disrupt reproductive and developmental processes, potentially affecting future generations. BPA, a common plasticizer and resin component, mimics estrogen and disrupts thyroid hormone metabolism, contributing to obesity, diabetes, and cardiovascular issues. BPS, a BPA substitute, exhibits similar endocrine-disrupting properties and persists longer in the environment. Phthalates, which are widely used as plasticizers, are associated with reproductive issues, metabolic conditions, and developmental issues in children. Combined exposure to multiple EDCs can amplify health risks, underscoring the need for further research on the synergistic impacts of these chemicals. This review underscores the urgent need for effective regulatory measures and further investigations into the health impacts of EDCs to mitigate their harmful impacts on the health of humans and the environment.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"894-918"},"PeriodicalIF":2.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Studies on the toxic effects of acute mercuric chloride poisoning in mice: primary toxicity evaluation analysis of HgCl₂.","authors":"Chenyu Zhao, Simin Jiang, Fan Jin, Lixiang Gu, Mingming Liang, Ying Zhao, Qin Han","doi":"10.1080/15376516.2025.2500547","DOIUrl":"10.1080/15376516.2025.2500547","url":null,"abstract":"<p><p>The aim of this study was to explore the acute damage caused by acute mercuric chloride poisoning to mice. The mice model of acute mercury (HgCl₂) poisoning was prepared by gavage and intraperitoneal injection, respectively. The experimental results showed that the LD50 was about 24 mg/kg for gavage and 4 mg/kg for intraperitoneal injection. On the basis of gavage, there were differences in the time required for water maze and righting reflex tests between groups of mice gavaged with different doses of HgCl₂ (<i>p < 0.05</i>); The levels of SOD, MDA, GSH-PX, CRE, BUN, AST and ALT in mice were different from those in the control (Normal saline) group (<i>p < 0.05</i>); The degree of inflammation response under microscope was different in different dose groups after HE staining of liver tissues, and there were differences in the degree of intimal thickening and lumen stenosis in different dose groups after HE staining of kidney tissue; The inductively coupled plasma mass spectrometry (ICP-MS) measured the levels of mercury in mice increased with increasing mercuric chloride concentration, with the accumulation in kidney much higher than that in liver. Based on the results of the study, it was concluded that the damage caused by mercuric chloride to memory, oxidative stress, liver and kidney tissues in mice starts from 4 mg/kg, and the mortality rate of mice reached 100% when the gavage dose was greater than or equal to 32 mg/kg, and the intraperitoneal injection of mercuric chloride produced faster and stronger toxic effects than gavage.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"969-981"},"PeriodicalIF":2.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144038465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Occupational nanoparticles: major sources, physicochemical properties, multi-organ toxic effects, and associated mechanisms.","authors":"Yinci Zhang, Ying Zhang, Haosheng Que, Chao Lu, Shuping Zhou","doi":"10.1080/15376516.2025.2505629","DOIUrl":"10.1080/15376516.2025.2505629","url":null,"abstract":"<p><p>Increased exposure to nanoscale particles (NPs) in living and occupational environments has produced various harmful effects in recent years. Owing to their small particle size and physicochemical properties, NPs can evade engineered defenses, exhibit greater toxicity, and affect the physiological functions of multiple organs in the human body through the circulatory system and biological barriers. Therefore, we should pay attention to the multi-organ toxicity effects caused by NPs and their mechanisms. High-level occupational exposure to NPs at elevated concentrations constitutes a substantial threat to the health of workers. Therefore, it is necessary to conduct a targeted assessment of the health risks of NPs in the occupational environment. This paper provides a comprehensive review of the sources of NPs in both living and occupational environments. Specifically, it highlights the disparities in the characteristics and associated toxicities between nanoscale and microscale inhalable particulate matter within the occupational context. Moreover, it delves deeply into the contributions of NPs to multi-organ toxicity effects and the underlying pathological mechanisms.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"847-864"},"PeriodicalIF":2.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondria Under Fire: Toxicological Mechanisms of Brominated Flame Retardants.","authors":"Raul Ghiraldelli Miranda, Ivo F Machado, Anabela Pinto Rolo, Daniel Junqueira Dorta, Carlos M Palmeira","doi":"10.1080/15376516.2025.2568145","DOIUrl":"https://doi.org/10.1080/15376516.2025.2568145","url":null,"abstract":"<p><p>Brominated flame retardants (BFRs) are ubiquitous and persistent environmental contaminants owing to their extensive use in consumer products. Although linked to various adverse health effects, the underlying molecular mechanisms remain complex. This review consolidates scientific evidence positioning mitochondria as a central target of BFR toxicity, unraveling the pathways that drive cellular damage. The analysis revealed that BFRs converge on the fundamental mechanisms of mitochondrial injury. They consistently impair bioenergetics by disrupting the electron transport chain and uncoupling oxidative phosphorylation, leading to ATP depletion and collapse of the mitochondrial membrane potential (ΔΨm). This energetic failure triggers a surge in reactive oxygen species, overwhelming antioxidant defenses, and causing severe oxidative damage. Beyond these common effects, this review highlights remarkable mechanistic plasticity. Tetrabromobisphenol A can induce distinct cell death programs, including apoptosis, necroptosis, and ferroptosis, depending on the cellular context of the study. Furthermore, BFR biotransformation can yield metabolites such as hydroxylated polybrominated diphenyl ethers (PBDEs) that exhibit significantly greater toxicity than their parent compounds. Finally, mitochondrial dysfunction is a central hub that orchestrates cellular damage by BFRs. This is critically highlighted by the replacement of BDE-209 with decabromodiphenyl ethane, a regrettable substitution, where the new compound shares similar mitotoxic mechanisms and has become a widespread pollutant. This underscores the urgent need for a paradigm shift toward mechanism-based risk assessment to prevent future cycles of hazardous chemical replacements and to guide the design of genuinely safer alternatives.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-43"},"PeriodicalIF":2.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145193117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}