Food and Chemical Toxicology最新文献_第7页

Cadmium-induced activation of inflammatory cancer-associated fibroblasts-like cells enhances malignant phenotypes of lung cancer cells 镉诱导的炎性癌相关成纤维细胞样细胞的激活增强了肺癌细胞的恶性表型。

IF 3.5 3区医学 Q2 FOOD SCIENCE & TECHNOLOGY

Food and Chemical Toxicology

Pub Date : 2026-01-08 DOI: 10.1016/j.fct.2026.115927

Qi Jiang , Lujiao Wang , Biyun Chen, Tianyi Dong, Wanyou Shen, Xue Zhou

Cancer-associated fibroblasts (CAFs), as key stromal components of the tumor microenvironment (TME), exert profound influences on tumor progression by secreting cytokines, exosomes, and remodeling the extracellular matrix (ECM). Cadmium (Cd), a hazardous heavy metal, is strongly associated with lung carcinogenesis through environmental and occupational exposure. However, the molecular mechanisms underlying Cd-induced activation of fibroblasts and their functional contributions to lung cancer development remain poorly understood. Our study demonstrated that acute Cd exposure promoted the transformation of normal fibroblasts (MRC-5 cells) into an inflammatory CAFs-like (iCAFs) phenotype through upregulation of fibroblast activation protein (FAP). This Cd-driven FAP overexpression was accompanied by upregulated IL-6 and CCL2 release. Functionally, Cd-activated iCAFs-like cells significantly promoted the proliferation, migration, and invasion of lung cancer cell lines (H460 and A549) via paracrine signaling. Notably, FAP knockdown in MRC-5 cells using siRNA abrogated Cd-induced secretion of inflammatory factors and reversed the tumor-promoting effects of Cd-activated fibroblasts on cancer cells, establishing FAP as a central mediator of Cd-driven stromal reprogramming. These findings uncover a novel mechanism by which environmental Cd exposure exacerbates lung cancer progression through FAP-dependent fibroblast activation. Furthermore, they identify FAP as a potential therapeutic target for mitigating Cd-induced carcinogenesis, with implications for environmental toxin-associated cancer prevention and treatment.

癌症相关成纤维细胞（CAFs）作为肿瘤微环境（TME）的关键基质成分，通过分泌细胞因子、外泌体和重塑细胞外基质（ECM），对肿瘤进展产生深远影响。镉（Cd）是一种有害重金属，通过环境和职业暴露与肺癌发生密切相关。然而，cd诱导成纤维细胞活化的分子机制及其对肺癌发展的功能贡献仍然知之甚少。我们的研究表明，急性Cd暴露通过上调成纤维细胞激活蛋白（FAP），促进正常成纤维细胞（MRC-5细胞）向炎性cafs样（iCAFs）表型的转化。这种cd驱动的FAP过表达伴随着IL-6和CCL2释放的上调。在功能上，cd激活的icafs样细胞通过旁分泌信号显著促进肺癌细胞系（H460和A549）的增殖、迁移和侵袭。值得注意的是，在MRC-5细胞中，使用siRNA敲除FAP可以消除cd诱导的炎症因子分泌，逆转cd激活的成纤维细胞对癌细胞的促瘤作用，从而确立FAP作为cd驱动的基质重编程的中心介质。这些发现揭示了环境镉暴露通过fap依赖性成纤维细胞激活加剧肺癌进展的新机制。此外，他们确定FAP是减轻cd诱导的致癌作用的潜在治疗靶点，对环境毒素相关的癌症预防和治疗具有重要意义。

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引用次数: 0

Metabolic profiling of the maternal liver in pregnant mice exposed to Di(2-ethylhexyl) phthalate (DEHP) 暴露于邻苯二甲酸二（2-乙基己基）酯（DEHP）的妊娠小鼠母体肝脏代谢谱

IF 3.5 3区医学 Q2 FOOD SCIENCE & TECHNOLOGY

Food and Chemical Toxicology

Pub Date : 2026-01-07 DOI: 10.1016/j.fct.2026.115928

Tomomi Asano , Yuto Ohtani , Shinnosuke Sugiura , Masaru Taniguchi , Kei Zaitsu

In this study, pregnant mice were exposed to dietary Di(2-ethylhexyl) phthalate (DEHP) (0.1 % or 0.2 %) from gestational day (GD) 0 to GD18, and maternal liver metabolomes were profiled by GC–MS/MS-based metabolomics followed by bioinformatics analysis using our PiTMaP platform. Multivariate analysis revealed clear separation between the control and DEHP groups, indicating substantial metabolic alterations in maternal liver. Among the metabolites contributing to group separation, 20 compounds, including malic acid, tryptophan, niacinamide, cysteine, and hypotaurine, showed significant differences (FDR <0.05), suggesting mitochondrial dysfunction and alterations in the tryptophan–niacinamide and hypotaurine metabolic pathways. In addition, a machine learning–based Random Forest classifier demonstrated that these significantly altered metabolites could accurately discriminate among the three groups. Further network analysis identified hypotaurine as the top network hub in the liver. These results demonstrate tissue-specific rewiring of metabolic networks under DEHP exposure, with mitochondrial and tryptophan–niacinamide pathways being prominently affected in the liver. Overall, this study provides novel mechanistic insights into maternal metabolic disturbances induced by DEHP exposure during pregnancy and contributes to the identification of organ-specific biomarkers relevant to such exposure.

在本研究中，怀孕小鼠从妊娠日（GD） 0至GD18暴露于饮食中二（2-乙基己基）邻苯二甲酸二酯（DEHP）（0.1%或0.2%），并通过GC-MS/MS-based代谢组学分析母体肝脏代谢组学，然后使用我们的PiTMaP平台进行生物信息学分析。多变量分析显示对照组和DEHP组之间存在明显的差异，表明母体肝脏发生了实质性的代谢改变。在导致组分离的代谢物中，苹果酸、色氨酸、烟酰胺、半胱氨酸和次牛磺酸等20个化合物差异显著（FDR < 0.05），提示线粒体功能障碍，色氨酸-烟酰胺和次牛磺酸代谢途径发生改变。此外，基于机器学习的随机森林分类器表明，这些显著改变的代谢物可以准确地区分三组。进一步的网络分析确定了次牛磺酸是肝脏中的顶级网络枢纽。这些结果表明，在DEHP暴露下，代谢网络的组织特异性重新布线，肝脏中的线粒体和色氨酸-烟酰胺途径受到显著影响。总的来说，本研究为妊娠期间暴露于DEHP引起的母体代谢紊乱提供了新的机制见解，并有助于鉴定与此类暴露相关的器官特异性生物标志物。

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引用次数: 0

Polystyrene nanoplastics disrupted cholesterol/testosterone homeostasis via Smurf1-dependent FTO degradation 聚苯乙烯纳米塑料通过smurf1依赖的FTO降解破坏胆固醇/睾酮稳态。

IF 3.5 3区医学 Q2 FOOD SCIENCE & TECHNOLOGY

Food and Chemical Toxicology

Pub Date : 2026-01-02 DOI: 10.1016/j.fct.2025.115926

Jianhui Liu , Shaofei Su , Ruixia Liu , Shuanghua Xie , Chenghong Yin , Enjie Zhang , Lihua Ren

Polystyrene nanoplastics (PS-NPs) exposure can induce testosterone decline, but the underlying mechanism remains elusive. In the present study, prepubertal PS-NPs exposure caused testicular injury and reduced testosterone levels. RNA sequence analysis indicated that cholesterol homeostasis and PPARα signaling pathways may be involved in the disruption of testosterone biosynthesis. Compared with the control group, exposure to PS-NPs resulted in no significant change in serum cholesterol levels but a marked reduction in testicular and TM3 cell cholesterol levels. Western blot analysis revealed prepubertal PS-NPs exposure activated the PPARα pathway, with a consequent significant downregulation in the expression of cholesterol uptake receptors SCARB1 and LDLR. Using immunoprecipitation, we found that PS-NPs disrupted cholesterol uptake by facilitating the ubiquitin-dependent degradation of FTO. Ultimately, we observed that PS-NPs exposure markedly upregulated Smurf1 protein expression. Knocking down Smurf1 repressed PS-NPs caused the ubiquitin-dependent degradation of FTO protein, thereby alleviating cholesterol and testosterone decline. Overall, our study elucidated a novel mechanism by which prepubertal PS-NPs exposure disrupted cholesterol/testosterone homeostasis via Smurf1-dependent FTO degradation.

聚苯乙烯纳米塑料（PS-NPs）暴露可导致睾丸激素下降，但其潜在机制尚不清楚。在本研究中，青春期前PS-NPs暴露导致睾丸损伤和睾丸激素水平降低。RNA序列分析表明胆固醇稳态和PPARα信号通路可能参与睾酮生物合成的破坏。与对照组相比，暴露于PS-NPs导致血清胆固醇水平无显著变化，但睾丸和TM3细胞胆固醇水平显著降低。Western blot分析显示，青春期前暴露于PS-NPs激活了PPARα途径，导致胆固醇摄取受体SCARB1和LDLR的表达显著下调。通过免疫沉淀，我们发现PS-NPs通过促进FTO的泛素依赖性降解来破坏胆固醇的摄取。最终，我们观察到PS-NPs暴露显著上调Smurf1蛋白表达。敲除Smurf1抑制的PS-NPs导致FTO蛋白的泛素依赖性降解，从而缓解胆固醇和睾酮的下降。总的来说，我们的研究阐明了青春期前暴露于PS-NPs通过smurf1依赖的FTO降解破坏胆固醇/睾酮稳态的新机制。

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引用次数: 0

Corrigendum to “Ameliorative effects of rutin and rutin-loaded chitosan nanoparticles on testicular oxidative stress and histological damage induced by cyclophosphamide in male rats” [Food and Chemical Toxicology 184 (2024) 114436] “芦丁和负载芦丁的壳聚糖纳米颗粒对雄性大鼠睾丸氧化应激和环磷酰胺诱导的组织学损伤的改善作用”[食品和化学毒理学184(2024)114436]的更正。

IF 3.5 3区医学 Q2 FOOD SCIENCE & TECHNOLOGY

Food and Chemical Toxicology

Pub Date : 2025-12-31 DOI: 10.1016/j.fct.2025.115923

Dina A. AbdElrazek , Neven H. Hassan , Marwa A. Ibrahim , Eman I. Hassanen , Khaled Y. Farroh , H.I. Abass

引用次数: 0

The cytotoxic effects of a single and combined exposure to the mycotoxins, deoxynivalenol and zearalenone, on a rat Leydig cell line (LC-540) 脱氧雪腐菌烯醇和玉米赤霉烯酮单一和联合暴露对大鼠间质细胞系（LC-540）的细胞毒性作用

IF 3.5 3区医学 Q2 FOOD SCIENCE & TECHNOLOGY

Food and Chemical Toxicology

Pub Date : 2025-12-30 DOI: 10.1016/j.fct.2025.115924

Mohammed I.A. Ibrahim , Antoinette V. Lensink , Christo J. Botha

Deoxynivalenol (DON) and zearalenone (ZEA) are among the most prevalent mycotoxins synthesized by Fusarium species, with 60 % and 80 % prevalence in grains containing mycotoxins, respectively. These mycotoxins often co-contaminate feedstuffs and induce male reproductive toxicity. This study investigated in vitro cytotoxicity, the structure of selected cytoskeletal proteins, mitochondrial morphology, lysosomal activity, and ultrastructural changes associated with individual and combined DON and ZEA exposure in rat Leydig cells (LC-540). Deoxynivalenol (IC₅₀: 2.66, 0.50, and 0.44 μM) induced higher cytotoxicity than ZEA (IC₅₀: 117.0, 69.1, and 34.4 μM) after 24, 48, and 72 h, respectively. Combined DON + ZEA exposure revealed concentration- and time-dependent cytotoxic effects that were synergistic at low concentrations (0.125 + 10 μM), but additive or antagonistic at higher concentrations (2 + 30 and 5 + 50 μM). Microscopic analysis revealed both mycotoxins disrupted F-actin and β-tubulin, impaired mitochondrial morphology, and increased lysosomal acidification. Ultrastructurally, marked cellular alterations included mitochondrial damage, autophagosome formation, and apoptosis. The observed cytotoxicity, disruption of cytoskeletal proteins, and mitochondrial damage in the Leydig cells may play a role in clarifying the male reproductive toxicity induced by DON and ZEA or their co-exposure.

脱氧雪腐镰刀菌醇（DON）和玉米赤霉烯酮（ZEA）是镰刀菌合成的最常见的真菌毒素，在含有真菌毒素的谷物中分别占60%和80%。这些真菌毒素通常会污染饲料并引起雄性生殖毒性。本研究对大鼠间质细胞（LC-540）的体外细胞毒性、选定的细胞骨架蛋白结构、线粒体形态、溶酶体活性以及与DON和ZEA单独或联合暴露相关的超微结构变化进行了研究。脱氧雪腐镰刀菌醇（IC50分别为2.66、0.50和0.44 μM）作用24、48和72 h后的细胞毒性分别高于ZEA （IC50分别为117.0、69.1和34.4 μM）。在低浓度（0.125 + 10 μM）和高浓度（2 + 30和5 + 50 μM）下，DON + ZEA联合暴露显示出浓度依赖性和时间依赖性的细胞毒性作用。显微镜分析显示，真菌毒素破坏了f -肌动蛋白和β-微管蛋白，损害了线粒体形态，并增加了溶酶体酸化。超微结构上，显著的细胞改变包括线粒体损伤、自噬体形成和细胞凋亡。观察到的细胞毒性、细胞骨架蛋白的破坏和间质细胞的线粒体损伤可能有助于阐明DON和ZEA或它们共同暴露诱导的男性生殖毒性。

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引用次数: 0

Effective in vitro evaluation of biogenic amines in fermented food using mast cells 利用肥大细胞体外有效评价发酵食品中的生物胺。

IF 3.5 3区医学 Q2 FOOD SCIENCE & TECHNOLOGY

Food and Chemical Toxicology

Pub Date : 2025-12-29 DOI: 10.1016/j.fct.2025.115925

Leeseon An , Jung-Eun Kim , Eunseo Park , Hyo-Jeong Lee

Legal limits and toxic thresholds for histamine levels in food have been established by the Codex Alimentarius Commission as well as by national food safety authorities in various countries In this study, we found that mast cell degranulation was increased in a histamine concentration-dependent manner, and this degranulation was found to be associated with MRGPRX2, a receptor involved in non-IgE-mediated allergic reactions, as demonstrated by molecular docking analysis and mRNA expression. A strong positive correlation was observed between MRGPRX2 and mast cell degranulation, indicating that higher MRGPRX2 mRNA levels were associated with increased degranulation activity. We analyzed histamine concentrations, MRGPRX2 mRNA expression, and mast cell degranulation for fermented soy sauce and shrimp sauce (FSS, used as a positive control). DS, FS, and JS demonstrated a histamine concentration below 200 μg/mL and showed no significant effect on mast cell degranulation and MRGPRX2 mRNA levels in HMC-1.2 cells. Especially, FS contained high GABA concentrations. A strong negative correlation and the expression of MRGPRX2 mRNA as well as mast cell degranulation. Finally, this assay, anchored to the histamine limits recommended by the Codex, enables routine screening of biogenic amine-containing foods to verify regulatory compliance and help ensure a safe food supply.

在本研究中，我们发现肥大细胞脱粒以组胺浓度依赖的方式增加，并且通过分子对接分析和mRNA表达发现，这种脱粒与MRGPRX2有关，MRGPRX2是一种参与非ige介导的过敏反应的受体。MRGPRX2与肥大细胞脱颗粒之间存在强正相关，表明MRGPRX2 mRNA水平升高与脱颗粒活性增加相关。我们分析了发酵酱油和虾酱（FSS，作为阳性对照）的组胺浓度、MRGPRX2 mRNA表达和肥大细胞脱颗粒。DS、FS和JS组胺浓度均低于200 μg/mL，对HMC-1.2细胞肥大细胞脱颗粒和MRGPRX2 mRNA水平无显著影响。特别是FS含有较高的GABA浓度。MRGPRX2 mRNA的表达与肥大细胞脱颗粒呈强负相关。最后，该检测方法以食典委推荐的组胺限量为基础，可对含生物胺食品进行常规筛查，以验证是否符合法规，并有助于确保安全的食品供应。

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引用次数: 0

The Expanded Decision Tree: Predicting Chronic Toxic Potential and Safe Intake Levels. 扩展决策树：预测慢性潜在毒性和安全摄入水平。

IF 3.5 3区医学 Q2 FOOD SCIENCE & TECHNOLOGY

Food and Chemical Toxicology

Pub Date : 2025-12-27 DOI: 10.1016/j.fct.2025.115903

Szabina Stice, Timothy Adams

The Expanded Decision Tree (EDT) was developed by the U.S. Food and Drug Administration (FDA) to address the significant limitations of the original Cramer Decision Tree (CDT), a tool historically used for estimating the relative oral toxic potential of chemicals based on their structure. Over the past four decades, scientific understanding of structure-toxicity relationships has advanced significantly, exposing the CDT's limitations in logic, reliance on some ambiguous and non-structure-based questions, and limited ability to classify substances with high specificity. The EDT was designed as a science-forward, structure-based revision of the CDT that leverages contemporary toxicology data, metabolism insights, and mechanistic knowledge to assess a broader array of chemical substances. This article provides a high-level summary of the EDT's development, the construction and use of its underlying database, the logic and structure of its expanded classification framework, the scientific rationale for its updates, and the findings from its extensive external validation and peer review. The EDT represents a robust, transparent, and scientifically defensible tool for regulatory toxicology, especially in the context of threshold of toxicological concern (TTC) screening.

扩展决策树（EDT）是由美国食品和药物管理局（FDA）开发的，以解决原始克莱默决策树（CDT）的重大局限性。克莱默决策树是一种历史上用于根据化学物质的结构估计其相对口服毒性潜力的工具。在过去的四十年里，对结构-毒性关系的科学理解有了显著的进步，暴露了CDT在逻辑上的局限性，依赖于一些模糊和非结构基础的问题，以及对物质进行高特异性分类的能力有限。EDT被设计为CDT的一个科学的、基于结构的修订版，利用当代毒理学数据、代谢见解和机制知识来评估更广泛的化学物质。本文对EDT的开发、其底层数据库的构建和使用、其扩展分类框架的逻辑和结构、其更新的科学原理以及其广泛的外部验证和同行评审的结果进行了高层次的总结。EDT是一种强有力的、透明的、科学上可辩护的监管毒理学工具，特别是在毒理学关注阈值（TTC）筛选的背景下。

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引用次数: 0

RIFM natural complex substance (NCS) fragrance ingredient safety assessment, styrax absolute, CAS registry Number 8024-01-9, RIFM ID 6877.K2.1 天然复合物质（NCS）香料成分安全性评价，styrax绝对，CAS注册号8024-01-9，RIFM ID 6877.K2.1。

IF 3.5 3区医学 Q2 FOOD SCIENCE & TECHNOLOGY

Food and Chemical Toxicology

Pub Date : 2025-12-26 DOI: 10.1016/j.fct.2025.115913

A.M. Api , A. Bartlett , D. Belsito , D. Botelho , M. Bruze , A. Bryant-Friedrich , G.A. Burton Jr. , M.A. Cancellieri , H. Chon , M. Cronin , S. Crotty , M.L. Dagli , W. Dekant , C. Deodhar , K. Farrell , A.D. Fryer , L. Jones , K. Joshi , A. Lapczynski , D.L. Laskin , Y. Thakkar

引用次数: 0

Update to RIFM fragrance ingredient safety assessment, 2-ethyl-5-methoxybicyclo[2.2.1]heptane, CAS registry number 122795-41-9 更新RIFM香料成分安全性评估，2-乙基-5-甲氧基双环[2.2.1]庚烷，CAS注册号122795-41-9。

IF 3.5 3区医学 Q2 FOOD SCIENCE & TECHNOLOGY

Food and Chemical Toxicology

Pub Date : 2025-12-26 DOI: 10.1016/j.fct.2025.115914

A.M. Api , A. Bartlett , D. Belsito , D. Botelho , M. Bruze , A. Bryant-Friedrich , G.A. Burton Jr. , M.A. Cancellieri , H. Chon , M. Cronin , S. Crotty , M.L. Dagli , W. Dekant , C. Deodhar , K. Farrell , A.D. Fryer , L. Jones , K. Joshi , A. Lapczynski , D.L. Laskin , Y. Thakkar

引用次数: 0

RIFM fragrance ingredient safety assessment, α,α-dimethyl-p-ethylphenylpropanal, CAS Registry Number 67634-15-5 RIFM香精成分安全性评价，α，α-二甲基-对乙基苯基丙烷，中国科学院登记号67634-15-5。

IF 3.5 3区医学 Q2 FOOD SCIENCE & TECHNOLOGY

Food and Chemical Toxicology

Pub Date : 2025-12-25 DOI: 10.1016/j.fct.2025.115916

A.M. Api , A. Bartlett , D. Belsito , D. Botelho , M. Bruze , A. Bryant-Friedrich , G.A. Burton Jr. , M.A. Cancellieri , H. Chon , M. Cronin , S. Crotty , M.L. Dagli , W. Dekant , C. Deodhar , K. Farrell , A.D. Fryer , L. Jones , K. Joshi , A. Lapczynski , D.L. Laskin , Y. Thakkar

引用次数: 0