{"title":"Metabolic profiling of the maternal liver in pregnant mice exposed to Di(2-ethylhexyl) phthalate (DEHP)","authors":"Tomomi Asano , Yuto Ohtani , Shinnosuke Sugiura , Masaru Taniguchi , Kei Zaitsu","doi":"10.1016/j.fct.2026.115928","DOIUrl":"10.1016/j.fct.2026.115928","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"210 ","pages":"Article 115928"},"PeriodicalIF":3.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145942079","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}
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
{"title":"Update to RIFM fragrance ingredient safety assessment, γ-octalactone, CAS Registry number 104-50-7","authors":"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","doi":"10.1016/j.fct.2025.115917","DOIUrl":"10.1016/j.fct.2025.115917","url":null,"abstract":"","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"210 ","pages":"Article 115917"},"PeriodicalIF":3.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843036","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}
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
{"title":"RIFM natural complex substance (NCS) fragrance ingredient safety assessment, styrax absolute, CAS registry Number 8024-01-9, RIFM ID 6877.K2.1","authors":"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","doi":"10.1016/j.fct.2025.115913","DOIUrl":"10.1016/j.fct.2025.115913","url":null,"abstract":"","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"210 ","pages":"Article 115913"},"PeriodicalIF":3.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145848604","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}
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
{"title":"Update to RIFM fragrance ingredient safety assessment, 6-methyl-3,5-heptadien-2-one, CAS Registry Number 1604-28-0","authors":"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","doi":"10.1016/j.fct.2026.115964","DOIUrl":"10.1016/j.fct.2026.115964","url":null,"abstract":"","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"210 ","pages":"Article 115964"},"PeriodicalIF":3.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146016922","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}
Simeng Li , Peiwen Yu , Bowen Li , Xiaohui Li , Hongping Wang , Fen Jin
{"title":"Sex-dependent acute oral toxicity and in vivo distribution of 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA) in rats","authors":"Simeng Li , Peiwen Yu , Bowen Li , Xiaohui Li , Hongping Wang , Fen Jin","doi":"10.1016/j.fct.2026.115978","DOIUrl":"10.1016/j.fct.2026.115978","url":null,"abstract":"<div><div>6:2 Chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA), a widely used substitute for perfluorooctane sulfonic acid (PFOS), has raised increasing concern due to its environmental persistence and potential health risks. However, its acute toxicity profile and sex-dependent effects remain insufficiently characterized. This study conducted a 14-day acute oral toxicity study for single exposure (46.4–464 mg/kg·BW) in male and female Sprague–Dawley (SD) rats to quantify lethality and evaluate sex-dependent differences. The median lethal dose (LD<sub>50</sub>) was estimated to be 147 mg/kg·BW for both sexes, classifying 6:2 Cl-PFESA as moderately toxic (GHS Category Ⅲ) with neurotoxicity signs, more acutely hazardous than PFOS. Sex dependence produced different internal exposure patterns, leading to divergent toxic effects: females maintained higher circulating burdens, accompanied by pronounced thrombocytopenia, whereas males exhibited strong hepatic sequestration and erythrocyte toxicity. Gonadal accumulation was also sex-dependent, with substantially higher levels in the ovaries than in the testes. Histopathology identified the liver and kidneys as primary targets and further revealed the lung as a potential target organ marked by foam cell infiltration and lymphoid depletion. Collectively, these findings demonstrate that 6:2 Cl-PFESA induces acute, multi-organ toxicity through strongly sex-dependent mechanisms, highlighting the necessity of additional attention to the pulmonary and reproductive toxicity hazards of 6:2 Cl-PFESA and the necessity of integrating sex as a critical biological variable in future toxicological evaluation and regulatory assessment of PFAS alternatives.</div></div>","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"210 ","pages":"Article 115978"},"PeriodicalIF":3.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146049777","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}
Pavan K. Jayaswamy , Trupthi Ambrish , Vinay C. Sangamesh , Adithi Kellarai , Prakash Patil , Lobo Manuel Alexander , Praveenkumar Shetty
{"title":"Butyrate antagonizes Annexin A2–mediated tauopathy via Annexin A1 reciprocity in Alzheimer's disease","authors":"Pavan K. Jayaswamy , Trupthi Ambrish , Vinay C. Sangamesh , Adithi Kellarai , Prakash Patil , Lobo Manuel Alexander , Praveenkumar Shetty","doi":"10.1016/j.fct.2026.115968","DOIUrl":"10.1016/j.fct.2026.115968","url":null,"abstract":"<div><h3>Background</h3><div>The balance between Annexin A1 (AnxA1), a pro-resolving mediator, and Annexin A2 (AnxA2), a pro-inflammatory counterpart, is essential for immune homeostasis but remains poorly explored in Alzheimer's disease (AD).</div></div><div><h3>Aim</h3><div>To evaluate butyrate's ability to restore AnxA1/AnxA2 equilibrium and attenuate tauopathy and neuroinflammation in cellular and aluminum chloride (AlCl<sub>3</sub>)/<span>d</span>-galactose AD models.</div></div><div><h3>Methods</h3><div><em>In vitro</em>, BV2 cells were used to study AnxA1/AnxA2 reciprocity in microglia, while retinoic acid–differentiated C6 cells with a neuron-like phenotype were employed to assess tau phosphorylation and AnxA1/AnxA2 interplay. <em>In vivo</em>, AlCl<sub>3</sub>/<span>d</span>-galactose rats underwent behavioral testing, Western blotting, ELISA, and immunohistochemistry evaluating butyrate's effects on annexin balance, tau pathology, redox homeostasis, and acetylcholinesterase activity.</div></div><div><h3>Results</h3><div><em>In vitro,</em> Aβ<sub>1</sub>–<sub>42</sub> suppressed AnxA1 and elevated AnxA2 in BV2 microglia, increasing TNF-α, and promoted GSK-3α/β–driven tau phosphorylation in differentiated C6 neuron-like cells through AnxA1/AnxA2 reciprocal regulation. Butyrate restored AnxA1, suppressed AnxA2/GSK-3β/TNF-α, and attenuated tau pathology. <em>In vivo,</em> prophylactic butyrate preserved hippocampal cytoarchitecture, improved cognition, reduced amyloid burden, normalized redox balance, inhibited acetylcholinesterase, and re-equilibrated hippocampal/systemic AnxA1/AnxA2 with decreased p-tau.</div></div><div><h3>Conclusion</h3><div>Butyrate modulates the AnxA1/AnxA2 axis to suppress neuroinflammation and tauopathy, positioning it as a gut-brain axis therapeutic for sporadic AD.</div></div>","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"210 ","pages":"Article 115968"},"PeriodicalIF":3.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043675","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":"Cadmium-induced activation of inflammatory cancer-associated fibroblasts-like cells enhances malignant phenotypes of lung cancer cells","authors":"Qi Jiang , Lujiao Wang , Biyun Chen, Tianyi Dong, Wanyou Shen, Xue Zhou","doi":"10.1016/j.fct.2026.115927","DOIUrl":"10.1016/j.fct.2026.115927","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"210 ","pages":"Article 115927"},"PeriodicalIF":3.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948334","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}
Mariana Meneses , Inês Ferreira , Ana Patrícia Gomes , Rita Pacheco , Helena Gaspar
{"title":"Gastrointestinal permeability and hepatic mechanisms of toxicity of chloro-cathinones","authors":"Mariana Meneses , Inês Ferreira , Ana Patrícia Gomes , Rita Pacheco , Helena Gaspar","doi":"10.1016/j.fct.2026.115981","DOIUrl":"10.1016/j.fct.2026.115981","url":null,"abstract":"<div><div>Understanding the biochemical effects of synthetic cathinone is essential to elucidate its pharmacological actions and systemic impact. Synthetic cathinones are β-keto amphetamine derivatives structurally related to cathinone, widely used as psychoactive substances and commonly consumed orally. In this study, the gastrointestinal permeation and hepatocellular responses of twelve chloro-cathinones were evaluated using complementary <em>in vitro</em> models. Differentiated Caco-2 monolayers demonstrated variable permeability, with 3-CIC (3-chloro-<em>N</em>-isopropylcathinone) and 4-CEC (4-chloro-<em>N</em>-ethylcathinone) exhibiting the highest apparent permeability (P<em>app</em> 7.75 × 10<sup>−6</sup> and 4.89 × 10<sup>−6</sup> <em>cm/s</em>). The cytotoxic profiles were evaluated in Caco-2 and HepG2 cells, IC<sub>50</sub> values ranged from 1.87 to 6.20 mM and from 0.80 to 3.10 mM, respectively. Among the tested compounds, 3-CEC (3-chloro-<em>N</em>-ethylcathinone) and 4-CEC exhibited the greatest potency. Cell-based assays demonstrated that 3-CIC and 4-CIC (4-chloro-<em>N</em>-isopropylcathinone) increased reactive oxygen species levels, suggesting a contribution of-oxidative stress-mediated damage to the cytotoxic effects of these cathinones. These findings provide new insights into the absorption properties of synthetic cathinones and their impact on liver cells, supporting the assessment of their health risks.</div></div>","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"210 ","pages":"Article 115981"},"PeriodicalIF":3.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073405","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}
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
{"title":"Update to RIFM fragrance ingredient safety assessment, bicyclo[3.1.0]hexan-3-one, 4-methyl-1-(1-methylethyl)-, CAS Registry Number 1125-12-8","authors":"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","doi":"10.1016/j.fct.2026.115938","DOIUrl":"10.1016/j.fct.2026.115938","url":null,"abstract":"","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"210 ","pages":"Article 115938"},"PeriodicalIF":3.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987459","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":"Safety and toxicity assessment of Lactobacillus salivarius AP-32 with Probiotic potential in vivo and in vitro","authors":"Yu-Hsuan Chin, Yi-Wen Chen, Yen-Yu Huang, Ching-Min Li, Jia-Hung Lin, Yi-Wei Kuo, Chen-Yu Chen, Yen-Feng Lee, Cian-Dai Ciou, Ko-Chiang Hsia, Shin-Yu Tsai, Hsieh-Hsun Ho","doi":"10.1016/j.fct.2026.115970","DOIUrl":"10.1016/j.fct.2026.115970","url":null,"abstract":"<div><div><em>Lactobacillus salivarius</em> AP-32 (namely <em>Ligilactobacillus salivarius</em> AP-32, <em>L. salivarius</em> AP-32), isolated from the human gut, has shown a favorable safety profile. In 14-day acute and 90-day subchronic toxicity studies in rodents, no adverse effects were observed. The maximum tolerated dose was 16 g/kg body weight in the acute study, and the no-observed-adverse-effect level in the 90-day study was 1.88 g/kg body weight. It showed no mutagenicity <em>in vivo</em> or <em>in vitro</em>, including no chromosomal aberrations in mouse spermatogonia, no bone marrow cytotoxicity, and no mutagenic response in the Ames test (5000 μg/mL). <em>L. salivarius</em> AP-32 exhibited γ-hemolysis and bile salt hydrolase activity. It was non-toxic to Caco-2 cells, did not induce cytotoxicity, and demonstrated strong acid and bile tolerance, intestinal adhesion, and antimicrobial activity against <em>Helicobacter pylori</em>, <em>Salmonella enterica</em> subsp. <em>enterica</em>, <em>Escherichia coli</em>, <em>Listeria monocytogenes</em>, and <em>Vibrio parahaemolyticus</em>, while inducing M2 macrophages. Prior research indicated milk and soybean fermentated <em>L. salivarius</em> AP-32 held potential in regulating blood glucose, alleviating neonatal jaundice, and suppressing vaginal and urinary tract pathogens. These findings supported its safety and potential as a probiotic.</div></div>","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"210 ","pages":"Article 115970"},"PeriodicalIF":3.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040036","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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