Pub Date : 2026-01-01Epub Date: 2025-11-10DOI: 10.1016/j.crtox.2025.100270
Brianna N. Rivera , Isabel A. Lea , Seneca Fitch , Neepa Choksi , Allison Franzen , James Bus , Erik Rushton , Susan J. Borghoff
Ethyl tert-butyl ether (ETBE), a fuel additive, and tert-butyl alcohol (TBA), a solvent and metabolite of ETBE and methyl tert-butyl ether (MTBE), may be encountered via inhalation, oral, or dermal exposure. This assessment evaluated the human carcinogenic hazard of ETBE and TBA by systematically reviewing available human, animal, and mechanistic data. No epidemiological studies were identified, and two standard cancer bioassays were available for each compound. Tumor responses were limited to low incidences at high exposure levels: liver tumors in male F344 rats, kidney tumors in male F344 rats, and thyroid tumors in female B6C3F1 mice exposed to ETBE or TBA, respectively. Mechanistic evidence was organized within the framework of the key characteristics of carcinogens (KCC) and established rodent non-genotoxic modes of action (MoAs) for the overall evaluation. Aside from supportive evidence for KCC2 (is genotoxic) and KCC10 (alters cell proliferation, death, or nutrient supply), mechanistic data across KCCs were sparse and inconsistent. Both substances lacked genotoxic activity with available data supporting non-genotoxic MoAs that are not relevant to humans. Overall, the evidence indicates little concern for a carcinogenic hazard of ETBE or TBA in humans.
{"title":"Systematic evaluation of the evidence base on ethyl tert-butyl ether and tert-butyl alcohol for carcinogenic potential in humans; lack of concern based on animal cancer studies and mechanistic data","authors":"Brianna N. Rivera , Isabel A. Lea , Seneca Fitch , Neepa Choksi , Allison Franzen , James Bus , Erik Rushton , Susan J. Borghoff","doi":"10.1016/j.crtox.2025.100270","DOIUrl":"10.1016/j.crtox.2025.100270","url":null,"abstract":"<div><div>Ethyl <em>tert</em>-butyl ether (ETBE), a fuel additive, and <em>tert</em>-butyl alcohol (TBA), a solvent and metabolite of ETBE and methyl <em>tert</em>-butyl ether (MTBE), may be encountered via inhalation, oral, or dermal exposure. This assessment evaluated the human carcinogenic hazard of ETBE and TBA by systematically reviewing available human, animal, and mechanistic data. No epidemiological studies were identified, and two standard cancer bioassays were available for each compound. Tumor responses were limited to low incidences at high exposure levels: liver tumors in male F344 rats, kidney tumors in male F344 rats, and thyroid tumors in female B6C3F1 mice exposed to ETBE or TBA, respectively. Mechanistic evidence was organized within the framework of the key characteristics of carcinogens (KCC) and established rodent non-genotoxic modes of action (MoAs) for the overall evaluation. Aside from supportive evidence for KCC2 (is genotoxic) and KCC10 (alters cell proliferation, death, or nutrient supply), mechanistic data across KCCs were sparse and inconsistent. Both substances lacked genotoxic activity with available data supporting non-genotoxic MoAs that are not relevant to humans. Overall, the evidence indicates little concern for a carcinogenic hazard of ETBE or TBA in humans.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"10 ","pages":"Article 100270"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145683929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2026-02-26DOI: 10.1016/j.crtox.2026.100286
Hongxia Chen , Shenglong He , Zhuoran Zhu , Xia Wang , Zhongji Meng
The growing prevalence of male infertility has become a significant clinical and public health issue, with environmental exposures increasingly recognized as a major modifiable risk factor. This review synthesizes current evidence within the framework of the “male reproductive exposome”, linking lifelong exposure to environmental toxicants—ranging from endocrine-disrupting chemicals to emerging contaminants—to clinically relevant outcomes such as impaired semen parameters, altered reproductive hormone profiles, and an increased risk of testicular dysfunction. We critically evaluate the concept of life-course vulnerability, highlighting how exposures during critical developmental windows—including prenatal, peripubertal, and adult stages—may program distinct pathological trajectories that manifest as reproductive disorders in later life. In addition to classical mechanisms of endocrine disruption, we emphasize oxidative stress and, particularly, epigenetic reprogramming of the germline as key biological pathways contributing to both immediate fertility impairments and potential transgenerational health effects. Furthermore, we discuss the translational importance of these insights, focusing on the development of mechanism-informed biomarker panels for early detection and risk stratification, as well as addressing the persistent challenge of assessing toxicity from complex chemical mixtures. Finally, we underscore the necessity of integrating epidemiological research, mechanistic toxicology, and clinical practice to advance preventive and clinical strategies. This integration requires overcoming methodological challenges in mixture exposure assessment, accelerating biomarker discovery for personalized risk prediction, and formulating evidence-based public health interventions. In a word, this review advocates for a proactive, science-driven approach to mitigate environmental threats to male reproductive health and protect the well-being of future generations.
{"title":"Bridging the Gap: How environmental exposures compromise male fertility and clinical Outlook","authors":"Hongxia Chen , Shenglong He , Zhuoran Zhu , Xia Wang , Zhongji Meng","doi":"10.1016/j.crtox.2026.100286","DOIUrl":"10.1016/j.crtox.2026.100286","url":null,"abstract":"<div><div>The growing prevalence of male infertility has become a significant clinical and public health issue, with environmental exposures increasingly recognized as a major modifiable risk factor. This review synthesizes current evidence within the framework of the “male reproductive exposome”, linking lifelong exposure to environmental toxicants—ranging from endocrine-disrupting chemicals to emerging contaminants—to clinically relevant outcomes such as impaired semen parameters, altered reproductive hormone profiles, and an increased risk of testicular dysfunction. We critically evaluate the concept of life-course vulnerability, highlighting how exposures during critical developmental windows—including prenatal, peripubertal, and adult stages—may program distinct pathological trajectories that manifest as reproductive disorders in later life. In addition to classical mechanisms of endocrine disruption, we emphasize oxidative stress and, particularly, epigenetic reprogramming of the germline as key biological pathways contributing to both immediate fertility impairments and potential transgenerational health effects. Furthermore, we discuss the translational importance of these insights, focusing on the development of mechanism-informed biomarker panels for early detection and risk stratification, as well as addressing the persistent challenge of assessing toxicity from complex chemical mixtures. Finally, we underscore the necessity of integrating epidemiological research, mechanistic toxicology, and clinical practice to advance preventive and clinical strategies. This integration requires overcoming methodological challenges in mixture exposure assessment, accelerating biomarker discovery for personalized risk prediction, and formulating evidence-based public health interventions. In a word, this review advocates for a proactive, science-driven approach to mitigate environmental threats to male reproductive health and protect the well-being of future generations.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"10 ","pages":"Article 100286"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147384963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2026-01-22DOI: 10.1016/j.crtox.2026.100283
Reese M. Valdez , Yvonne Chang , Jamie M. Pennington , Susan C. Tilton
There is increased emphasis on understanding how non-chemical stressors that contribute to inflammation in the lung may influence adverse health outcomes after chemical exposures. Prior studies in an in vitro respiratory model of type 2 asthmatic inflammation found cells from the asthmatic phenotype respond uniquely to benzo[a]pyrene (BAP) treatment compared to normal cells across multiple endpoints related to mucus production, goblet cell hyperplasia, mucociliary dysfunction and airway remodeling. To further understand how cellular response to BAP is regulated in a model of inflammation-based disease, this study examines changes in miRNA and mRNA regulation following BAP exposure in primary human bronchial epithelial cells (HBECs) cultured at the air–liquid interface with normal and interlukin-13 (IL-13) induced asthmatic phenotypes. Primary 3D HBECs differentiated in the presence and absence of 10 ng/mL IL-13 were treated on day 25 with 158 µM BAP for 48 h. Differentially expressed (q < 0.01) miRNA and mRNA were analyzed to predict miRNA target interactions and assess the functional consequences of miRNAs in each phenotype. While BAP-treated HBEC with the IL-13 asthmatic phenotype had a similar number of differentially expressed miRNA (93 up- and 100 down-regulated) compared to BAP-treated normal HBEC (93 up- and 94 down-regulated), IL-13 HBEC treated with BAP were shown to have unique enrichment of miRNA targets involved in up-regulation of cell cycle processes and down-regulation of processes related to NOTCH, WNT, and Hedgehog signaling. These data are the first to provide insight into the role of miRNAs as regulators of chemical toxicity in a respiratory model of inflammation-based disease.
{"title":"MicroRNA-mediated changes contributing to benzo[a]pyrene toxicity in a 3D respiratory model for asthma","authors":"Reese M. Valdez , Yvonne Chang , Jamie M. Pennington , Susan C. Tilton","doi":"10.1016/j.crtox.2026.100283","DOIUrl":"10.1016/j.crtox.2026.100283","url":null,"abstract":"<div><div>There is increased emphasis on understanding how non-chemical stressors that contribute to inflammation in the lung may influence adverse health outcomes after chemical exposures. Prior studies in an <em>in vitro</em> respiratory model of type 2 asthmatic inflammation found cells from the asthmatic phenotype respond uniquely to benzo[a]pyrene (BAP) treatment compared to normal cells across multiple endpoints related to mucus production, goblet cell hyperplasia, mucociliary dysfunction and airway remodeling. To further understand how cellular response to BAP is regulated in a model of inflammation-based disease, this study examines changes in miRNA and mRNA regulation following BAP exposure in primary human bronchial epithelial cells (HBECs) cultured at the air–liquid interface with normal and interlukin-13 (IL-13) induced asthmatic phenotypes. Primary 3D HBECs differentiated in the presence and absence of 10 ng/mL IL-13 were treated on day 25 with 158 µM BAP for 48 h. Differentially expressed (q < 0.01) miRNA and mRNA were analyzed to predict miRNA target interactions and assess the functional consequences of miRNAs in each phenotype. While BAP-treated HBEC with the IL-13 asthmatic phenotype had a similar number of differentially expressed miRNA (93 up- and 100 down-regulated) compared to BAP-treated normal HBEC (93 up- and 94 down-regulated), IL-13 HBEC treated with BAP were shown to have unique enrichment of miRNA targets involved in up-regulation of cell cycle processes and down-regulation of processes related to NOTCH, WNT, and Hedgehog signaling. These data are the first to provide insight into the role of miRNAs as regulators of chemical toxicity in a respiratory model of inflammation-based disease.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"10 ","pages":"Article 100283"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2026-03-10DOI: 10.1016/j.crtox.2026.100288
Chenjing Zhang , Zhanming Liu , Yingxin Wang , Weilin Deng , Hailong Wang , Jing Zhang , Qilong Feng
This study aims to explore the impact of microwave radiation on the electrophysiological functions of human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and to focus on the critical role and underlying mechanism of autophagy in this process. The iPSC-CMs were irradiated with S-band microwaves at a power of 30 mw/cm2. Through techniques such as immunofluorescence, Western blotting, electrophysiological recording, scanning electron microscopy, and transcriptomic analysis, the changes in electrophysiological indicators, ultrastructure, and autophagy levels of iPSC-CMs after microwave radiation were systematically evaluated. Further intervention with Acadesine (AICAR) was conducted to verify the role of autophagy in radiation-induced damage. After microwave radiation, iPSC-CMs exhibited significant electrophysiological dysfunction. Ultrastructural observations revealed aggravated mitochondrial damage after radiation, manifested as vacuolization, loss of cristae, and increased mitochondrial autophagy, accompanied by decreased ATP content and mitochondrial membrane potential. At the molecular level, transcriptomic analysis suggested that autophagy-related genes such as ULK1 were key regulatory nodes. After radiation, the expression of autophagy marker LC3II/I was upregulated while p62 expression was downregulated, indicating activation of the autophagic flux. Inhibition of autophagy with AICAR significantly improved the radiation-induced electrophysiological disorders. Microwave radiation can cause severe electrophysiological dysfunction in iPSC-CMs, and the mechanism is closely related to the abnormally elevated autophagy level induced by radiation. Inhibiting autophagy can effectively alleviate the electrophysiological damage caused by radiation, suggesting that targeting the autophagy pathway may be a potential strategy for protecting against the cardiotoxic effects of microwave radiation.
{"title":"The role of autophagy in microwave radiation induced toxicity in iPSC-derived cardiomyocytes","authors":"Chenjing Zhang , Zhanming Liu , Yingxin Wang , Weilin Deng , Hailong Wang , Jing Zhang , Qilong Feng","doi":"10.1016/j.crtox.2026.100288","DOIUrl":"10.1016/j.crtox.2026.100288","url":null,"abstract":"<div><div>This study aims to explore the impact of microwave radiation on the electrophysiological functions of human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and to focus on the critical role and underlying mechanism of autophagy in this process. The iPSC-CMs were irradiated with S-band microwaves at a power of 30 mw/cm<sup>2</sup>. Through techniques such as immunofluorescence, Western blotting, electrophysiological recording, scanning electron microscopy, and transcriptomic analysis, the changes in electrophysiological indicators, ultrastructure, and autophagy levels of iPSC-CMs after microwave radiation were systematically evaluated. Further intervention with Acadesine (AICAR) was conducted to verify the role of autophagy in radiation-induced damage. After microwave radiation, iPSC-CMs exhibited significant electrophysiological dysfunction. Ultrastructural observations revealed aggravated mitochondrial damage after radiation, manifested as vacuolization, loss of cristae, and increased mitochondrial autophagy, accompanied by decreased ATP content and mitochondrial membrane potential. At the molecular level, transcriptomic analysis suggested that autophagy-related genes such as ULK1 were key regulatory nodes. After radiation, the expression of autophagy marker LC3II/I was upregulated while p62 expression was downregulated, indicating activation of the autophagic flux. Inhibition of autophagy with AICAR significantly improved the radiation-induced electrophysiological disorders. Microwave radiation can cause severe electrophysiological dysfunction in iPSC-CMs, and the mechanism is closely related to the abnormally elevated autophagy level induced by radiation. Inhibiting autophagy can effectively alleviate the electrophysiological damage caused by radiation, suggesting that targeting the autophagy pathway may be a potential strategy for protecting against the cardiotoxic effects of microwave radiation.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"10 ","pages":"Article 100288"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147448996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-12-03DOI: 10.1016/j.crtox.2025.100272
Eriton E.L. Valente , David L. Harmon , John May , Huihua Ji , Ronald J. Trotta , James L. Klotz
Ergot alkaloids can bind serotonin (5-HT) receptors interfering with many physiological functions. However, the mechanism has not been completely established. The objective was to evaluate whether the association of 5-HT and the ergot alkaloid, ergovaline, in a 24-h pre-incubation can affect vascular tissue partitioning and contractile responses. Cross-sections of saphenous veins from five steers were used. In the tissue partitioning experiment, the treatments were the combination of three levels of ergovaline (2.01 × 10−8 M, 2.01 × 10−7 M and 2.01 × 10−6 M) with three levels of 5-HT and a control (5 × 10−8 M, 5 × 10−7 M, 5 × 10−6 M and 0 M). After 24-h exposure to the treatments, the blood vessels were washed. Afterward, the tissues were analyzed for ergovaline and 5-HT concentrations. For the contractility experiment, a parallel set of blood vessels was evaluated in the myograph after 24-h pre-incubation with the respective treatments: 1) no additional compound; 2) tall fescue seed extract (2.01 × 10−7 M of ergovaline); 3) serotonin (5 × 10−7 M); or 4) ERV plus 5-HT. The tissue ergovaline increased (P < 0.001) about 27.5-fold when the concentration in the media increased 100-fold (2.01 × 10−8 M to 2.01 × 10−6 M). However, the presence of 5-HT did not affect (P = 0.368) tissue ergovaline partitioning. When 5-HT was not added, ergovaline reduced (P < 0.05) the 5-HT concentration in the blood vessel. Pre-incubation with ergovaline reduced contractile response by about 95 % (P < 0.05) and 5-HT did not change its effect. Ergot alkaloid partitioning is associated with reduced tissue 5-HT levels and blood vessel contractility.
{"title":"Association of serotonin and ergot alkaloids on tissue partitioning and contractile response of bovine blood vessels","authors":"Eriton E.L. Valente , David L. Harmon , John May , Huihua Ji , Ronald J. Trotta , James L. Klotz","doi":"10.1016/j.crtox.2025.100272","DOIUrl":"10.1016/j.crtox.2025.100272","url":null,"abstract":"<div><div>Ergot alkaloids can bind serotonin (5-HT) receptors interfering with many physiological functions. However, the mechanism has not been completely established. The objective was to evaluate whether the association of 5-HT and the ergot alkaloid, ergovaline, in a 24-h pre-incubation can affect vascular tissue partitioning and contractile responses. Cross-sections of saphenous veins from five steers were used. In the tissue partitioning experiment, the treatments were the combination of three levels of ergovaline (2.01 × 10<sup>−8</sup> M, 2.01 × 10<sup>−7</sup> M and 2.01 × 10<sup>−6</sup> M) with three levels of 5-HT and a control (5 × 10<sup>−8</sup> M, 5 × 10<sup>−7</sup> M, 5 × 10<sup>−6</sup> M and 0 M). After 24-h exposure to the treatments, the blood vessels were washed. Afterward, the tissues were analyzed for ergovaline and 5-HT concentrations. For the contractility experiment, a parallel set of blood vessels was evaluated in the myograph after 24-h pre-incubation with the respective treatments: 1) no additional compound; 2) tall fescue seed extract (2.01 × 10<sup>−7</sup> M of ergovaline); 3) serotonin (5 × 10<sup>−7</sup> M)<em>;</em> or 4) ERV plus 5-HT. The tissue ergovaline increased (P < 0.001) about 27.5-fold when the concentration in the media increased 100-fold (2.01 × 10<sup>−8</sup> M to 2.01 × 10<sup>−6</sup> M). However, the presence of 5-HT did not affect (P = 0.368) tissue ergovaline partitioning. When 5-HT was not added, ergovaline reduced (P < 0.05) the 5-HT concentration in the blood vessel. Pre-incubation with ergovaline reduced contractile response by about 95 % (P < 0.05) and 5-HT did not change its effect. Ergot alkaloid partitioning is associated with reduced tissue 5-HT levels and blood vessel contractility.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"10 ","pages":"Article 100272"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145735325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The NLRP3 inhibitor, MCC950, attenuates environmental pollutant PM2.5-induced acute lung injury by inhibiting alveolar macrophage pyroptosis","authors":"Zhuoxiao Han , Ying Han , Ranran Li , Kexin Fan , Xiao Zhang , Tengfei Sun , Yue Li , Hua Qiao","doi":"10.1016/j.crtox.2026.100282","DOIUrl":"10.1016/j.crtox.2026.100282","url":null,"abstract":"<div><div>PM<sub>2.5</sub> is a key environmental pollutant that induces inflammatory lung injury.</div><div>Effective prevention and treatment for PM<sub>2</sub>.<sub>5</sub>-induced lung damage remain lacking.</div><div>This study investigated MCC950′s protective role in PM<sub>2</sub>.<sub>5</sub>-exposed mice and macrophages.</div><div>PM<sub>2</sub>.<sub>5</sub> triggers NLRP3/Caspase-1-mediated pyroptosis, amplifying pulmonary inflammation.</div><div>MCC950 attenuates injury by inhibiting pyroptosis, suggesting therapeutic potential.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"10 ","pages":"Article 100282"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147303424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Microglia, parenchymal macrophages resident in the central nervous system, regulate brain development by dynamically changing their functional and morphological states in a spatiotemporal-dependent manner. Because the function of microglia may differ depending on their location, their status should ideally be assessed within discrete brain regions. In this study, we developed a novel whole-brain imaging method to visualize microglial morphology in the forebrain, midbrain, and hindbrain of live zebrafish larvae at 5–6days post-fertilization, and quantified various morphological parameters using MorphoLibJ, a publicly available tool for mathematical analysis of three-dimensional images. We applied this method to assess the developmental toxicity of ethanol and valproic acid on microglial morphology in the zebrafish larvae, and were able to detect marked differences in the spatiotemporal effects of each compound. The duration of exposure required to detect significant changes in microglial morphology was shorter for ethanol than for valproic acid, and microglia in the forebrain diencephalon region were more susceptible to toxicity induced by ethanol compared with valproic acid. These results suggest that our whole-brain microglial imaging and modeling method may be a versatile tool to assess the developmental toxicity of chemicals in zebrafish.
{"title":"Application to developmental toxicity testing of a novel method for whole-brain imaging of microglia in zebrafish","authors":"Mizuki Yuge , Junko Koiwa , Takashi Shiromizu , Eri Wakai , Akira Migoguchi , Yuhei Nishimura","doi":"10.1016/j.crtox.2025.100276","DOIUrl":"10.1016/j.crtox.2025.100276","url":null,"abstract":"<div><div>Microglia, parenchymal macrophages resident in the central nervous system, regulate brain development by dynamically changing their functional and morphological states in a spatiotemporal-dependent manner. Because the function of microglia may differ depending on their location, their status should ideally be assessed within discrete brain regions. In this study, we developed a novel whole-brain imaging method to visualize microglial morphology in the forebrain, midbrain, and hindbrain of live zebrafish larvae at 5–6days post-fertilization, and quantified various morphological parameters using MorphoLibJ, a publicly available tool for mathematical analysis of three-dimensional images. We applied this method to assess the developmental toxicity of ethanol and valproic acid on microglial morphology in the zebrafish larvae, and were able to detect marked differences in the spatiotemporal effects of each compound. The duration of exposure required to detect significant changes in microglial morphology was shorter for ethanol than for valproic acid, and microglia in the forebrain diencephalon region were more susceptible to toxicity induced by ethanol compared with valproic acid. These results suggest that our whole-brain microglial imaging and modeling method may be a versatile tool to assess the developmental toxicity of chemicals in zebrafish.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"10 ","pages":"Article 100276"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Infertility is a significant public health issue that can be influenced by environmental pollutants. As a radioactive heavy metal and environmental contaminant, uranium has the potential to impact fertility.
Objective
This study assesses the multigenerational reproductive effects of chronic, non-nephrotoxic uranium exposure across three generations of male rats.
Methods
In this study, a non-nephrotoxic uranium solution (40 mg/L) was chronically administered via drinking water to male and female F0 rats (n = 20 per group) throughout their lifespan. The objective was to evaluate the potential reprotoxic effects of uranium on males across three generations (F0, F1, F2), with a focus on spermatogenesis, steroidogenesis, and testicular homeostasis, including oxidative stress, inflammation, apoptosis, and vitamin D metabolism.
Results
Steroidogenesis was modulated in all generation, with dysregulation of sex and pituitary hormones (testosterone, estradiol, gonadotropins, Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH). Morphological and histological changes in the testes were observed in both the F1 and F2 generations. Spermatogenesis was dysregulated by an increased proportion of seminiferous tubules at stage I-VI and reduced expression of TH2B and eppin mRNA. Interestingly, gene expression analysis of several markers involved in the regulation and protection of testicular homeostasis revealed significant effects only on the F2 generation. In this generation, uranium exposure also disrupted vitamin D metabolism in the testes.
Conclusion
Uranium may impair testicular function, with more pronounced effects observed in the F2 generation. These findings highlight its potential for multigenerational toxicity and underscore the need for further research into its impact on human reproductive health.
{"title":"Multigenerational effects of uranium exposure reveal stronger testicular dysregulation in the second generation","authors":"Audrey Legendre , Céline Gloaguen , Dimitri Kereselidze , Nawel Saci , Sophia Murat El Houdigui , Pascal Froment , Christelle Elie , Catherine Defoort , Philippe Lestaevel , Mohamed Amine Benadjaoud , Maâmar Souidi , Stéphane Grison","doi":"10.1016/j.crtox.2025.100279","DOIUrl":"10.1016/j.crtox.2025.100279","url":null,"abstract":"<div><h3>Background</h3><div>Infertility is a significant public health issue that can be influenced by environmental pollutants. As a radioactive heavy metal and environmental contaminant, uranium has the potential to impact fertility.</div></div><div><h3>Objective</h3><div>This study assesses the multigenerational reproductive effects of chronic, non-nephrotoxic uranium exposure across three generations of male rats.</div></div><div><h3>Methods</h3><div>In this study, a non-nephrotoxic uranium solution (40 mg/L) was chronically administered <em>via</em> drinking water to male and female F0 rats (n = 20 per group) throughout their lifespan. The objective was to evaluate the potential reprotoxic effects of uranium on males across three generations (F0, F1, F2), with a focus on spermatogenesis, steroidogenesis, and testicular homeostasis, including oxidative stress, inflammation, apoptosis, and vitamin D metabolism.</div></div><div><h3>Results</h3><div>Steroidogenesis was modulated in all generation, with dysregulation of sex and pituitary hormones (testosterone, estradiol, gonadotropins, Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH). Morphological and histological changes in the testes were observed in both the F1 and F2 generations. Spermatogenesis was dysregulated by an increased proportion of seminiferous tubules at stage I-VI and reduced expression of <em>TH2B</em> and <em>eppin</em> mRNA. Interestingly, gene expression analysis of several markers involved in the regulation and protection of testicular homeostasis revealed significant effects only on the F2 generation. In this generation, uranium exposure also disrupted vitamin D metabolism in the testes.</div></div><div><h3>Conclusion</h3><div>Uranium may impair testicular function, with more pronounced effects observed in the F2 generation. These findings highlight its potential for multigenerational toxicity and underscore the need for further research into its impact on human reproductive health.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"10 ","pages":"Article 100279"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145973233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2026-03-04DOI: 10.1016/j.crtox.2026.100287
Michael Furlong , Venkata Gupta , Stephanie Galanti , Srinivasan Narasimhan , Divya Pulivarthi , Syam S. Andra , Annemarie Stroustrup
In the neonatal intensive care unit (NICU), infants face treatments that convey high-dose exposure to phthalates, a family of ubiquitous endocrine-disrupting organic chemicals. Past research shows that NICU-based phthalate exposure, particularly exposure to di (2-ethylhexyl) phthalate (DEHP), is associated with increased risk of abnormal multisystem outcomes among preterm infants. Blood product transfusion is a recognized significant source of DEHP exposure in hospitalized patients. In this pilot study we collected serial urine samples from one preterm subject following a clinically indicated blood transfusion as a sentinel DEHP exposure. Each specimen was analyzed for DEHP metabolites via liquid chromatography coupled with triple quadrupole tandem mass spectrometry. The calculated half-lives of DEHP metabolites in this subject were generally shorter than reported for adults. Our pilot data demonstrate the need for future studies to estimate population-level half-lives of DEHP metabolites in preterm infants to allow for more accurate NICU-based DEHP source identification than possible with estimates of DEHP metabolism in adults. Source identification is critical to mitigate exposure in the highly vulnerable NICU population.
{"title":"Determination of the half-life of di(2-ethylhexyl) phthalate (DEHP) in a preterm neonate using blood transfusion as the source of intravenous exposure","authors":"Michael Furlong , Venkata Gupta , Stephanie Galanti , Srinivasan Narasimhan , Divya Pulivarthi , Syam S. Andra , Annemarie Stroustrup","doi":"10.1016/j.crtox.2026.100287","DOIUrl":"10.1016/j.crtox.2026.100287","url":null,"abstract":"<div><div>In the neonatal intensive care unit (NICU), infants face treatments that convey high-dose exposure to phthalates, a family of ubiquitous endocrine-disrupting organic chemicals. Past research shows that NICU-based phthalate exposure, particularly exposure to di (2-ethylhexyl) phthalate (DEHP), is associated with increased risk of abnormal multisystem outcomes among preterm infants. Blood product transfusion is a recognized significant source of DEHP exposure in hospitalized patients. In this pilot study we collected serial urine samples from one preterm subject following a clinically indicated blood transfusion as a sentinel DEHP exposure. Each specimen was analyzed for DEHP metabolites via liquid chromatography coupled with triple quadrupole tandem mass spectrometry. The calculated half-lives of DEHP metabolites in this subject were generally shorter than reported for adults. Our pilot data demonstrate the need for future studies to estimate population-level half-lives of DEHP metabolites in preterm infants to allow for more accurate NICU-based DEHP source identification than possible with estimates of DEHP metabolism in adults. Source identification is critical to mitigate exposure in the highly vulnerable NICU population.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"10 ","pages":"Article 100287"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147384961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-12-13DOI: 10.1016/j.crtox.2025.100277
Haonan Ruan , Jing Zhang , Yunyun Wang , Dan Zhang , Jiaoyang Luo , Meihua Yang
Zearalenone (ZEN) is an oestrogen-like mycotoxin that widely contaminates food and feed worldwide. Current research suggests that ZEN causes liver injury by disrupting hepatic lipid metabolism. Furthermore, prolonged disturbances in hepatic lipid metabolism are believed to play a role in the progression of non-alcoholic fatty liver disease (NAFLD). However, the exact association between ZEN exposure and the development of NAFLD is unclear. In this study, we established a rat model of ZEN-induced hepatic lipid accumulation (2.5, 5, 10 mg/kg/d b.w.,14 d, i.g.) to investigate the key targets of ZEN-induced hepatic lipid accumulation and to explore the potential link between ZEN exposure and NAFLD. Histological staining of rat liver showed that ZEN caused significant pathological changes and lipid accumulation; biochemical analysis showed that ZEN significantly and dose-dependently increased serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and disrupted the serum lipid profile in rats; proteomic analysis showed that ZEN significantly altered protein expression levels in rat liver, especially SOAT1, SOAT2, CYP1B1 and SCD1 (p < 0.05). Through bioinformatics analyses, we combined ZEN exposure with a database of NAFLD clinical samples to reveal that ZEN exposure may increase the risk of NAFLD through activation of the CYP1B1-SCD1 pathway, and further animal experiments confirmed this. This study identifies the key target of ZEN-induced lipid accumulation and provides a basis for further research on the intrinsic link between ZEN exposure and NAFLD.
{"title":"Zearalenone exposure may increase the risk of non-alcoholic fatty liver disease by activating CYP1B1-SCD1","authors":"Haonan Ruan , Jing Zhang , Yunyun Wang , Dan Zhang , Jiaoyang Luo , Meihua Yang","doi":"10.1016/j.crtox.2025.100277","DOIUrl":"10.1016/j.crtox.2025.100277","url":null,"abstract":"<div><div>Zearalenone (ZEN) is an oestrogen-like mycotoxin that widely contaminates food and feed worldwide. Current research suggests that ZEN causes liver injury by disrupting hepatic lipid metabolism. Furthermore, prolonged disturbances in hepatic lipid metabolism are believed to play a role in the progression of non-alcoholic fatty liver disease (NAFLD). However, the exact association between ZEN exposure and the development of NAFLD is unclear. In this study, we established a rat model of ZEN-induced hepatic lipid accumulation (2.5, 5, 10 mg/kg/d b.w.,14 d, i.g.) to investigate the key targets of ZEN-induced hepatic lipid accumulation and to explore the potential link between ZEN exposure and NAFLD. Histological staining of rat liver showed that ZEN caused significant pathological changes and lipid accumulation; biochemical analysis showed that ZEN significantly and dose-dependently increased serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and disrupted the serum lipid profile in rats; proteomic analysis showed that ZEN significantly altered protein expression levels in rat liver, especially SOAT1, SOAT2, CYP1B1 and SCD1 (p < 0.05). Through bioinformatics analyses, we combined ZEN exposure with a database of NAFLD clinical samples to reveal that ZEN exposure may increase the risk of NAFLD through activation of the CYP1B1-SCD1 pathway, and further animal experiments confirmed this. This study identifies the key target of ZEN-induced lipid accumulation and provides a basis for further research on the intrinsic link between ZEN exposure and NAFLD.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"10 ","pages":"Article 100277"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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