Toxicology最新文献

{"title":"KCNJ15 inhibits chemical-induced lung carcinogenesis and progression through GNB1 mediated Hippo pathway","authors":"Hong-qiang Chen ,&nbsp;Na Wang ,&nbsp;Yong Zeng ,&nbsp;Yu Shi ,&nbsp;Zhe Zhang ,&nbsp;Jiang-ying Li ,&nbsp;Ya-wen Li ,&nbsp;Shuang-wu Deng ,&nbsp;Zi-yuan Zhou ,&nbsp;Wen-bin Liu","doi":"10.1016/j.tox.2024.154034","DOIUrl":"10.1016/j.tox.2024.154034","url":null,"abstract":"<div><div>Polycyclic aromatic hydrocarbons (PAHs) are important environmental carcinogens that can cause lung cancer. However, the underlying epigenetic mechanism during PAHs-induced lung carcinogenesis has remained largely unknown. Previously, we screened some novel epigenetic regulatory genes during 3-methylcholanthrene (3-MCA)-induced lung carcinogenesis, including the potassium inwardly rectifying channel subfamily J member 15 (KCNJ15) gene. This study aimed to investigate the expression regulation, function, and mechanism of KCNJ15 through database analysis, malignant transformed cell model, and xenograft tumor models. We found that KCNJ15 was remarkably under-expressed during lung carcinogenesis and progression. High levels of DNA methylation led to low KCNJ15 expression in 3-MCA-induced malignantly transformed HBE cells. High expression of KCNJ15 was positively correlated with good survival prognosis in lung cancer patients. KCNJ15 overexpression significantly inhibited the growth, invasion, and migration of lung cancer cells both <em>in vitro</em> and <em>in vivo</em>. Knockdown of KCNJ15 resulted in an opposite phenotype. KCNJ15 regulated the Hippo pathway by activating YAP phosphorylation and inhibiting YAP expression. There was a significant protein-protein interaction between KCNJ15 and the G protein subunit beta 1 (GNB1). GNB1 overexpression effectively reduced the effect of KCNJ15 on Hippo pathway. Our data demonstrated that KCNJ15, as a novel epigenetic silencing tumor suppressor, regulates cell growth, invasion, and migration by interaction with GNB1 protein mediating the Hippo-YAP signaling pathway during chemical-induced lung carcinogenesis and progression. It provides novel insights into epigenetic regulation mechanism during carcinogenesis induced by environmental pollutants.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154034"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142898464","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":"EGFR-TKIs induce acneiform rash and xerosis via Caspase-3/GSDME-mediated pyroptosis of keratinocytes and sebocytes","authors":"Huiling Zhu ,&nbsp;Qiuyun She ,&nbsp;Hongmei Li ,&nbsp;Ning Zhang ,&nbsp;Weining Huang ,&nbsp;Yingping Xu ,&nbsp;Zhongrong Liu ,&nbsp;Yunsheng Liang","doi":"10.1016/j.tox.2024.154018","DOIUrl":"10.1016/j.tox.2024.154018","url":null,"abstract":"<div><div>Skin toxicities are the most common adverse effects of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). While EGFR-TKIs induce pyroptosis in lung cancer cells through Gasdermin E (GSDME) activation, it is unknown whether they can similarly affect skin cells. In this study, we used immunohistochemistry to demonstrate that in acneiform rash, the N-terminus of GSDME (GSDME-N) is predominantly expressed in the basal layer of the follicular epithelium and sebocytes, while it is absent in the interfollicular epidermis. In contrast, in cases of xerosis or secondary eczematous rash, GSDME-N was significantly expressed in the basal layer of the interfollicular epidermis and weakly or partially positive in the follicular epithelium. Bright-field microscopy of HaCaT and SZ95 cells treated with afatinib revealed cell swelling and large bubble formation, while scanning electron microscopy showed a reduction in microvilli and membrane pores formation. Transmission electron microscopy further revealed multiple membrane pores and decreased cytoplasmic density. Importantly, we found that GSDME is cleaved during afatinib-induced pyroptosis via caspase-3 activation. ELISA analysis further confirmed that afatinib-treated cells released elevated levels of HMGB1 and IL-1α. Meanwhile, inhibition of caspase-3 activity or knockdown of GSDME both suppressed afatinib-induced pyroptosis, while GSDME elimination did not affect caspase-3 activation. These results indicate that afatinib-induced pyroptosis in keratinocytes and sebocytes is mediated by the caspase-3/GSDME pathway. Our findings suggest that GSDME-dependent pyroptosis in HaCaT and SZ95 cells contributes to the development of acneiform rash and xerosis, highlighting the need for further investigation into the underlying mechanisms.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154018"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142751678","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":"Dynamic analysis of intrahepatic T cells reveals a unique group of restorative Cxcr3+ tissue-resident CD4 T cells in acute liver injury","authors":"Shen-Xi Ouyang ,&nbsp;Yong-Gang Xu ,&nbsp;Peng Ding ,&nbsp;Yue Long ,&nbsp;Zhen Zhang ,&nbsp;Si-Jia Sun ,&nbsp;Yan Zhang ,&nbsp;Hang Yin ,&nbsp;Jia-Bao Zhang ,&nbsp;Qi Cao ,&nbsp;Fu-Ming Shen ,&nbsp;Pei Wang ,&nbsp;Jian Liu ,&nbsp;Dong-Jie Li","doi":"10.1016/j.tox.2025.154058","DOIUrl":"10.1016/j.tox.2025.154058","url":null,"abstract":"<div><div>Acetaminophen (APAP) stands as one of the most prevalent triggers of drug-induced acute liver injury (ALI). The intricate modulation of immune system activation and inflammatory cascades by hepatic immune cells is paramount in managing liver injury and subsequent restoration. In this study, we employed an integrative approach that fused our proprietary flow cytometry analyses across various time points post-APAP injury with publicly available single-cell RNA sequencing (scRNA-seq) datasets, encompassing time-series data from liver tissue of mice subjected to APAP intoxication. This allowed us to delve into the dynamics of T cell profiles during APAP-induced ALI. Our comprehensive analyses unveiled the intricate temporal shifts in intrahepatic T cell populations across different phases following APAP-induced ALI. Notably, we observed a persistent augmentation of intrahepatic CD4⁺ T cells post-APAP injury. Amongst these, a distinct population of restorative <em>Cxcr3</em>⁺ tissue-resident CD4⁺ T cells emerged. Inhibition of CXCR3 using a neutralizing antibody exacerbated APAP-induced liver function impairment and hepatocyte death. Furthermore, we identified that the <em>Cxcr3</em>⁺ tissue-resident CD4⁺ T cells were tightly regulated by intrahepatic ‘'Lgals9-Cd45'’ and ‘CXCL13-Cxcr3’ signaling pathways. These discoveries underscore the novel protective function of CXCR3, a vital biological macromolecule, in mitigating APAP-induced ALI, and may shed lights on new therapeutic strategies targeting this condition.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154058"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143011532","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":"Integrative assessment of mixture toxicity of household chemicals using the toxic unit approach and mode of action","authors":"Hye-Jin Jeong ,&nbsp;Yeon-Ho Kang ,&nbsp;Ah-Yoon Song ,&nbsp;Hye-In Park ,&nbsp;Myungwon Seo ,&nbsp;Yong Joo Park","doi":"10.1016/j.tox.2025.154060","DOIUrl":"10.1016/j.tox.2025.154060","url":null,"abstract":"<div><div>Household chemicals used daily are often combined, leading to inhalation exposure to mixtures. However, methods for assessing their toxic effects are limited. This study proposes an <em>in vitro</em> assay strategy for evaluating household chemical mixtures using benzalkonium chloride (BKC) and didecyldimethylammonium chloride (DDAC), a common disinfectant. Our approach utilizes the mode of action (MOA) of chemicals by applying toxicity units (TU) to assess the key events related to lung disease, such as reactive oxygen species (ROS) production and cell death. The TU (EC₅₀) values for BKC and DDAC were 3.97 µg/mL and 1.89 µg/mL, respectively, from cytotoxicity results. The TU value of the mixture (5:5 ratio of BKC to DDAC) was calculated as 2.56 µg/mL. Using the OpenMRA platform, the TU values were predicted as 2.37 µg/mL with the concentration addition (CA) model and 11.26 µg/mL with the independent action (IA) model, indicating that the mixture effects were additive and closer to that predicted using the CA model. Both BKC and DDAC induced apoptosis and ROS production in human epithelial cells in a dose-dependent manner, suggesting similar modes of action in promoting cell death. Our results suggested that BKC and DDAC exhibited additive toxicity when combined. Our results demonstrate the utility of the TU-based approach, which combines cytotoxicity, ROS induction, and apoptosis measurements to evaluate mixture toxicity. This approach may be beneficial for assessing early key events relevant to lung diseases and offers a practical strategy for evaluating the inhalation toxicity of household chemical mixtures.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154060"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143011542","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":"Microplastics/nanoplastics and neurological health: An overview of neurological defects and mechanisms","authors":"Junjie Sun ,&nbsp;Siwan Peng ,&nbsp;Qiongxia Yang ,&nbsp;Jiawei Yang ,&nbsp;Yanfei Dai ,&nbsp;Lingyan Xing","doi":"10.1016/j.tox.2024.154030","DOIUrl":"10.1016/j.tox.2024.154030","url":null,"abstract":"<div><div>The widespread use of plastic products worldwide has brought about serious environmental issues. In natural environments, it’s difficult for plastic products to degrade completely, and so they exist in the form of micro/nanoplastics (M/NPs), which have become a new type of pollutant. Prolonged exposure to M/NPs can lead to a series of health problems in humans, particularly toxicity to the nervous system, with consequences including neurodevelopmental abnormalities, neuronal death, neurological inflammation, and neurodegenerative diseases. Although direct evidence from humans is still limited, model organisms and organoids serve as powerful tools to provide important insights. This article summarizes the effects of M/NPs on the nervous system, focusing on cognitive function, neural development, and neuronal death. Mechanisms such as neurotransmitter synthesis and release, inflammatory responses, oxidative stress, the gut-brain axis, and the liver-brain axis are covered. The neurotoxicity induced by M/NPs may exacerbate or directly trigger neurodegenerative diseases and neurodevelopmental disorders. We particularly emphasize potential therapeutic agents that may counteract the neurotoxic effects induced by M/NPs, highlighting a novel future research direction. In summary, this paper cites evidence and provides mechanistic perspectives on the effects of M/NPs on neurological health, providing clues for eliminating M/NP hazards to human health in the future.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154030"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142802147","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":"Teratological, neurochemical and histomorphic changes in the limbic areas of F1 mice progeny due to co-parental polystyrene nanoplastic exposure","authors":"Manjyot Kaur,&nbsp;Anju Sharma,&nbsp;Kirti Sharma,&nbsp;Placheril John,&nbsp;Pradeep Bhatnagar","doi":"10.1016/j.tox.2024.154043","DOIUrl":"10.1016/j.tox.2024.154043","url":null,"abstract":"<div><div>In the present study, co-parental exposure to polystyrene nanoplastics (PS-NPs) elicits profound teratological impacts, including skeletal and visceral malformations, post-natal effects on neonatal growth and neurobehavioral development in F1 progeny. A comprehensive investigation was conducted on Swiss albino mice fetuses, neonates (PND 1–21) and adult mice offsprings (PND 60) following parental exposure during spermatogenesis and oogenesis period, as well as continued maternal exposure during gestation and weaning. The parental mice were administered PS-NPs via oral gavage at low dose (0.2 mg/kg/day) and high dose (1 mg/kg/day). Both male and female parental mice were exposed to PS-NPs for 60 days and 14 days, respectively before mating. After the mating, the pregnant female mice continued to receive PS-NPs treatment during the gestation, till the subsequent weaning period. Our findings revealed that PS-NPs led to significant reductions in growth, and heightened skeletal and visceral anomalies in developing fetuses. Exposure further impaired reflexes in neonatal mice such as grasping, surface righting and negative geotaxis. Moreover, the adult progeny also exhibited learning impairments. Neurodevelopmental assessment unveiled alterations in neurotransmitter levels, antioxidant enzyme activities, and structural changes in key limbic areas such as the cortex, hippocampus, and hypothalamus of adult mice offspring. These alterations included increased vacuolization, vascular dilation, and reduced pyramidal neurons in the hippocampus. Thus, this transgenerational study underscores the detrimental effects of PS-NPs on both prenatal and postnatal development, emphasizing teratological and enduring neurological consequences in the limbic regions of F1 progeny mice brains.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154043"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142923373","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":"Assessing the impact of TiO2 nanomaterials on intestinal cells: New evidence for epithelial translocation and potential pro-inflammatory effects","authors":"Dora Rolo ,&nbsp;Joana F.S. Pereira ,&nbsp;Lídia Gonçalves ,&nbsp;Ana Bettencourt ,&nbsp;Peter Jordan ,&nbsp;Maria João Silva ,&nbsp;Paulo Matos ,&nbsp;Henriqueta Louro","doi":"10.1016/j.tox.2025.154066","DOIUrl":"10.1016/j.tox.2025.154066","url":null,"abstract":"<div><div>Understanding the potential impact of nanomaterials (NMs) on human health requires further investigation into the organ-specific nano-bio interplay at the cellular and molecular levels. We showed increased chromosomal damage in intestinal cells exposed to some of <em>in vitro</em> digested Titanium dioxide (TiO₂) NMs. The present study aimed to explore possible mechanisms linked to the uptake, epithelial barrier integrity, cellular trafficking, as well as activation of pro-inflammatory pathways, after exposure to three TiO₂-NMs (NM-102, NM-103, and NM-105).</div><div>Using confocal microscopy, we show that all NMs, digested or not, were able to enter different types of intestinal cells. At the physiologically relevant concentration of 14 µg/mL, the digested TiO₂-NMs did not compromise the transepithelial resistance, nor the levels of epithelial markers E-cadherin and Zonula occludens protein 1 (ZO-1), of polarized enterocyte monolayers. Nonetheless, all NMs were internalized by intestinal cells and, while NM-102 was retained in lysosomes, NM-103 and NM-105 were able to transverse the epithelial barrier through transcytosis. Moreover, 24 h exposure of 14 and 1.4 μg/mL digested NM-105, promoted interleukin IL-1β expression in activated M1 macrophages, indicating a potential pro-inflammatory action in the gut.</div><div>Taken together, our findings shed light on the cell-specific nano-bio interplay of TiO₂-NMs in the context of the intestinal tract and highlight transcytosis as a potential gateway for their systemic distribution. The potential pro-inflammatory action of digested NM-105 emphasizes the importance of pursuing research into the potential impact of NMs on human health and contribute to the weight of evidence to limit their use in food.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154066"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143053768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Health impacts of PM2.5 emissions from brake pad wear: A comprehensive study on pulmonary, metabolic, and microbiota alterations","authors":"Li Zhou ,&nbsp;Chenchen Song ,&nbsp;Yuhan Lei ,&nbsp;Lianlian Zhao ,&nbsp;Yunlin Han ,&nbsp;Yanfeng Xu ,&nbsp;Baicun Li ,&nbsp;Jianguo Guo","doi":"10.1016/j.tox.2025.154055","DOIUrl":"10.1016/j.tox.2025.154055","url":null,"abstract":"<div><div>The environmental impact of harmful particles from tire and brake systems is a growing concern. This study investigated the health impacts of PM_2.5 emissions from brake pad wear on adult C57BL/6 mice. The mice were exposed to brake pad particles via intratracheal infusion, and various health parameters were assessed. The results showed that brake pad particle exposure significantly reduced lung function parameters such as tidal volume, peak expiratory time ratio, and peak inspiratory flow rate, while increasing the apnea index and airway stenosis index. Histological analysis revealed particle deposition, inflammatory damage, and potential fibrosis in the lungs. Additionally, inflammatory markers and fibrosis indicators were elevated in the lung tissue. Metabolomic analysis indicated changes in metabolites related to purine metabolism, protein digestion, nucleic acid metabolism, and pathways involving Caffeine, Xanthine, Inosine, and others. Gut microbiota analysis showed increased abundance of Odoribacter and Tuzzerella, and decreased abundance of Desulfovibrio and Butyricimonas. Correlation analysis further suggested a significant link between the abundance of Odoribacter and plasma metabolic changes. Overall, this study underscores the health risks associated with brake dust pollution, particularly its adverse effects on lung function and induction of lung damage and fibrosis.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154055"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984821","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":"An ex vivo model of systemically-mediated effects of ozone inhalation on the brain","authors":"Mercedes Rose ,&nbsp;Errol M. Thomson","doi":"10.1016/j.tox.2025.154052","DOIUrl":"10.1016/j.tox.2025.154052","url":null,"abstract":"<div><div>Air pollution is associated with increased risk of neurodegenerative and neuropsychiatric conditions. While animal models have increased our understanding of how air pollution contributes to brain pathologies – including through oxidative stress, inflammatory, and stress hormone pathways – investigation of underlying mechanisms remains limited due to a lack of human-relevant models that incorporate systemic processes. Our objective was to establish an <em>ex vivo</em> approach that enables assessment of the roles of plasma mediators in pollutant-induced effects in the brain. As a proof-of-concept for application in the human context, we assessed whether such effects reproduced <em>in vivo</em> responses to pollutant exposure. Primary rat hippocampal neurons and microglia were each treated with plasma collected from rats immediately or 24 h after ozone inhalation (0 or 0.8 ppm) ± pre-treatment with the glucocorticoid synthesis inhibitor metyrapone. Microglia were further challenged with lipopolysaccharide to evaluate modification of inflammatory responses. Plasma from the ozone-exposed group produced transcriptional changes (inflammatory, antioxidant, glucocorticoid-responsive) in neurons, some of which were glucocorticoid-dependent. <em>Ex vivo</em> and hippocampal responses were strongly correlated, establishing the <em>in vivo</em> relevance of the model. Plasma from the ozone-exposed group modified inflammatory responses to lipopolysaccharide challenge in microglia, demonstrating the model’s utility to assess functional changes resulting from pollutant exposure. This study establishes that an <em>ex vivo</em> approach can reproduce ozone-induced effects in the brain. The model was sensitive to specific plasma mediators and temporal effects, and enabled assessment of functional responses. This approach may serve to investigate mechanisms underlying effects of pollutants on the human brain.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154052"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disruption of serotonin homeostasis in intestinal organoids provides insights into drug-induced gastrointestinal toxicity","authors":"Georgia M. Rouseti ,&nbsp;Audrey Fischer ,&nbsp;Nicole Rathfelder ,&nbsp;Karen Grimes ,&nbsp;Annick Waldt ,&nbsp;Rachel Cuttat ,&nbsp;Sven Schuierer ,&nbsp;Sophia Wild ,&nbsp;Magali Jivkov ,&nbsp;Valerie Dubost ,&nbsp;Heiko S. Schadt ,&nbsp;Alex Odermatt ,&nbsp;Axel Vicart ,&nbsp;Francesca Moretti","doi":"10.1016/j.tox.2024.154028","DOIUrl":"10.1016/j.tox.2024.154028","url":null,"abstract":"<div><div>Drug-induced gastrointestinal toxicity is a frequent clinical adverse event that needs to be carefully monitored and managed to ensure patient compliance. While preclinical assessment of drug-induced gastrointestinal toxicity mostly relies on animal experimentation, intestinal organoids have gained increasing attention to identify gastrointestinal toxicants <em>in vitro</em>. Nonetheless, current <em>in vitro</em> protocols primarily assess structural alterations induced by drugs, whereas gastrointestinal adverse events can often stem from functional disturbances. Disruption of serotonin signaling in the gastrointestinal tract is associated with impaired motility, as well as nausea and vomiting. We aimed to investigate alterations of serotonin homeostasis in organoids derived from the canine small intestine as a driver of drug-induced gastrointestinal toxicity. Treatment of the organoids with a compound (NVS-1) inducing acute gastrointestinal toxicity in dogs as well as with three tyrosine kinase inhibitors with known preclinical and clinical gastrointestinal adverse effects (afatinib, crizotinib and vandetanib) led to increased supernatant serotonin levels. Mechanistic assays showed that, while NVS-1 and afatinib stimulate serotonin release, crizotinib and vandetanib inhibit serotonin re-uptake via direct inhibition of the serotonin re-uptake transporter. Using a data mining approach, we further suggest that inhibition of serotonin re-uptake could contribute to gastrointestinal toxicity observed with multiple marketed drugs. In conclusion, we present the implementation of a novel <em>in vitro</em> gastrointestinal toxicity endpoint that could complement current methods and serve as a mechanistic and predictive/screening tool for drug-induced gastrointestinal toxicity.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154028"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}