Toxicology最新文献

{"title":"Cx43 phosphorylation at Ser368 facilitates PASMC dedifferentiation in nicotine-induced pulmonary arterial remodeling","authors":"Yi Xu ,&nbsp;Xiaomin Hou ,&nbsp;Su Guo ,&nbsp;Jin Zhou ,&nbsp;Xuelu Jiang ,&nbsp;Zhifa Zheng ,&nbsp;Liangyuan Zhao ,&nbsp;Xiaoxia Ren ,&nbsp;Lingbo Yang ,&nbsp;Yiwei Shi ,&nbsp;Xiaojiang Qin","doi":"10.1016/j.tox.2025.154389","DOIUrl":"10.1016/j.tox.2025.154389","url":null,"abstract":"<div><h3>Background</h3><div>Pulmonary arterial hypertension is a severe disease characterized by pulmonary vascular remodeling, which is closely associated with the phenotypic switching of pulmonary artery smooth muscle cells (PASMCs). Connexin 43 (Cx43) phosphorylation is a key regulator of intercellular communication. However, the specific mechanism underlying nicotine-induced dedifferentiation of PASMCs remains unclear.</div></div><div><h3>Purpose</h3><div>This study aimed to investigate the molecular mechanism by which Cx43 phosphorylation promotes nicotine-induced phenotypic switching of PASMCs, thereby driving pulmonary vascular remodeling.</div></div><div><h3>Methods</h3><div>Using <em>Tagln-Cre; Cx43</em>^{<em>+ /+</em>} and <em>Tagln-Cre; Cx43</em>^{<em>flox/+</em>} deletion mice exposed to nicotine, a series of <em>in vivo</em> and <em>in vitro</em> experiments were conducted to investigate the mechanism by which nicotine promotes pulmonary arterial remodeling via protein kinase C-mediated phosphorylation of Cx43 and subsequent dedifferentiation of PASMCs. The involvement of this kinase pathway was further validated with its specific inhibitor, chelerythrine chloride.</div></div><div><h3>Results</h3><div>Nicotine increased PASMC dedifferentiation by promoting Cx43 phosphorylation at Ser368 (Cx43-pS368). In <em>Tagln-Cre; Cx43</em> ^{<em>flox/+</em>} mice, these pathological changes were reduced. In vitro, chelerythrine chloride was utilized to inhibit nicotine-induced Cx43-pS368. This suppression of Cx43-pS368 effectively attenuated nicotine-induced PASMC dedifferentiation, thereby ameliorating pulmonary arterial remodeling.</div></div><div><h3>Conclusion</h3><div>Nicotine can induce PASMC phenotypic transformation by modulating Cx43-pS368, thereby promoting pulmonary artery remodeling. Targeting this pathway could provide a therapeutic strategy for nicotine-related pulmonary vascular diseases.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154389"},"PeriodicalIF":4.6,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889886","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":"Macrophage-epithelial cells crosstalk and the role of CCL2-CCR2 axis in single-walled carbon nanotubes-induced lung inflammation and fibrosis","authors":"Yalu Shen ,&nbsp;Zhen Shi ,&nbsp;Jiayang Zou ,&nbsp;Yunfei Zhou ,&nbsp;Qingqing Yang ,&nbsp;Wenrui Zhao ,&nbsp;Yu Gan ,&nbsp;Xinxin Hu ,&nbsp;Tong Shen ,&nbsp;Xiang Zhang","doi":"10.1016/j.tox.2025.154388","DOIUrl":"10.1016/j.tox.2025.154388","url":null,"abstract":"<div><div>Environmental and occupational exposure to carbon nanotube (CNT) raises concerns over their safety and adverse health impacts, especially lung inflammation and fibrosis. Immune cells and epithelial cells within alveoli interact with each other to maintain lung homeostasis. To date, the contribution of lung macrophage-epithelial cells crosstalk to single-walled CNT (SWCNT)-caused lung injury and underlying mechanisms have not been systematically investigated. Here, we established a mice model of lung exposure to SWCNT and found that SWCNT induced M1-typed lung macrophages polarization during inflammation stage and abnormal epithelium regeneration during fibrosis stage, characterized by impaired alveolar epithelial type Ⅱ (AT2) cells to alveolar epithelial type Ⅰ (AT1) cells transition. Mechanistically, conditioned medium experiments combined with chemokines CCL2 siRNA intervene revealed that damaged lung epithelial cells-derived CCL2 by SWCNT activated CCR2 in macrophages, subsequently polarizing to M1 state. <em>In vivo</em> experiments further demonstrated CCL2-CCR2 axis regulated SWCNT-polarized M1 lung macrophages and pro-inflammatory cytokines secretion, which are involved in the impairment of AT2-AT1 cells transition. Importantly, inhibition of CCL2-CCR2 axis effectively restored SWCNT-induced lung inflammation and fibrosis. In conclusion, our findings elucidate the crosstalk of lung macrophages and epithelial cells, which further regulates the progression of SWCNT-induced lung injury, and target CCL2-CCR2 axis is expected to be potential therapeutic strategy for the prevention and treatment of lung injury induced by nanoparticles.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154388"},"PeriodicalIF":4.6,"publicationDate":"2025-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145858130","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":"PPAR subtypes determine distinct modes of action of phthalate esters (PAEs) and per- and polyfluoroalkyl substances (PFAS) in disrupting human macrophage alternative activation","authors":"Zhisen Zhuang ,&nbsp;Lijuan You ,&nbsp;Jianbo Kong ,&nbsp;Yaru Tian ,&nbsp;Yongning Li ,&nbsp;Yuan Zhi ,&nbsp;Bo Zhang ,&nbsp;Yi Wan ,&nbsp;Xudong Jia ,&nbsp;Hui Yang","doi":"10.1016/j.tox.2025.154387","DOIUrl":"10.1016/j.tox.2025.154387","url":null,"abstract":"<div><div>Phthalate esters (PAEs) and per- and polyfluoroalkyl substances (PFAS) are ubiquitous pollutants tied to metabolic and immune disorders. The peroxisome proliferator-activated receptor (PPAR) pathway has been indicated to mediate their toxic effects, but the specific functions of PPAR subtypes and their mediating roles remain unclear. In this study, we generated PPARα-, δ-, and γ-specific knockout THP-1 cell lines by using CRISPR/Cas9 system and then differentiated them into interleukin-4 (IL-4) and interleukin-13 (IL-13)-polarized macrophages (alternative activation). During the induction process, the cells were exposed to 0, 6.25, 12.5, 25, 50, 100 μM of five PAE metabolites: Mono-(2-ethylhexyl) phthalate (MEHP), Monocyclohexyl phthalate (MCHP), Monoisonyl phthalate (MINP), Monoisobutyl phthalate (MIBP), and Monobenzyl phthalate (MBzP); and five PFAS: Perfluoroundecanoic acid (PFUnDA), Perfluorodecanoic acid (PFDA), Perfluorooctanoic acid (PFOA), Potassium perfluorooctanesulfonate (PFOS-K), and Potassium 9-chlorohexadecafluoro-3-oxanonane-1-sulfonate (F53B) for 48 h. The results showed that PPARδ deletion abolished CD209 expression, confirming its essential role, whereas PPARα deletion reduced and PPARγ deletion enhanced CD209, indicating PPARα promotes and PPARγ restrains alternative activation. Compounds displayed subtype-selective actions: MEHP activated PPARα/γ; MBzP/MCHP inhibited PPARδ yet activated PPARγ; MINP activated PPARγ only. Among PFAS, PFOS-K activated PPARδ/γ; F53B inhibited PPARα; PFOA activated PPARγ; PFDA inhibited PPARα/δ. Transcriptomics revealed compound-specific enrichments—cholesterol (MEHP), fatty-acid (MCHP), glycolysis (PFOS-K), TCA cycle (PFOA)—despite common PPAR pathway engagement. In conclusion, PAEs and PFAS disrupt macrophage plasticity through distinct PPAR-subtype signatures, providing molecular landmarks for future hazard assessment of environmental pollutants.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154387"},"PeriodicalIF":4.6,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850303","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":"Transcriptomic analysis of BPA alternative chemicals in primary human mammary epithelial cells","authors":"Geronimo Matteo ,&nbsp;Andrea Rowan-Carroll ,&nbsp;Lauren M. Bradford ,&nbsp;Matthew J. Meier ,&nbsp;Andrew Williams ,&nbsp;J. Christopher Corton ,&nbsp;Carole L. Yauk ,&nbsp;Ella Atlas","doi":"10.1016/j.tox.2025.154375","DOIUrl":"10.1016/j.tox.2025.154375","url":null,"abstract":"<div><div>Some everyday consumer products contain endocrine disruptors like bisphenol A (BPA) and its replacements. To date, most <em>in vitro</em> chemical screening to evaluate these compounds has been accomplished using immortalized cell lines, which differ significantly from human tissues. Our goal was to test BPA and select alternatives previously screened in breast cancer cells for toxicological potency and mechanism of action in human mammary epithelial cells (HMECs). HMECs from three human donors were exposed to BPA and four alternative chemicals (in concentration response format from 0.001 to 50 µM) for 48 h and global transcriptomic changes were quantified. Transcriptomic biomarker analysis was employed to explore chemically induced estrogen receptor alpha (ERα) activation and alterations in stress response pathways. Benchmark concentration (BMC) analysis was applied to gene expression data to derive transcriptomic points of departure (tPODs) to compare chemicals for potency. Pathway and upstream regulator analysis was applied among the genes fitting BMCs. All chemicals had tPODs within a single order of magnitude. Bisphenol AF (BPAF) was the most potent, followed by tetramethyl bisphenol F (TMBPF), bisphenol C (BPC), 4,4’-bisphenol S (BPS), and BPA. None of the chemicals activated the ERα biomarker. Some stress response biomarkers were activated at high exposure concentrations. Genes fitting BMCs clustered chemicals into two groups, with one group (BPAF and TMBPF) primarily inhibiting expression patterns and the other (BPC, BPS, and BPA) mostly activating. These data suggest that the BPA alternatives tested have similar toxicological potencies in HMECs and oppositely enrich various gene sets.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154375"},"PeriodicalIF":4.6,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145811034","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":"A scalable human liver-on-a-chip platform for predictive safety assessment","authors":"Gauri Kulkarni ,&nbsp;Lizao Chen ,&nbsp;Jing Sang ,&nbsp;Ji Hye Seo ,&nbsp;Romain Grall ,&nbsp;Yunfang Wang ,&nbsp;Paige Gilbride ,&nbsp;Yu-Chieh Yuan ,&nbsp;Matthew Albaum-Getzen ,&nbsp;Jenna McCormack ,&nbsp;Jingzhe Ma ,&nbsp;Alyssa Fanelli ,&nbsp;Lingjun Meng ,&nbsp;Beibei Xu ,&nbsp;XuHai Huang ,&nbsp;Thomas Marshall ,&nbsp;Hardeep Singh ,&nbsp;Xiaohua Qian ,&nbsp;Zhiyong Xie ,&nbsp;Hui Bai ,&nbsp;Haiqing Bai","doi":"10.1016/j.tox.2025.154378","DOIUrl":"10.1016/j.tox.2025.154378","url":null,"abstract":"<div><div>Non-animal methods, including advanced <em>in-vitro</em> approaches such as liver-on-a-chip models, hold promise for hepatotoxicity testing but remain limited in pharmaceutical and regulatory adoption due to high costs, poor scalability, low reproducibility, and insufficient validation. To address these challenges, we introduce a drug-induced liver injury (DILI) model based on the commercially available and highly adaptable OC-Plex microfluidic platform. Primary human hepatocytes (PHHs) maintained long-term viability and metabolic competence, confirmed by albumin and urea production as well as cytochrome P450 gene expression. The system reliably detected acetaminophen (APAP) - induced hepatotoxicity across six mechanistic readouts—albumin, viability, cytokeratin-18 (CK18), urea, CYP3A4 activity, and mitochondrial function. As an initial proof-of-concept, we tested 17 compounds, including both drugs and cosmetic ingredients. Among 13 compounds with known toxicity liabilities in humans, our model shows a high predictive performance (85.7 % sensitivity, 100 % specificity, and 92.3 % accuracy). Together, these findings demonstrate the feasibility of a cost-effective, scalable, and human-relevant liver-on-a-chip system for predictive hepatotoxicity testing. With future development and validation, this model holds great potential to replace animal testing in chemical safety assessment.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154378"},"PeriodicalIF":4.6,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145805556","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":"Evaluating the absence of allometric scaling for hepatic microsomal Phase I and Phase II xenobiotic biotransformation among mammals","authors":"Luke Ockhuijsen,&nbsp;Ad M.J. Ragas,&nbsp;A. Jan Hendriks","doi":"10.1016/j.tox.2025.154377","DOIUrl":"10.1016/j.tox.2025.154377","url":null,"abstract":"<div><div>Elucidating consistent patterns for xenobiotic biotransformation among mammals is challenging because of intrinsic species differences. At the organism level, pharmacokinetic rate constants are believed to scale allometrically to body weight with a power of ¾, akin to metabolic rate constants, but the mechanism for biotransformation scaling is unclear. Predicting xenobiotic biotransformation through a quantitative <em>in vitro</em> to <em>in vivo</em> extrapolation (QIVIVE) approach combining allometric scaling relationships related to liver physiology and <em>in vitro</em> xenobiotic biotransformation could be promising. This study explores the previously unexplored potential of allometric scaling for hepatic microsomal Michaelis-Menten parameters. Hepatic microsomal Michaelis-Menten parameters, viz., affinity (K_m), maximum velocity (V_max), and <em>in vitro</em> clearance (CL_int), were examined for the xenobiotic biotransformation enzymes Cytochrome P450 (CYP) and UDP-glucuronosyl transferase (UGT). To ensure validity, data for ≥ 4 mammals per substrate biotransformation pathway were collected through a literature search and available databases. Ordinary linear regressions per pathway for each parameter showed that only a few individual regressions scaled statistically significantly to body weight. Averaging all scaling exponents of significant regressions revealed that hepatic microsomal Michaelis-Menten parameters are independent of body weight. Although not statistically significant, the average scaling exponent for each Michaelis-Menten parameter was close to 0. Therefore, differences in enzyme abundance or liver physiology between species are likely contributors to the observed ¾ exponent for allometric scaling relationships of <em>in vivo</em> xenobiotic clearance. Characterisation of underlying mechanisms at an enzyme-substrate level might ultimately improve understanding and estimation of xenobiotic clearance for mammals in QIVIVE approaches.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154377"},"PeriodicalIF":4.6,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800627","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":"Neurotoxic potential of synthetic cannabinoids’ pyrolysis products","authors":"Filipa Pita ,&nbsp;Ricardo Jorge Dinis-Oliveira ,&nbsp;João Pedro Silva ,&nbsp;Paula Guedes de Pinho ,&nbsp;Félix Carvalho","doi":"10.1016/j.tox.2025.154374","DOIUrl":"10.1016/j.tox.2025.154374","url":null,"abstract":"<div><div>Synthetic cannabinoids (SCs) represent a prominent class of new psychoactive substances (NPS), primarily consumed via inhalation methods such as smoking or vaping. Although the direct neurotoxic effects of SCs are well established, the pyrolysis process that occurs during smoking induces structural alterations that generate novel, frequently unidentified toxicants with potentially severe neurobiological consequences. This review addresses the neurotoxicity associated with parent SC compounds and their pyrolysis products, with particular emphasis on mechanisms, including oxidative stress, mitochondrial dysfunction, excitotoxicity, and neuroinflammation. A PRISMA-guided systematic review identified only nine studies specifically investigating the neurotoxic effects of SC pyrolysis products, revealing a significant gap in the literature and underscoring the urgent need for targeted research in this domain. The review further highlights that additional constituents, such as plant materials incorporated into SC formulations, can contribute to the generation of harmful byproducts and complicate forensic interpretation. The structural heterogeneity of SCs, in conjunction with variables such as polydrug use and chronic exposure, further exacerbates their toxicological profile. Future research should prioritise the identification and characterisation of pyrolysis-derived toxicants, the advancement of analytical methodologies for their detection, and the implementation of evidence-based public health strategies aimed at risk mitigation.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154374"},"PeriodicalIF":4.6,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145799682","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":"PM2.5 exposure exacerbates airway pyroptosis related inflammatory response in asthmatic mice by activating NLRP3 inflammasome","authors":"Hui Du ,&nbsp;Zhi Liu ,&nbsp;Lingli Ge ,&nbsp;Yuxi Lei ,&nbsp;Yuxin Wang ,&nbsp;Jian Lan ,&nbsp;Dongchi Zhao","doi":"10.1016/j.tox.2025.154376","DOIUrl":"10.1016/j.tox.2025.154376","url":null,"abstract":"<div><h3>Background</h3><div>Fine particulate matter (PM2.5)-induced airway epithelial damage plays a pivotal role in driving the development of airway inflammation. Although pyroptosis is recognized for its highly proinflammatory nature, its precise role in PM2.5-associated airway inflammation, particularly in asthmatic condition, remains to be fully elucidated.</div></div><div><h3>Methods</h3><div>In ovalbumin (OVA)-sensitized asthmatic mice, we assessed pulmonary histopathology, inflammatory cell counts and Th2 cytokine levels (IL-4, IL-5, and IL-13) in bronchoalveolar lavage fluid (BALF), airway hyperresponsiveness (AHR), and airway epithelial pyroptosis. To investigate the effects of PM2.5 on airway epithelial cells, BEAS-2B cells were exposed to PM2.5. Cell viability was evaluated using the CCK-8 assay, while pyroptosis-related protein levels and inflammatory cytokine release were analyzed by Western blot and ELISA, respectively. Additionally, transmission electron microscopy (TEM) was employed to examine PM2.5-induced ultrastructural changes in BEAS-2B cells. To further elucidate the underlying mechanism, we administered the NLRP3 inhibitor MCC950 and the Caspase-1 inhibitor Ac-YVAD-cmk to verify the involvement of NLRP3 inflammasome activation and pyroptosis in PM2.5-exposed asthmatic mice.</div></div><div><h3>Results</h3><div>PM2.5 exposure significantly aggravated airway inflammation in asthmatic mice, as demonstrated by elevated histopathological inflammatory scores in lung tissues and increased pro-inflammatory cytokine levels in BALF. Furthermore, PM2.5 upregulated the abundance of pyroptosis-related markers, namely NLRP3, Caspase-1, GSDMD, and IL-1β, in the lung tissues of asthmatic mice. In BEAS-2B cells, PM2.5 exposure led to a dose-dependent reduction in cell viability and promoted the activation of NLRP3 inflammasome, subsequently leading to Caspase-1-mediated GSDMD cleavage and IL-1β secretion. TEM further confirmed pyroptosis, revealing characteristic morphological alterations such as cytoplasmic vacuolation, mitochondrial swelling, and plasma membrane pore formation in BEAS-2B cells exposed to PM2.5. Critically, inhibition of NLRP3 (MCC950) or Caspase-1 (Ac-YVAD-cmk) markedly attenuated PM2.5-induced pyroptosis and ameliorated airway inflammation in asthmatic mice, underscoring the pivotal role of the NLRP3/Caspase-1/GSDMD axis in this pathogenic process.</div></div><div><h3>Conclusion</h3><div>Our findings demonstrate that PM2.5 exposure induces airway epithelial pyroptosis through NLRP3 inflammasome activation, thereby exacerbating airway inflammation in asthmatic mice.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154376"},"PeriodicalIF":4.6,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800687","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":"Mixture toxicity revisited: A translational review of experimental evidence from animal models to human health risk assessment","authors":"Jose L. Domingo","doi":"10.1016/j.tox.2025.154372","DOIUrl":"10.1016/j.tox.2025.154372","url":null,"abstract":"<div><div>This review examines research investigating how simultaneous exposure to multiple chemicals affects biological systems, highlighting deficiencies in conventional single-substance risk evaluation frameworks. Living organisms in their natural habitats face continuous exposure to diverse chemical combinations, which frequently result in interactive effects, including synergism and antagonism, that diverge from the straightforward additive outcomes anticipated by traditional toxicological approaches. Research using animal and aquatic experimental models has shown that these exposures depend on numerous variables, such as the specific chemicals involved, their dose relationships, duration of contact, measured biological outcomes, and underlying mechanistic processes. This review examines fundamental methodological frameworks, particularly concentration addition (CA) and independent action (IA) models, used for predicting mixture toxicity, with most mixture effects falling within a two-fold range of additivity predictions though important deviations occur. Additional complicating factors include the timing of exposure and the specific biological traits of test species. The present review also addresses difficulties in applying findings from animal research to human populations, given differences in toxicokinetic processes and genetic makeup across species. To navigate these complexities, this review supports the adoption of mechanism-based frameworks incorporating high-throughput omics technologies, computational approaches, and standardized protocols for evaluating environmentally realistic mixtures. The review advocates for implementing tiered, cumulative risk-assessment methodologies that accurately represent real-world exposure conditions and emphasize protection of susceptible populations. This transformation is vital for advancing predictive toxicology and strengthening protections for public and environmental health. Ultimately, the review argues for moving beyond the obsolete single-substance paradigm toward comprehensive, evidence-driven approaches equipped to handle the multifaceted nature of chemical exposures. This review critically evaluates experimental animal studies in chemical mixture toxicology, emphasizing the complexities and prospects of applying animal findings to human health risk assessment. It identifies key gaps linking controlled experiments with epidemiological data and proposes research directions to advance risk evaluation and management of real-world chemical co-exposures.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"520 ","pages":"Article 154372"},"PeriodicalIF":4.6,"publicationDate":"2025-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145769309","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":"Prenatal diesel exhaust exposure enhances neonatal hyperoxia-induced kidney injury via oxidative stress and lipid disruption","authors":"Sheng-Yuan Ho ,&nbsp;Yu-Shan Chang ,&nbsp;Hsiu-Chu Chou ,&nbsp;Chung-Ming Chen","doi":"10.1016/j.tox.2025.154373","DOIUrl":"10.1016/j.tox.2025.154373","url":null,"abstract":"<div><div>Prenatal exposure to diesel exhaust particles (DEP) and postnatal oxygen therapy are both clinically relevant perinatal stressors, but their combined effects on kidney development are not well characterized. Using a rat model (Sprague Dawley, n = 10/group), pregnant dams received DEP via intranasal instillation (500 μg/day in PBS, gestational day 16–21; NIST SRM 2975), and offspring were maintained in either room air or 85 % oxygen chambers from birth through postnatal day 14. At postnatal day 14, kidneys were analyzed by histology, Western blot, ELISA, and LC-MS metabolomics. Offspring that received both prenatal DEP and postnatal oxygen showed more severe tubular injury across sexes, and higher kidney-to-body weight ratios that were driven primarily by significant increases in male offspring, whereas changes in females did not reach statistical significance. Kidney injury molecule-1 (KIM-1) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels were increased, and 8-OHdG showed a significant interaction between DEP and oxygen exposure. Interleukin-1 (IL-1), IL-6, and tumor necrosis factor-α (TNF-α) were elevated by both DEP and oxygen, indicating additive effects. Serum cystatin C, a marker of renal dysfunction, was also increased in all exposed groups and was highest in the dual-exposure group. Cystatin C levels showed strong positive correlations with renal levels of IL-1, IL-6, and TNF-α. Untargeted metabolomics revealed changes in glycerophospholipid metabolism that were specific to the group exposed to both DEP and oxygen. These results suggest that prenatal DEP exposure may increase renal sensitivity to postnatal oxidative stress, pointing to a time-sensitive window of vulnerability during early kidney development.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"520 ","pages":"Article 154373"},"PeriodicalIF":4.6,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145763870","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}