Toxicology最新文献_第9页

Involvement of ARTS in bisphenol A-induced apoptosis of mouse Leydig cells ARTS参与双酚a诱导的小鼠间质细胞凋亡

IF 4.6 3区医学

Toxicology Pub Date : 2026-01-01 Epub Date: 2025-10-02 DOI: 10.1016/j.tox.2025.154297

Ying Yang , Si Yang , Meijuan Zhang , Linlin Xu , Jiaxiang Chen

{"title":"Involvement of ARTS in bisphenol A-induced apoptosis of mouse Leydig cells","authors":"Ying Yang , Si Yang , Meijuan Zhang , Linlin Xu , Jiaxiang Chen","doi":"10.1016/j.tox.2025.154297","DOIUrl":"10.1016/j.tox.2025.154297","url":null,"abstract":"<div><div>As a widely used organic chemical raw material in the world, bisphenol A (BPA) can induce apoptosis in mouse Leydig cells, yet the underlying mechanism remains insufficiently elucidated. Herein, we confirmed that BPA could induce apoptosis of TM3 cells, accompanied with the upregulation of apoptosis-related protein in the TGF-β signaling pathway (ARTS). Overexpression of ARTS promoted apoptosis of TM3 cells, while ARTS depletion attenuated BPA-induced apoptosis of the cells, indicating that ARTS plays a key role in BPA-induced apoptosis of mouse Leydig cells. Subsequently, BPA was found to increase the expression of transcription factor p53 in the cells. Interestingly, overexpression of p53 enhanced the expression of ARTS and induced apoptosis of TM3 cells, while knockdown of p53 by siRNA attenuated the upregulation of ARTS and the induction of apoptosis caused by BPA, implying that BPA induces apoptosis of mouse Leydig cells through p53/ARTS signals. In addition, we also found that oxidative stress was involved in BPA-induced apoptosis of TM3 cells through p53/ARTS signals. Taken together, these findings suggest that BPA-triggered oxidative stress activates p53/ARTS signaling pathway, thereby inducing apoptosis of mouse Leydig cells.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"519 ","pages":"Article 154297"},"PeriodicalIF":4.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145227807","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}

引用次数: 0

Oil mists and vapours: A review of exposure and toxicity, with dose descriptors from inhalation studies 油雾和蒸汽：接触和毒性的综述，以及吸入研究的剂量描述符。

IF 4.6 3区医学

Toxicology Pub Date : 2026-01-01 Epub Date: 2025-10-16 DOI: 10.1016/j.tox.2025.154314

Niels Hadrup , Jorid B. Sørli , Marie Frederiksen , Anoop K. Sharma , Sabine Kafert-Kasting , Sven Schuchardt , Annette Bitsch , Per A. Clausen , Anne Thoustrup Saber , Ulla Vogel , Karin S. Hougaard

{"title":"Oil mists and vapours: A review of exposure and toxicity, with dose descriptors from inhalation studies","authors":"Niels Hadrup , Jorid B. Sørli , Marie Frederiksen , Anoop K. Sharma , Sabine Kafert-Kasting , Sven Schuchardt , Annette Bitsch , Per A. Clausen , Anne Thoustrup Saber , Ulla Vogel , Karin S. Hougaard","doi":"10.1016/j.tox.2025.154314","DOIUrl":"10.1016/j.tox.2025.154314","url":null,"abstract":"<div><div>Inhalation of oil mists and vapours may induce adverse effects. Here we review the literature on human exposure to oil mists and vapours and their toxicity following inhalation exposure. We collected data on inhalation of all types of oils, on all toxicity endpoints other than genotoxicity and cancer. Toxicological dose descriptors (no-observed-adverse-effect concentrations (NOAECs) and lowest-observed-adverse-effect concentrations (LOAECs)) were collected to identify exposure levels at which toxicity occurs. Occupational mean exposure concentrations typically range from 0.2 to 5 mg/m<sup>3</sup> for mist and up to 36 mg/m<sup>3</sup> for vapours during oil drilling. Affected toxicological endpoints in humans of exposure to refined oil include lung function, lung pathology (including fibrosis), asthma and irritation of nose and throat. Sudden death has been reported after acute exposure to hydrocarbon gas and vapour (e.g. during oil tank hatch operation, potentially involving oxygen deficiency). In animals, endpoints affected include lung function, lung pathology, increases in pulmonary immune cells, decreased body weight and in one study on monkeys also lethality. Dose descriptors in human studies with exposure to mineral oil mists included LOAECs as low as 0.3, 0.4. 0.5, 0.7 and 2.2 mg/m<sup>3</sup> concerning lung function/respiratory symptoms. In general, higher dose descriptors were observed in animal studies, e.g. LOAECs for lung pathology of 50 mg/m<sup>3</sup> in rats and 63 mg/m<sup>3</sup> in monkeys. In conclusion, toxicological effects were observed in humans at occupationally relevant exposure levels. The collected data inform hazard assessment of airborne oil at the workplace and in society.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"519 ","pages":"Article 154314"},"PeriodicalIF":4.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318652","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}

引用次数: 0

Toxic effects of gadolinium on spermatogenesis are associated with inflammation, oxidative stress, apoptosis and autophagy 钆对精子发生的毒性作用与炎症、氧化应激、细胞凋亡和自噬有关。

IF 4.6 3区医学

Toxicology Pub Date : 2026-01-01 Epub Date: 2025-11-09 DOI: 10.1016/j.tox.2025.154335

Sara Falvo , Giulia Grillo , Massimo Venditti , Gabriella Chieffi Baccari , Maria Maddalena Di Fiore , Tiziana Cappello , Maria Maisano , Giuseppe Petito , Rosalba Senese , Concetta De Stefano , Giuseppe Zaffino , Alessandra Santillo

{"title":"Toxic effects of gadolinium on spermatogenesis are associated with inflammation, oxidative stress, apoptosis and autophagy","authors":"Sara Falvo , Giulia Grillo , Massimo Venditti , Gabriella Chieffi Baccari , Maria Maddalena Di Fiore , Tiziana Cappello , Maria Maisano , Giuseppe Petito , Rosalba Senese , Concetta De Stefano , Giuseppe Zaffino , Alessandra Santillo","doi":"10.1016/j.tox.2025.154335","DOIUrl":"10.1016/j.tox.2025.154335","url":null,"abstract":"<div><div>The widespread use of gadolinium (Gd) in industrial and medical applications has raised concerns about its environmental persistence, particularly in water and soil. Once ingested, Gd may exert toxic effects on various organs, but its impact on male reproductive health remains largely unexplored. This study investigated the effects of orally administered GdCl₃ or Gd₂O₃ on spermatogenesis and sperm quality in adult rats. To this purpose, male rats were allowed to drink GdCl<sub>3</sub> or Gd<sub>2</sub>O<sub>3</sub> (10–20–40 mg/Kg bw) for 4 weeks. Gd exposure triggered a strong inflammatory response, evidenced by NF-κB activation and increased TNFα and IL-6 levels in serum and testis. This was accompanied by oxidative stress, as indicated by elevated TBARS levels, as well as apoptosis and autophagy processes activation. Notably, Gd-treated animals exhibited a downregulation of spermatogenesis-related proteins (PCNA, p-H3, SYCP3, PRM2). Histological analysis revealed morphological and morphometric alterations in the seminiferous tubules, along with compromised sperm quality. To explore the cellular mechanisms, <em>in vitro</em> experiments were carried out using mouse GC-1 spermatogonial cells treated with GdCl₃ or Gd₂O₃ for 24 h. Gd exposure resulted in cytotoxicity and reduced cell proliferation, with decreased levels of p-ERK1/2 and PCNA. Gd exposure also disrupted oxidative homeostasis and induced autophagy and apoptosis, likely through the inhibition of the AKT signaling pathway. This study provides the first evidence that oral Gd exposure adversely affects spermatogenesis through inflammation, oxidative stress, and impairment of key cellular pathways, highlighting Gd as a potential environmental threat to male reproductive health.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"519 ","pages":"Article 154335"},"PeriodicalIF":4.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145496798","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}

引用次数: 0

Induction of human cytochrome P450 enzyme activities by metabolism disrupting chemicals in the hepatic cell line HepaRG 代谢干扰物对人肝细胞系HepaRG细胞色素P450酶活性的诱导作用。

IF 4.6 3区医学

Toxicology Pub Date : 2026-01-01 Epub Date: 2025-10-09 DOI: 10.1016/j.tox.2025.154300

Elodie Person , Nicolas J. Cabaton , Laurie Urien , Marlène Z. Lacroix , Jorke H. Kamstra , Louisa Mediouni , Barbara Kubickova , Agnès Jamin , Sylvie Chevolleau , Sebastian Hoffmann , Juliette Legler , Miriam N. Jacobs , Daniel Zalko

{"title":"Induction of human cytochrome P450 enzyme activities by metabolism disrupting chemicals in the hepatic cell line HepaRG","authors":"Elodie Person , Nicolas J. Cabaton , Laurie Urien , Marlène Z. Lacroix , Jorke H. Kamstra , Louisa Mediouni , Barbara Kubickova , Agnès Jamin , Sylvie Chevolleau , Sebastian Hoffmann , Juliette Legler , Miriam N. Jacobs , Daniel Zalko","doi":"10.1016/j.tox.2025.154300","DOIUrl":"10.1016/j.tox.2025.154300","url":null,"abstract":"<div><div>Metabolism disrupting chemicals (MDCs) are a class of endocrine disrupting substances that promote metabolic changes leading to metabolic disorders in humans. Central to assessing their adverse effects is the need to better understand their modes of action (MoA). Cytochrome P450 (CYP) enzymes play a major role in xenobiotic metabolism, but also catalyse many endogenous metabolic reactions. Therefore, modulation of CYP functionality may impact homeostasis, contributing to adverse outcomes. At the functional level, alteration of the activity of human CYPs by MDCs largely remains unexplored. In this study we investigated the capability of six candidate MDCs, bisphenol A (BPA), perfluorooctanoic acid (PFOA), tributyltin (TBT), dichlorodiphenyldichloroethylene (p,p’-DDE), triclosan (TCS) and triphenylphosphate (TPP) to induce CYP1A2, CYP2B6 and CYP3A4 activities in the human hepatic HepaRG cell line. The CYP induction test method previously validated for pharmaceuticals was optimised and selected MDCs were tested in the context of the European Horizon 2020 GOLIATH project. Induction was revealed using a cocktail of CYP-selective probe substrates, followed by probe metabolite quantification by mass spectrometry. All MDCs except TCS induced CYP activities. PFOA, TBT, p,p’-DDE and TPP induced CYP1A2, TPP being the most potent inducer. BPA, PFOA, TBT and TPP induced CYP2B6, PFOA being the most potent inducer. BPA, PFOA, TBT, p,p’-DDE and TPP all induced CYP3A4, p,p’-DDE and BPA being the most potent inducers. These results highlight the capability of candidate MDCs to induce key CYP activities in a human relevant hepatic model, paving the way for a better understanding of MDCs mechanisms of action.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"519 ","pages":"Article 154300"},"PeriodicalIF":4.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145259224","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}

引用次数: 0

Deleterious effects of plastic component bisphenol a on mitochondrial function in human intestinal cells 塑料成分双酚A对人肠细胞线粒体功能的有害影响。

IF 4.6 3区医学

Toxicology Pub Date : 2026-01-01 Epub Date: 2025-10-15 DOI: 10.1016/j.tox.2025.154313

Giovanni Perra , Andrea Caddeo , Francesca Sedda , Giacomo Cao , Raffaella Isola , Alessandro Concas , Andrea Perra , Nicola Lai

{"title":"Deleterious effects of plastic component bisphenol a on mitochondrial function in human intestinal cells","authors":"Giovanni Perra , Andrea Caddeo , Francesca Sedda , Giacomo Cao , Raffaella Isola , Alessandro Concas , Andrea Perra , Nicola Lai","doi":"10.1016/j.tox.2025.154313","DOIUrl":"10.1016/j.tox.2025.154313","url":null,"abstract":"<div><div>Plastic compounds released into the environment can be accumulated in human tissues causing various health issues. It has been demonstrated that Bisphenol A (BPA), widely used in polycarbonate plastics and food packaging, can accumulate in gastrointestinal (GI) tract, inducing oxidative stress, metabolic dysfunction, and other cellular disturbances, including mitochondrial damage. However, the mechanisms by which BPA affects the GI function and affects mitochondrial function in the absorptive cells of the intestine, are still not completely understood. The aim of this study is to investigate whether BPA enters intact human intestinal cells and affects mitochondrial electron transport chain (ETC) function. High-resolution respirometry (O2k system, OROBOROS) and fluorometry were used to assess mitochondrial respiration and membrane potential (mt-MP) in Caco-2 cells under acute exposure to BPA. Cellular respiration was stimulated with complex I (C-I), II (C-II), IV (C-IV) and β-oxidation substrates in both intact and permeabilized Caco-2 cells. Morphological analysis of cells exposed to BPA was performed by electron microscopy. In intact cells, respiration rate decreased in presence of BPA, thus confirming the detrimental effects of BPA on ETC. In permeabilized cells, BPA caused a decrease of respiratory activity in presence of C-I and C-II substrates following a reduction of the ETC oxidative capacity and a depolarization of mt-MP. Morphological analysis suggested that BPA can be internalized by endocytosis. The reduced respiration rate in both intact and permeabilized cells indicates that BPA reaches mitochondria even without membrane permeabilization. BPA compromises both oxidative phosphorylation (OxPhos) and mt-MP, thus leading to an impairment of energy metabolism that could contribute to pathological alterations of the gastrointestinal function.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"519 ","pages":"Article 154313"},"PeriodicalIF":4.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145313804","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}

引用次数: 0

Mechanistic toxicity profiling of chemicals: A comparative study in 2D and 3D HepaRG models using high-content analysis 化学物质的机械毒性分析：使用高含量分析在2D和3D HepaRG模型中的比较研究。

IF 4.6 3区医学

Toxicology Pub Date : 2026-01-01 Epub Date: 2025-09-16 DOI: 10.1016/j.tox.2025.154280

Mariam Saleh, Kevin Hogeveen, Valérie Fessard, Ludovic Le Hégarat

{"title":"Mechanistic toxicity profiling of chemicals: A comparative study in 2D and 3D HepaRG models using high-content analysis","authors":"Mariam Saleh, Kevin Hogeveen, Valérie Fessard, Ludovic Le Hégarat","doi":"10.1016/j.tox.2025.154280","DOIUrl":"10.1016/j.tox.2025.154280","url":null,"abstract":"<div><div>Humans and the environment are exposed to a diverse range of chemicals, many of which are introduced through the human activities. This growing chemical burden has given rise to concerns related to their potential adverse effects. Traditionally, chemical toxicity evaluation has relied on animal tests that are time consuming, expensive, pose ethical concerns, and may not be directly extrapolated to humans. This highlights the urgent need to develop New Approach Methodologies (NAMs) to evaluate chemical- associated toxicity. Since the liver is a primary target organ for xenobiotics, our objective is to use both 2D and 3D HepaRG models combined with High-Content Analysis (HCA) for chemical mechanistic toxicity profiling. HepaRG models were exposed to eight chemicals (Chlorothalonil, Tebuconazole, Thioacetamide, Benzoyl peroxide, Diethyl maleate, clofibrate, indeno[1,2,3-cd]pyrene, 3-methylcholanthrene) for 72 h with daily media renewal. Cellular endpoints including cytotoxicity, oxidative stress, mitochondrial dysfunction, lipid accumulation and the pro-inflammatory response were quantified. Additionally, four chemicals were added in this study to test chemicals having different MOA and to demonstrate the sensitivity of the 3D HepaRG spheroid model (FICZ, Diuron, 12-O-Tetradecanoylphorbol-13-acetate, Azoxystrobin). Our findings revealed that 3D HepaRG cells exhibited more pronounced positive responses to chemical treatment compared to the 2D HepaRG cells. In addition to the chemical-specific toxicity profiling generated by HCA, we identified correlations between different cellular alterations such as mitochondrial dysfunction, dysregulated lipid metabolism and oxidative stress in the treated 3D HepaRG spheroids. Overall, this approach proposed in this study provides a rapid, human-relevant in vitro method that enhances the predictive power of NAMs for chemical associated toxicity.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"519 ","pages":"Article 154280"},"PeriodicalIF":4.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145087359","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}

引用次数: 0

Integrated assessment of bisphenols, phthalates, and biocides for estrogenic and androgenic endocrine-disrupting properties 双酚类、邻苯二甲酸盐和杀生剂对雌激素和雄激素内分泌干扰特性的综合评估。

IF 4.6 3区医学

Toxicology Pub Date : 2026-01-01 Epub Date: 2025-10-09 DOI: 10.1016/j.tox.2025.154301

Seok-Hee Lee , Yooheon Park

{"title":"Integrated assessment of bisphenols, phthalates, and biocides for estrogenic and androgenic endocrine-disrupting properties","authors":"Seok-Hee Lee , Yooheon Park","doi":"10.1016/j.tox.2025.154301","DOIUrl":"10.1016/j.tox.2025.154301","url":null,"abstract":"<div><div>The integrated assessment of estrogenic and androgenic endocrine disruption using a combination of receptor dimerization and transactivation assays is an effective approach for providing information the mechanistic action of chemical compounds that disrupt estrogen and androgen signaling pathways at the cellular level. This study integratedly evaluated the estrogenic and androgenic endocrine-disrupting properties of a total of 29 chemicals, including representative bisphenols, phthalates, and biocides, which are commonly exposed to humans. As a result, most bisphenols showed estrogenic agonist activity through transactivation via dimerization of estrogen receptors alpha and beta, while also exhibiting androgenic antagonist activity by inhibiting dihydrotestosterone-induced transactivation through interference with androgen receptor dimerization. Most phthalates also exhibited estrogenic agonist activity through transactivation via dimerization of estrogen receptors alpha and beta, and only some of them showed androgenic antagonist activity by interfering with androgen receptor dimerization and inhibiting dihydrotestosterone-induced transactivation. Biocides showed estrogenic and androgenic endocrine-disrupting properties through various mechanisms depending on their structural diversity. This integrated assessment effectively provided clues to the mechanism of action of endocrine-disrupting chemicals in estrogen and androgen signaling pathways at the cellular level, based on the adverse outcome pathway framework.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"519 ","pages":"Article 154301"},"PeriodicalIF":4.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275987","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}

引用次数: 0

Premature aging and neuropathic behaviours induced by an acute low-dose exposure to a sarin surrogate 急性低剂量暴露于沙林替代物诱导的过早衰老和神经病变行为。

IF 4.6 3区医学

Toxicology Pub Date : 2026-01-01 Epub Date: 2025-10-29 DOI: 10.1016/j.tox.2025.154327

Alexandre Champault , Sarah Leterrier , Rosalie Bel , Julie Knoertzer , Amélie Soyer , Sébastien Goutal , Rachid Baati , Sabine Francois , Nicolas Tournier , Gregory Dal Bo , Karine Thibault

{"title":"Premature aging and neuropathic behaviours induced by an acute low-dose exposure to a sarin surrogate","authors":"Alexandre Champault , Sarah Leterrier , Rosalie Bel , Julie Knoertzer , Amélie Soyer , Sébastien Goutal , Rachid Baati , Sabine Francois , Nicolas Tournier , Gregory Dal Bo , Karine Thibault","doi":"10.1016/j.tox.2025.154327","DOIUrl":"10.1016/j.tox.2025.154327","url":null,"abstract":"<div><div>Acute poisoning from organophosphorus (OP) compounds induced a cholinergic toxidrome. Neurological complications may manifest weeks after the initial exposure, including muscle weakness and progressive loss of sensitivity. These symptoms may be analogous to those observed in elderly individuals. However, the delayed neurological impact of OP exposure has received limited attention and remains an under-explored area of research. The present study investigated the long-term effects of OP exposure on the sensorimotor system using a mouse model exposed to a sublethal dose of a sarin surrogate. The mice received a 0.5 LD50 dose of 4-nitrophenyl isopropylmethylphosphonate (NIMP), and were observed for a period of six months. Our results demonstrate that NIMP exposure induced a mild intoxication severity in mice, without affecting weight evolution. Behavioral evaluation, using locomotor and sensory tests, revealed that mice exhibited persistent muscle weakness and an increase in mechanical sensitivity. Six months after NIMP exposure, acetylcholinesterase activity remained inhibited in specific regions of the cerebral cortex, while the spinal cord exhibited a return to normal values. Positron emission tomography scans and microcomputed tomography imaging revealed alterations in cerebral glucose metabolism and bone density. Luminex multiplex immunoassay analyses revealed an increase in specific biomarkers of aging. The present study demonstrates that a sublethal dose of NIMP triggered premature aging phenotype, resulting in long-term sensorimotor impairments, neurometabolic and cellular disturbances. These findings underscore the importance of identifying intoxication hallmarks, even in cases of asymptomatic OP exposure.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"519 ","pages":"Article 154327"},"PeriodicalIF":4.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145422905","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}

引用次数: 0

Deciphering the quantitative relationship between NRF2 and SRXN1 through semi-mechanistic computational modeling 通过半机械计算模型解读NRF2与SRXN1之间的定量关系。

IF 4.6 3区医学

Toxicology Pub Date : 2026-01-01 Epub Date: 2025-09-17 DOI: 10.1016/j.tox.2025.154284

Raju Prasad Sharma , Liesanne Loonstra-Wolters , Bas ter Braak , Marije Niemeijer , Andrew White , Bob van de Water , Alistair M. Middleton , Joost B. Beltman

{"title":"Deciphering the quantitative relationship between NRF2 and SRXN1 through semi-mechanistic computational modeling","authors":"Raju Prasad Sharma , Liesanne Loonstra-Wolters , Bas ter Braak , Marije Niemeijer , Andrew White , Bob van de Water , Alistair M. Middleton , Joost B. Beltman","doi":"10.1016/j.tox.2025.154284","DOIUrl":"10.1016/j.tox.2025.154284","url":null,"abstract":"<div><div>Nuclear factor erythroid 2-related factor 2 (NRF2) plays a vital role in the regulation of various antioxidant response element (ARE) genes, which control physiological processes such as oxidative stress, autophagy, proliferation and apoptosis to maintain cellular homeostasis. It is not understood in detail how the NRF2 program acquires its flexibility with respect to regulation of its downstream targets. Various NRF2 binding partners and cofactors specific to ARE genes are involved in this regulation, and are potentially condition-specific (e.g., type of stressor) and dependent on non-canonical signaling pathways (i.e., crosstalk). Here, we explored the quantitative relationship between NRF2 and sulfiredoxin 1 (SRXN1), a bona fide key NRF2 target gene. We developed a semi-mechanistic mathematical model based on time course experimental data of NRF2 and SRXN1 protein expression in HepG2 cells following single or repeated exposure to NRF2 activating soft electrophiles (sulforaphane, andrographolide, ethacrynic acid or CDDO-me) at a wide concentration range. We showed that a nonlinear mixed effect modeling approach with partially hierarchical parameters accurately captures the observed experimental dynamics. Our analysis highlights that NRF2 requires a cofactor or post-translational modification to regulate its activity as a transcription factor. Moreover, this modulation of the transcription factor activity of NRF2 is time-, compound- and exposure scenario specific. We conclude that a complete understanding of NRF2-mediated ARE genes activation requires detailed dynamic information on NRF2 binding partners and cofactors.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"519 ","pages":"Article 154284"},"PeriodicalIF":4.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092409","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}

引用次数: 0

A next generation physiologically-based kinetic model for quantitative in vitro to in vivo extrapolation of cisplatin-induced nephrotoxicity in humans 新一代基于生理的动力学模型，用于体外到体内定量推断顺铂诱导的人类肾毒性

IF 4.6 3区医学

Toxicology Pub Date : 2026-01-01 Epub Date: 2025-10-24 DOI: 10.1016/j.tox.2025.154320

Kiri G.J. Romano Olmedo, Jiaqi Chen, Ivonne M.C.M. Rietjens, Nynke I. Kramer

{"title":"A next generation physiologically-based kinetic model for quantitative in vitro to in vivo extrapolation of cisplatin-induced nephrotoxicity in humans","authors":"Kiri G.J. Romano Olmedo, Jiaqi Chen, Ivonne M.C.M. Rietjens, Nynke I. Kramer","doi":"10.1016/j.tox.2025.154320","DOIUrl":"10.1016/j.tox.2025.154320","url":null,"abstract":"<div><div>Animal-based toxicity tests inadequately predict human nephrotoxicity, hence the call for human-based new approach methodologies. Nephrotoxic chemicals often accumulate in the proximal tubule as transporters on the polarized membrane of these cells can actively take-up chemicals. The aim of the present study was to develop next generation human physiologically-based kinetic (PBK) models to simulate plasma and kidney concentrations and predict the nephrotoxicity of <em>i.v.-</em>administered cisplatin as the model compound. The PBK models were used to predict nephrotoxic doses of this chemotherapeutic by quantitative <em>in vitro</em> to <em>in vivo</em> extrapolation (QIVIVE) of literature available concentration-response relationships of cytotoxicity in renal cell lines. Two forms of the PBK model were developed: one with a simple single kidney compartment and another including a multi-compartmental kidney that includes organic cation transporter 2 (OCT2)-mediated active renal secretion. Observed single dose of 50 mg/m<sup>2</sup> lead to nephrotoxicity in 30 % of patients. Using only <em>in vitro</em> and <em>in</em> silico-derived pharmacokinetic parameters, human benchmark dose levels (BMDL)<sub>30</sub> values were calculated for all QIVIVE obtained dose-response curves using the maximum concentration in kidney blood or proximal tubule and the area under the concentration-time curve (AUC) in the proximal tubule. Based on the AUC in proximal tubule, the complex form of the model predicts nephrotoxicity in 30 % of patients best, between 23.1 and 65 mg/m<sup>2</sup>. This study provides a case study for next generation risk assessment using PBK models that incorporate active renal secretion to better predict plasma concentration-time profiles are well as <em>in vivo</em> nephrotoxic dose levels.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"519 ","pages":"Article 154320"},"PeriodicalIF":4.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145424670","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}

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