ToxicologyPub Date : 2025-05-12DOI: 10.1016/j.tox.2025.154188
Ken-An Lin , Chin-Chuan Su , Shing-Hwa Liu , Kuan-I. Lee , Kai-Min Fang , Chih-Hsin Tang , Chun-Ying Kuo , Kai-Chih Chang , Jun-An Ke , Chun-Fa Huang , Ya-Wen Chen , Ching-Yao Yang
{"title":"Antimony induces mitochondria-dependent and ER stress-triggered apoptosis via the oxidative stress-activated JNK signaling pathway in pancreatic islet β-cells","authors":"Ken-An Lin , Chin-Chuan Su , Shing-Hwa Liu , Kuan-I. Lee , Kai-Min Fang , Chih-Hsin Tang , Chun-Ying Kuo , Kai-Chih Chang , Jun-An Ke , Chun-Fa Huang , Ya-Wen Chen , Ching-Yao Yang","doi":"10.1016/j.tox.2025.154188","DOIUrl":"10.1016/j.tox.2025.154188","url":null,"abstract":"<div><div>Antimony (Sb), a silvery-white metal, is a heavy metal of particular prevalence that has the ability to result in adverse effects in humans through environmental exposure resulting from natural processes and human activities. Epidemiological studies have suggested that Sb has an association with the potential for diabetes mellitus (DM) development. However, the mechanisms by which Sb exerts toxicological effects on pancreatic islet β-cells are still not clear. In this investigation, Sb exposure significantly inhibited rat pancreatic islet β-cell-derived RIN-m5F cell viability and insulin secretion, while inducing mitochondria-dependent apoptotic signals, inclusive of increased apoptotic cell populations, caspase-3 activity, the expression of PARP and caspase-3/-7/-9, and mitochondrial dysfunction. RIN-m5F cells exposure to Sb also led to the triggering of endoplasmic reticulum (ER) stress via the induction of a number of vital molecules, including CHOP, XBP-1s, and caspase-12. In Sb-exposed RIN-m5F cells, 4-PBA pretreatment (an inhibitor of ER stress) significantly suppressed protein expression related to ER stress and events of an apoptotic nature. Furthermore, exposure to Sb resulted in the significant activation of AMPKα, ERK1/2, and JNK signaling, as well as reactive oxygen species (ROS) generation. Pretreatment with SP600125 (an inhibitor of JNK) and antioxidant NAC, but not PD98059 (an inhibitor of ERK) or compound C (an inhibitor of AMPK), effectively abrogated the cytotoxicity, ER stress responses, mitochondrial dysfunction, apoptotic events, insulin secretion inhibition, and JNK activation in Sb-exposed rat pancreatic islet β-cells. However, SP600125 did not prevent ROS generation, which was inhibited by the antioxidant NAC. Collectively, the results demonstrate exposure to Sb to exert β-cell cytotoxicity through oxidative stress-activated JNK signaling downstream-regulated mitochondria-dependent and ER stress-triggered cell apoptotic pathways, eventually resulting in the death of rat pancreatic islet β-cells.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"516 ","pages":"Article 154188"},"PeriodicalIF":4.8,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943186","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":"Insights into the molecular mechanisms underlying phthalates-induced nephrotoxicity","authors":"Mohammed Nazish Quasmi , Jiten Singh , Dinesh Kumar , Dinesh Dhingra , Ashok Jangra","doi":"10.1016/j.tox.2025.154187","DOIUrl":"10.1016/j.tox.2025.154187","url":null,"abstract":"<div><div>Phthalates are the most common environmental toxicants<!--> <!-->that are added to plastics to improve their elasticity and extensibility. Different products such as baby toys, personal<!--> <!-->care products, packaging materials and pharmaceutical products contain various phthalates like Di-(2-ethylhexyl) phthalate (DEHP), Dibutyl phthalate (DBP), etc. During processing, transportation and preparation, these phthalates can leach out into food and<!--> <!-->drinks. Despite their commercial advantages, phthalates have shown multi-organ toxicity, including nephrotoxicity. Phthalates exposure can lead to morphological as well as functional alterations in renal tissues. Intoxication to these phthalates can increase the risk of nephrotoxicity through various signaling pathways, including ferroptosis, oxidative stress, inflammatory, mitochondrial and DNA damage-associated pathways. This review aims to outline recent <em>in-vivo</em> and epidemiological studies to deepen the knowledge on underlying molecular mechanisms of nephrotoxicity caused by different phthalates. Moreover, various pharmacological interventions have also been discussed in this review, which serve as the scientific basis for the prevention and treatment of the Phthalates-induced kidney damage.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"516 ","pages":"Article 154187"},"PeriodicalIF":4.8,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144080492","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}
ToxicologyPub Date : 2025-05-12DOI: 10.1016/j.tox.2025.154189
Agnieszka Galanty , Paweł Paśko , Paulina Koczurkiewicz-Adamczyk , Gabriela Siedlarczyk , Elżbieta Pękala , Irma Podolak
{"title":"Enantiospecific hepatotoxicity of usnic acid in vitro, and the attempt to modify the toxic effect","authors":"Agnieszka Galanty , Paweł Paśko , Paulina Koczurkiewicz-Adamczyk , Gabriela Siedlarczyk , Elżbieta Pękala , Irma Podolak","doi":"10.1016/j.tox.2025.154189","DOIUrl":"10.1016/j.tox.2025.154189","url":null,"abstract":"<div><div>Usnic acid, a chiral secondary lichen metabolite, is known for its diverse biological activities, yet concerns about its hepatotoxicity limit its therapeutic potential. Notably, the enantiospecific effects of its two forms, (+)- and (−)-usnic acid, remain underexplored. This study aimed to compare the hepatotoxic potential of the enantiomers of usnic acid in wide range of concentration to HepG2 cells, by evaluating their impact on cell viability, membrane integrity, and mitochondrial function. Additionally, we investigated whether hepatotoxicity could be mitigated by co-treatment with known hepatoprotectants: silybin, squalene, and N-acetylcysteine. Our results demonstrated for the first time that (−)-usnic acid exhibited significantly greater hepatotoxicity than its (+)-enantiomer, particularly after 24–48 h of exposure (IC₅₀: 16.0 vs. 28.2 µg/mL at 48 h). This enantiospecific toxicity was confirmed by LDH leakage and mitochondrial membrane depolarization, with more pronounced effect induced by (−)-usnic acid. Co-treatment with hepatoprotectants partially alleviated toxicity at 48 h, with squalene and N-acetylcysteine showing better protective effects than silybin. However, the protective effects diminished after 72 h. These findings underscore the importance of enantiospecific analysis in natural compound safety assessments and suggest that the hepatotoxicity of usnic acid is influenced by more than just mitochondrial uncoupling. Further in vivo studies and mechanistic analyses are necessary to evaluate the clinical potential of usnic acid and to identify strategies for safe therapeutic use.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"516 ","pages":"Article 154189"},"PeriodicalIF":4.8,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943187","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}
ToxicologyPub Date : 2025-05-09DOI: 10.1016/j.tox.2025.154182
Do-Yeal Ryu , Won-Ki Pang , Md Saidur Rahman , Yoo-Jin Park , Myung-Geol Pang
{"title":"Differential susceptibility of Leydig and Sertoli cells to bisphenol A","authors":"Do-Yeal Ryu , Won-Ki Pang , Md Saidur Rahman , Yoo-Jin Park , Myung-Geol Pang","doi":"10.1016/j.tox.2025.154182","DOIUrl":"10.1016/j.tox.2025.154182","url":null,"abstract":"<div><div>Bisphenol A (BPA) is an endocrine-disrupting chemical that is increasingly becoming a vital factor in public health due to its ubiquity and toxicity. BPA is associated with male infertility via the disrupted function of Leydig and Sertoli cells. Despite extensive research, the current understanding of the specific pathological concentrations and the mechanisms following BPA exposure still remain questionable. Therefore, we investigated the susceptibilities and underlying mechanisms in Leydig and Sertoli cells following treatment with various BPA doses (0.0001–100 µM in a 10-fold serial dilution). Our results showed that the lowest BPA levels (10<sup>−4</sup> μM) decreased mitochondrial membrane potential and ATP levels. In contrast, ROS levels were increased at high BPA levels regardless of exposure time (24 or 48 h) in both cell types. Mitochondrial-mediated apoptosis was identified along with increased ROS levels and abnormal mitochondrial dynamics, but both cell types showed different susceptibility to BPA toxicity. Subsequently, BPA had detrimental impacts on the mRNA expression levels of steroidogenic enzymes and testosterone synthesis in Leydig cells and reduced anchoring junction proteins in Sertoli cells. Consequently, our results demonstrated that both cells were affected via estrogen receptor alpha. However, protein kinase A was oppositely expressed following BPA exposure in each cell type. Therefore, it is plausible to suggest that each cell has distinct sensitivities and mechanisms in response to BPA.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"516 ","pages":"Article 154182"},"PeriodicalIF":4.8,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143937282","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}
ToxicologyPub Date : 2025-05-07DOI: 10.1016/j.tox.2025.154174
Marit Låg , Tonje Skuland , Jarle Ballangby , Vegard Sæter Grytting , Rikke Bramming Jørgensen , Brynhild Snilsberg , Johan Øvrevik , Jørn A. Holme , Magne Refsnes
{"title":"Mechanisms involved in pro-inflammatory responses to traffic-derived particulate matter (PM) in THP-1 macrophages compared to HBEC3-KT bronchial epithelial cells","authors":"Marit Låg , Tonje Skuland , Jarle Ballangby , Vegard Sæter Grytting , Rikke Bramming Jørgensen , Brynhild Snilsberg , Johan Øvrevik , Jørn A. Holme , Magne Refsnes","doi":"10.1016/j.tox.2025.154174","DOIUrl":"10.1016/j.tox.2025.154174","url":null,"abstract":"<div><div>The pro-inflammatory responses in THP-1-derived macrophages and human bronchial epithelial cells (HBEC3-KT) were examined after exposure to size-fractioned particulate matter (PM) sampled in two road tunnels. All tunnel PM samples induced release and expression of CXCL8 and IL-1β in THP-1 macrophages (50 µg/mL) and HBEC3-KT cells (100 µg/mL), but the potency of the samples differed between the cell types. The road tunnel PM induced pro-inflammatory responses in the macrophages to a much higher extent than diesel exhaust particles (DEP) and particles derived from the stone materials used in the asphalt. Tunnel PM induced a markedly higher increase in cytochrome P450 (CYP)1A1 expression in HBEC3-KT cells than in THP-1 macrophages. The content of organic carbon (OC) in PM correlated to the release of CXCL8 in HBEC3-KT cells, but not in THP-1 macrophages. Moreover, the aryl hydrocarbon receptor (AhR)-inhibitor CH223191 and the antioxidant N-acetyl cysteine (NAC) reduced the PM-induced cytokine release in the macrophages to a lower extent than in HBEC3-KT. In contrast, a toll-like receptor (TLR)2 antibody markedly reduced the PM-induced responses in THP-1 macrophages, but not in HBEC3-KT. A TLR4 antibody was without effect in both cell types. The levels of the microbial TLR2-ligand β-glucan in the PM samples were in a range that might be sufficient to induce pro-inflammatory responses. However, a microbial-independent mechanism could also be involved. In support of such a mechanism, the pro-inflammatory responses to a sample of α-quartz (Min-U-Sil 5), with low levels of β-glucan, were reduced by anti-TLR2. In conclusion, our results indicate that traffic-derived PM exert pro-inflammatory responses in THP-1 macrophages and HBEC3-KT cells via different PM constituents and mechanisms. OC/AhR-dependent mechanisms appeared to be important for PM-induced CXCL8 responses in HBEC3-KT cells, while the cytokine responses in THP-1 macrophages seemed to involve TLR2-mediated activation, either via β-glucan-dependent or -independent mechanisms.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"516 ","pages":"Article 154174"},"PeriodicalIF":4.8,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943185","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}
ToxicologyPub Date : 2025-05-05DOI: 10.1016/j.tox.2025.154173
Kendra L. Clark , Jitu W. George
{"title":"Environmentally relevant concentrations of individual per- and polyfluoroalkyl substances (PFAS) and a PFAS mixture impact proliferation, migration, and gene transcription in a human myometrial cell line","authors":"Kendra L. Clark , Jitu W. George","doi":"10.1016/j.tox.2025.154173","DOIUrl":"10.1016/j.tox.2025.154173","url":null,"abstract":"<div><div>Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants linked to adverse health effects. Epidemiological studies have linked PFAS with an increased risk of uterine diseases including fibroids however, the mechanisms involved remain to be elucidated. This study examined the impact of individual PFAS, such as legacy compounds [perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS)] and alternative short-chain compounds [GENX/HFPO-DA and perfluorobutanesulfonic acid (PFBS)], along with a PFAS mixture, on the function and transcriptome of immortalized human myometrial cells (UT-TERT). Exposure to these PFAS resulted in increased cell viability and proliferation. Flow cytometry showed that PFOS and the PFAS mixture altered cell cycle progression, while migration assays indicated significant enhancement of cell migration following PFOS and mixture exposure. Moreover, PFOA, PFBS, and the PFAS mixture impaired gap junction intercellular communication (GJIC), suggesting possible disruptions in cellular communication in the uterine environment. Transcriptomic analysis identified extensive changes in gene expression after exposure to environmentally relevant PFAS levels, revealing common molecular pathways involved in cell signaling, lipid metabolism, and cell survival. These findings provide crucial insights into how PFAS may contribute to reproductive health risks, warranting further investigation into the long-term effects of PFAS on uterine function and overall reproductive health.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154173"},"PeriodicalIF":4.8,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143911712","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}
ToxicologyPub Date : 2025-05-05DOI: 10.1016/j.tox.2025.154172
De Liu , Yuan Zhao , Jiao Dai , Rongxian Li , Jiamin Yuan , Kaiyan Shen , Zuoshun He , Shiyan Gu
{"title":"Changes of N6-methyladenosine and ferroptosis in cadmium-induced reproductive toxicity of male mice fed a high fat and high sugar diet","authors":"De Liu , Yuan Zhao , Jiao Dai , Rongxian Li , Jiamin Yuan , Kaiyan Shen , Zuoshun He , Shiyan Gu","doi":"10.1016/j.tox.2025.154172","DOIUrl":"10.1016/j.tox.2025.154172","url":null,"abstract":"<div><div>Cadmium (Cd) and high-fat and high-sugar diet (HFHS) are risk factors contributing to the decline in male sperm quality. N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) is essential in the processes of testicular development and spermatogenesis. Ferroptosis, a form of cell death that depends on iron, is prone to causing testicular dysfunction. However, the changes in m<sup>6</sup>A modification regulatory proteins and ferroptosis signaling molecules in male mice with sperm abnormalities resulting from combined exposure to Cd and HFHS remain incompletely elucidate. Our present data indicate that the combined treatment of Cd and HFHS significantly reduced sperm quality in comparison to those in single Cd or HFHS treatment. In addition, indicators related to ferroptosis in the combined treatment of Cd and HFHS group have also undergone significant changes. In detail, the contents of malondialdehyde (MDA) and Fe<sup>2+</sup> as well as Slc7a11 expression were increased while Gclc expressions were reduced in the testicular tissue of Cd and HFHS combined treatment mice. Further detect results showed that the combined exposure to Cd and HFHS synergistically elevated the m<sup>6</sup>A modification levels alongside a downregulation of the Mettl3, Fto, Alkbh5 and Ythdc2 at the protein level when compared with those in single Cd or HFHS treatment. Altogether, it can be inferred that Cd and HFHS combined treatment may alter the levels of m<sup>6</sup>A modification regulatory proteins in testicular tissue, leading to increased Fe<sup>2+</sup> and MDA production, thus activating the Slc7a11/Gpx4 signaling pathway, ultimately decreasing the sperm quality in mice, providing preliminary evidence for the occurrence of ferroptosis in testicular cells. Our findings may provide direction for the study of reproductive toxicity of cadmium and offer reference for the selection of molecular targets.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"516 ","pages":"Article 154172"},"PeriodicalIF":4.8,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143931505","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}
ToxicologyPub Date : 2025-05-05DOI: 10.1016/j.tox.2025.154171
Martin van den Berg PhD (Editor-in-Chief, Regulatory Toxicology & Pharmacology and Current Opinion in Toxicology) , Daniel R. Dietrich PhD (Editor-in-Chief, Chemico-Biological Interactions, Computational Toxicology, and Journal of Toxicology and Regulatory Policy) , Sonja von Aulock PhD (Editor-in-Chief, ALTEX – Alternatives to Animal Experimentation) , Anna Bal-Price PhD (Editor-in-Chief, Reproductive Toxicology) , Michael D. Coleman PhD (Editor-in-Chief, Environmental Toxicology and Pharmacology) , Mark T.D. Cronin PhD (Editor-in-Chief, Computational Toxicology) , Paul Jennings PhD (Editor-in-Chief, Toxicology in Vitro) , Angela Mally PhD (Editor-in-Chief, Toxicology Letters) , Mathieu Vinken PhD (Editor-in-Chief, Toxicology and NAM Journal) , Matthew C. Wright PhD (Editor-in-Chief, Food and Chemical Toxicology)
{"title":"The Alarming Consequences of Workforce Reductions at the FDA, EPA, NIH and CDC in the United States","authors":"Martin van den Berg PhD (Editor-in-Chief, Regulatory Toxicology & Pharmacology and Current Opinion in Toxicology) , Daniel R. Dietrich PhD (Editor-in-Chief, Chemico-Biological Interactions, Computational Toxicology, and Journal of Toxicology and Regulatory Policy) , Sonja von Aulock PhD (Editor-in-Chief, ALTEX – Alternatives to Animal Experimentation) , Anna Bal-Price PhD (Editor-in-Chief, Reproductive Toxicology) , Michael D. Coleman PhD (Editor-in-Chief, Environmental Toxicology and Pharmacology) , Mark T.D. Cronin PhD (Editor-in-Chief, Computational Toxicology) , Paul Jennings PhD (Editor-in-Chief, Toxicology in Vitro) , Angela Mally PhD (Editor-in-Chief, Toxicology Letters) , Mathieu Vinken PhD (Editor-in-Chief, Toxicology and NAM Journal) , Matthew C. Wright PhD (Editor-in-Chief, Food and Chemical Toxicology)","doi":"10.1016/j.tox.2025.154171","DOIUrl":"10.1016/j.tox.2025.154171","url":null,"abstract":"","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154171"},"PeriodicalIF":4.8,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143937186","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}
ToxicologyPub Date : 2025-05-02DOI: 10.1016/j.tox.2025.154170
Jing Yang , Xiaohong Wang , Qiannan Zhang , Hongyang Cui , Lijuan You , Zhisen Zhuang , Yaru Tian , Xiaomin Han , Miaoying Shi , Li Bai , Xudong Jia , Hui Yang
{"title":"Immunotoxic effect and mechanisms of Fusarium mycotoxins on human immune cells: A focus on T cells and macrophages","authors":"Jing Yang , Xiaohong Wang , Qiannan Zhang , Hongyang Cui , Lijuan You , Zhisen Zhuang , Yaru Tian , Xiaomin Han , Miaoying Shi , Li Bai , Xudong Jia , Hui Yang","doi":"10.1016/j.tox.2025.154170","DOIUrl":"10.1016/j.tox.2025.154170","url":null,"abstract":"<div><div><em>Fusarium</em> mycotoxins, including deoxynivalenol (DON), 15-acetyl-deoxynivalenol (15-Ac-DON), 3-acetyl-deoxynivalenol (3-Ac-DON), and nivalenol (NIV), are prevalent contaminants in food and animal feed, posing significant health risks to humans. Although immunotoxicity is acknowledged as a sensitive endpoint for DON exposure, the immunotoxic effects and mechanisms of its acetylated derivatives and NIV, especially in human-derived immune cells, are not fully elucidated. In this study, we explored the toxicological impacts and mechanisms of these mycotoxins on human immune cells, with a focus on T cells and macrophages. After treating human-derived cell models with four fungal toxins (0–5000 nM) for 48 h, Jurkat T cells showed heightened sensitivity to these mycotoxins, with NIV exhibiting the highest cytotoxicity, followed by DON, 15-Ac-DON, and 3-Ac-DON. Notably, these four mycotoxins dose-dependently inhibited the activation of human T cells in the Peripheral Blood Mononuclear Cells (PBMCs) model at much lower exposure levels (0–200 nM). Similarly, after treating macrophages with NIV (0–500 nM), DON (0–1000 nM), and 15-Ac-DON (0–1000 nM) for 48 h, dose-dependent inhibition of macrophage alternative activation, lysosomal biosynthesis, and cytokine production were observed. Transcriptomic analyses indicated that DON, 15-Ac-DON, and NIV disrupt ribosome biogenesis and protein processing pathways in both T cells and macrophages. These findings underscore the influence of chemical structure on the toxicity of <em>Fusarium</em> mycotoxins and provide critical insights into their immunotoxic mechanisms.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154170"},"PeriodicalIF":4.8,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143902543","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}
ToxicologyPub Date : 2025-05-01DOI: 10.1016/j.tox.2025.154168
Lennart V.J. van Melis, Kyra N. Zimnik, Arjuna R. Persad, Teije Bak, Manon J.H. van Rossum, Regina G.D.M. van Kleef, J. Pepijn Wopken, Juliette Legler, Remco H.S. Westerink
{"title":"Exposure to organophosphate flame retardants and phthalates alters neuronal activity and network development","authors":"Lennart V.J. van Melis, Kyra N. Zimnik, Arjuna R. Persad, Teije Bak, Manon J.H. van Rossum, Regina G.D.M. van Kleef, J. Pepijn Wopken, Juliette Legler, Remco H.S. Westerink","doi":"10.1016/j.tox.2025.154168","DOIUrl":"10.1016/j.tox.2025.154168","url":null,"abstract":"<div><div>Exposure to organophosphate flame retardants (OPFRs) and phthalates is associated with neurodevelopmental deficits, impaired neuronal proliferation and differentiation, altered neurotransmitter levels, and impaired learning and memory. Here, we assessed the effects of acute and chronic exposure to the OPFR triphenyl phosphate (TPhP) and several phthalates on neuronal activity and network development in male and female rat primary cortical cultures grown on micro-electrode arrays. Acute exposure to TPhP, diethyl phthalate (DEP), dibutyl phthalate (DBP), and benzyl butyl phthalate (BBzP) inhibited neuronal activity, while chronic exposure to TPhP and DEP induced a hyperexcitation. Chronic exposure to DBP, BBzP, bis(2-ethylhexyl) phthalate (DEHP), and its metabolite mono-2-ethylhexyl phthalate (MEHP) inhibited neuronal network development. Exposure to BBzP and DEHP affected neuronal function at human-relevant concentrations as low as 1 µM. Acute and chronic exposure to the metabolites of DEP, DBP, and BBzP had only limited effects. Although the underlying mechanisms remain to be elucidated, analysis of endocrine mechanisms, including retinoic acid, retinoic X, liver X, and prostaglandin E<sub>2</sub> receptor, suggested that the effects of OPFR and phthalates were not endocrine-mediated. Further research is needed to elucidate the mechanisms underlying the different responses to acute and chronic exposure. Taken together, these results add to the evidence that TPhP and various phthalates illicit neurotoxic effects, some at low concentrations. These novel results should be considered in the risk assessment of these chemicals.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154168"},"PeriodicalIF":4.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143905991","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}