Chemico-Biological Interactions最新文献

{"title":"Prenatal caffeine exposure contributes to adrenal dysfunction of progeny for sex-specific and its 11β-hydroxysteroid dehydrogenase system intrauterine programming mechanism","authors":"Guanghui Chen ,&nbsp;Yawen Chen ,&nbsp;Can Ai ,&nbsp;Li Bin ,&nbsp;Hui Wang","doi":"10.1016/j.cbi.2025.111625","DOIUrl":"10.1016/j.cbi.2025.111625","url":null,"abstract":"<div><div>Our previous study has confirmed that the occurrence of fetal-originated disease is related to the changes in the developmental programming of adrenal in offspring. The aim of this study was to investigate the effects of prenatal caffeine exposure (PCE) on adrenal developmental programming in offspring rats and the underlying mechanisms. Here, PCE inhibited adrenal morphology and steroidogenic function in female and male offspring, and the suppression persisted in female offspring up to postnatal week 28 (PW28), while no significant changes in male offspring. Besides, adrenal 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) expression was consistently decreased from intrauterine to PW28 in PCE female offspring, while it was decreased in male fetal offspring without significant change in PW28. Meanwhile, the adrenal 11β-HSD2 expression in PCE female offspring was positively correlated with developmental parameters. To explore its intrauterine origin, we found that PCE could elevate serum corticosterone levels in fetal rats. At the cellular level, high concentration of cortisol could inhibit 11β-HSD2 expression, and 11β-HSD2 overexpression could reverse the inhibition of steroidogenesis induced by cortisol. Further, we confirmed the epigenetic mechanism of the reduced adrenal 11β-HSD2 expression in PCE female offspring. On the one hand, high level of intrauterine glucocorticoid induced by PCE could lead to the decrease of H3K14ac level and expression of 11β-HSD2 through GR/HDAC4 pathway, which could last until birth. On the other hand, caffeine could decrease 11β-HSD2 expression through A2AR/cAMP/PKA signal, which synergistically enhanced the inhibitory effect of corticosterone on H3K14ac level and expression of 11β-HSD2. In conclusion, PCE could cause adrenal hypoplasia in female offspring, which was related to the low functional programming of 11β-HSD2 caused by the combination of high levels of glucocorticoids and caffeine.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"419 ","pages":"Article 111625"},"PeriodicalIF":4.7,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144604948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating podophyllotoxin-induced cardiotoxicity in rats by Toxicological Evidence Chain (TEC): Focus on the Akt1/Srebp-1c/PUFAs axis","authors":"Chuanxin Liu ,&nbsp;Jiao Kong ,&nbsp;Yali Lai ,&nbsp;Yongchun Zhang ,&nbsp;Ying Li ,&nbsp;Jiangnan Du ,&nbsp;Lu Sun ,&nbsp;Yue Tian","doi":"10.1016/j.cbi.2025.111634","DOIUrl":"10.1016/j.cbi.2025.111634","url":null,"abstract":"<div><div>Podophyllotoxin, an efficacious constituent derived from the traditional Chinese medicine <em>Dysosma versipellis</em>, exhibits antitumor properties; however, its toxicity limits clinical application. This study, based on the Toxicological Evidence Chain (TEC), employs metabolomics and lipidomics approaches to investigate the mechanisms underlying its cardiotoxicity. Injury phenotype evidence (IPE) was obtained through observation of the rats’ external phenotypes, including coat condition, body weight, fecal characteristics, mental status, and presence of bleeding. Cardiac enzyme levels, blood lipid profiles, and histopathological examinations of heart tissues were assessed as evidence of adverse outcomes (AOE). To obtain evidence of toxic events, an integrated analysis of metabolomics, lipidomics, network toxicology was conducted on rat serum and heart tissues and molecular biology experiments in vitro, revealing the mechanism of PPT-induced cardiotoxicity. The results indicated that PPT induced pathological changes in rats, including weight loss, dull and brittle fur, and lethargy, along with nasal bleeding and diarrhea. The levels of AST, TC, and LDL-C were significantly elevated, while TG and HDL-C showed significant decreases. Integrated metabolomics analysis revealed 21 significantly altered differential metabolites demonstrating concordant directional changes across both serum and cardiac tissues. Complementary lipidomics profiling identified 31 dysregulated lipid species with coordinated variations in both biological matrices. These perturbed metabolites were principally associated with the core metabolic pathways: synthesis and metabolism of unsaturated fatty acid lipids. Network toxicology predictions identified Akt1, Egfr, Mtor, and Nos3 as potential critical molecular targets of PPT. In vitro experiments show that targeting the Akt1/Rebp-1c axis with PPT induces oxidative stress and cell death in cardiomyocytes, which can be mitigated by unsaturated fatty acids. This discovery offers a new approach for using PPT in clinical settings, potentially reducing its cardiotoxicity by administering unsaturated fatty acid simultaneously.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"419 ","pages":"Article 111634"},"PeriodicalIF":4.7,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144621592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quo vadis human biomonitoring?","authors":"Gabriele Sabbioni","doi":"10.1016/j.cbi.2025.111643","DOIUrl":"10.1016/j.cbi.2025.111643","url":null,"abstract":"<div><div>The increasing presence of chemicals in commerce and their potential impacts on human and environmental health necessitate innovative approaches in exposure science, biomonitoring, and risk assessment. With over 450,000 synthetic chemicals currently in use and growing concerns about their ecological and human health effects, prioritizing chemicals for environmental risk assessment remains a critical objective. This review examines recent advancements in chemical prioritization, predictive toxicology, genomic databases, and biomonitoring techniques for evaluating health effects associated with chemical exposure. The significant progress achieved in recent years offers new opportunities for more comprehensive analyses of key factors influencing health outcomes.</div><div>Currently, fewer than 1000 chemicals have been analyzed in environmental studies, and fewer than 450 chemicals have been assessed in biomonitoring studies. This limited number constrains the ability to fully characterize real-world exposures and their potential health implications. Urinary biomarkers are frequently utilized in biomonitoring research, yet their interpretation remains complex due to the high intra-individual variability of non-persistent chemicals. As a result, single-sample assessments may not always provide an accurate representation of chronic exposure levels, underscoring the importance of refining biomonitoring methodologies to strengthen the reliability of exposure-health associations.</div><div>While biomonitoring effectively detects low-level exposures, linking these values to specific health outcomes is complex due to interactions between exposure, genetics, environmental factors, and individual health status. Furthermore, for many chronic diseases, long latency periods complicate direct exposure-disease correlations.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"419 ","pages":"Article 111643"},"PeriodicalIF":4.7,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144621594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exposure-response analysis of recent epidemiological data: Proposed risk based occupational exposure limits for various mineral types of asbestos","authors":"Michael E. Stevens ,&nbsp;Dennis J. Paustenbach ,&nbsp;Andrey Korchevskiy","doi":"10.1016/j.cbi.2025.111645","DOIUrl":"10.1016/j.cbi.2025.111645","url":null,"abstract":"<div><div>During the last few decades, numerous studies have investigated the incidence of mesothelioma among asbestos-exposed populations. Despite significant differences in the potency of various asbestos fiber types to cause mesothelioma, fiber-specific occupational exposure limits (OELs) based on these data are not available. This paper uses results from 14 epidemiological studies to model the exposure-response for fibers, estimate benchmark doses, and propose fiber-specific OELs. Extrapolation of these benchmark doses suggests that the cumulative lifetime exposure (i.e., dose) that corresponds to a theoretical 1 in 1000 risk of mesothelioma death (pleural and peritoneal combined) were approximately 0.3, 2, 10, and 100 f/cc-years for crocidolite, amosite, textile chrysotile, and non-textile chrysotile fibers, respectively. While the proposed estimates are expected to overpredict the risk, they can serve as conservative values to protect the health of workers potentially exposed to commercial asbestos. From this, we propose occupational exposure limits of 0.01, 0.05, 0.2, and 2 f/cc for each mineral type (crocidolite, amosite, textile chrysotile, and non-textile chrysotile fibers), respectively. To the best of our knowledge, this is the first proposal for separate occupational exposure limits based on the epidemiology of each mineral type of fibers since the ACGIH made such a proposal in 1978.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"419 ","pages":"Article 111645"},"PeriodicalIF":4.7,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144610611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Some new aspects of erastin-induced ferroptosis in cancer cells","authors":"P. Mlejnek ,&nbsp;K. Kikalova ,&nbsp;P. Jakubec ,&nbsp;H. Kartusakova ,&nbsp;P. Dolezel","doi":"10.1016/j.cbi.2025.111632","DOIUrl":"10.1016/j.cbi.2025.111632","url":null,"abstract":"<div><div>Ferroptosis, a form of regulated cell death (RCD) with unique morphological and biochemical features, has potential in cancer treatment. In this study, erastin (ER)-induced ferroptosis was investigated in cancer cell lines A549, Calu1, and K562. A detailed analysis of the Xc^–/GSH/GPX4 axis showed that glutathione (GSH) production, unlike GPX4 expression, is an important factor in influencing the sensitivity of tumor cells to ER despite oncogenic <em>KRAS</em> expression. Here we show for the first time that ferroptosis is associated with marked condensation of cell nuclei, a morphological change that was previously associated exclusively with apoptosis. Importantly, this phenomenon was observed in all three cell lines. Further, thiourea (TU), a known scavenger of reactive oxygen species (ROS) had a complex effect on ER induced ferroptosis. While TU significantly potentiated ER cytotoxicity and changed the mode of cell death from ferroptotic to apoptotic in A549 and K562 cells, it had a mild protective effect in Calu1 cells without changing the mode of cell death. In conclusion, the results show that Xc^–-dependent GHS production affects the sensitivity of oncogenic <em>RAS</em>-expressing tumor cells to ER treatment. ER-induced ferroptosis is associated with nuclear condensation. Further, we identified TU as a compound that can change the form of cell death from ferroptotic to apoptotic in some cancer cells. The latter two findings suggest a previously uncovered proximity of the regulatory pathways of ferroptosis and apoptosis.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"419 ","pages":"Article 111632"},"PeriodicalIF":4.7,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144585783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Esculin exerts Nrf2-mediated antioxidant response in DrF cell lines and zebrafish larvae","authors":"Srija Babu ,&nbsp;Ekambaram Perumal ,&nbsp;Mithra Sivaraj ,&nbsp;Seepoo Abdul Majeed ,&nbsp;Azeez Sait Sahul Hameed","doi":"10.1016/j.cbi.2025.111638","DOIUrl":"10.1016/j.cbi.2025.111638","url":null,"abstract":"<div><div>Nuclear factor E2-related factor 2 (Nrf2) plays a major role in cellular defense by regulating antioxidant response element (ARE)-driven genes in response to oxidative stress. The present study aimed to identify and validate AREs throughout the zebrafish genome in response to Esculin (ESC). <em>Danio rerio</em> fin (DrF) cell lines were treated with ESC and the positive control, sulforaphane (SFN) to assess cytotoxicity and Nrf2 activation. Cytotoxicity was measured using MTT and Alamar Blue assays. Nrf2-mediated ARE activation was analyzed using immunofluorescence and luciferase reporter assays. In addition, Chromatin immunoprecipitation sequencing (ChIP-Seq) was employed to identify Nrf2 binding sites in the genome of the zebrafish larvae, while qRT-PCR and ChIP-qPCR were used to validate Nrf2 binding to specific AREs in annotated genes. ESC treatment, similar to SFN, significantly increased Nrf2 expression and ARE-driven luciferase activity, confirming activation of the Nrf2-ARE pathway. ChIP-Seq analysis in ESC-treated zebrafish larvae revealed Nrf2 binding sites at various genomic regions, with few AREs near the proximal promoters. qRT-PCR further validated the upregulation of key genes, including <em>ash1</em> and <em>arhgef1a</em> in treated larvae, suggesting direct regulation by Nrf2. In conclusion, our findings confirmed that ESC effectively activates Nrf2 via ARE-mediated mechanisms in 3 dpf zebrafish larvae. These findings provide valuable insights into the conserved mechanism of Nrf2 in vertebrates and serve as a therapeutic option in oxidative-stress-mediated conditions.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"419 ","pages":"Article 111638"},"PeriodicalIF":4.7,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144577242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polystyrene microplastics disrupt kidney organoid development via oxidative stress and Bcl-2/Bax/caspase pathway","authors":"Anxiu Zhang ,&nbsp;Yujiao Wang ,&nbsp;Qunhang Xue ,&nbsp;Jiaxin Yao ,&nbsp;Long Chen ,&nbsp;Shuqi Feng ,&nbsp;Juan Shao ,&nbsp;Zhongyuan Guo ,&nbsp;Bingrui Zhou ,&nbsp;Jun Xie","doi":"10.1016/j.cbi.2025.111642","DOIUrl":"10.1016/j.cbi.2025.111642","url":null,"abstract":"<div><div>Microplastics (MPs), particularly polystyrene microplastics (PS-MPs), have emerged as significant environmental pollutants with potential risks to human health. Their presence has been detected in human tissues, including blood and placental tissue, raising concerns about developmental effects. However, MPs’ effects on the development of human organs are still mostly unknown. The kidney is essential to detoxification and waste excretion in the body and is highly sensitive to toxic substances, making it an important focus for research on toxicity. To study kidney development, human induced pluripotent stem cell (hiPSC)-derived kidney organoids offer a useful in vitro model. This research specifically examines the consequences of PS-MPs on the differentiation of hiPSCs into kidney organoids. Different concentrations of PS-MPs (0, 1.25, 2.5, 5, 10, 20 μg/mL) were set according to the concentration of PS-MPs detected in blood at 1.6 μg/mL. The aim is to understand how environmental contaminants may impact kidney development at the cellular level. Our findings indicate that PS-MP exposure leads to nephron progenitor cell damage and disrupts key processes involved in kidney development, including nephron formation and epithelial cell differentiation. Mechanistically, we demonstrate that PS-MPs induce mitochondrial oxidative stress, activate the Bcl-2 protein family, and trigger apoptosis via the Bcl-2/Bax/caspase-9/caspase-3 signaling pathway. This disruption ultimately impairs normal kidney organoid formation. These results underscore the detrimental impact of PS-MPs on embryonic kidney development and highlight the urgent need for further investigation into the health risks associated with microplastic exposure during early human development.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"419 ","pages":"Article 111642"},"PeriodicalIF":4.7,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144577244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic study of pexidartinib-induced toxicity in human hepatic cells","authors":"Si Chen ,&nbsp;Yuxi Li ,&nbsp;Xilin Li ,&nbsp;Nan Mei ,&nbsp;Xiaobo He ,&nbsp;Matthew S. Bryant ,&nbsp;Xuan Qin ,&nbsp;Feng Li ,&nbsp;Lei Guo","doi":"10.1016/j.cbi.2025.111641","DOIUrl":"10.1016/j.cbi.2025.111641","url":null,"abstract":"<div><div>Pexidartinib, a tyrosine kinase inhibitor, was approved by the U.S. Food and Drug Administration in 2019 for treating adult patients with symptomatic tenosynovial giant cell tumors. Because of its hepatotoxicity risks, pexidartinib received a boxed warning; however, mechanistic studies on this hepatotoxicity remain limited. In this study, we demonstrate that pexidartinib decreases cell viability in primary human hepatocytes and hepatic HepG2 cells. A 24-h treatment with pexidartinib led to apoptosis in HepG2 cells, as evidenced by increased caspase 3/7 activity and the induction of cleaved PARP and γ-H2A.X. Pexidartinib-induced endoplasmic reticulum (ER) stress was observed at early time points of 2 h and 5 h. The ER stress inhibitor 4-phenylbutyrate (4-PBA) partially attenuated pexidartinib-induced cytotoxicity. Additionally, mitochondrial dysfunction caused by pexidartinib was indicated by a strong inhibition of mitochondrial respiratory complexes II, IV, and V, a loss of mitochondrial potential, and greater toxicity in galactose media compared to glucose media. Pexidartinib also induced autophagy, as demonstrated by the formation of autophagosomes and autophagic flux. We investigated the role of cytochrome P450 (CYP)-mediated metabolism in pexidartinib-induced cytotoxicity by using HepG2 cell lines engineered to express 14 individual CYPs. The results indicated that CYP1A1, 2C9, 3A4, and 3A5 were involved in pexidartinib metabolism. Inhibition of CYP1A1, 2C9, and 3A4/5 significantly increased pexidartinib-induced cytotoxicity in primary human hepatocytes. Collectively, these data suggest that pexidartinib induced apoptosis, ER stress, mitochondria dysfunction, and autophagy in hepatic cells, and CYPs-mediated metabolism played a protective role in reducing pexidartinib toxicity.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"419 ","pages":"Article 111641"},"PeriodicalIF":4.7,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural iridoid glycosides, a treasure for drug candidates against type 2 diabetes mellitus pathogenesis","authors":"Tengjiao Zhao ,&nbsp;Yuanhai Sun ,&nbsp;Jelena Popović-Đorđević ,&nbsp;Wonnam Kim ,&nbsp;Hanbing Li","doi":"10.1016/j.cbi.2025.111636","DOIUrl":"10.1016/j.cbi.2025.111636","url":null,"abstract":"<div><div>In recent years, type 2 diabetes mellitus (T2DM) has become a global epidemic due to unhealthy lifestyles and genetic heritage. It is widely believed that the pathogenesis of T2DM involves numerous pathological factors including impaired insulin signaling, lipotoxicity, amyloid protein deposition, oxidative stress, and so forth. Although many drugs have been approved, unmet clinical needs should be paid attention to. A variety of iridoid glycosides have been found to possess strong protective effects upon impaired pancreatic function and peripheral insulin resistance. This review summarizes the effects of iridoid glycosides upon T2DM and potential mechanisms, discusses their structure-activity relationship, and analyzes issues hindering further development of iridoid glycosides and their derivatives, thus providing future options for searching and developing drug candidates against diabetes and related diseases.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"419 ","pages":"Article 111636"},"PeriodicalIF":4.7,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developmental toxicity and transcriptome analysis of zebrafish (Danio rerio) embryos exposed to anesthetic esketamine","authors":"Jiao Wang ,&nbsp;Ying Zhang ,&nbsp;Ying Liu ,&nbsp;Zeling You ,&nbsp;Jiaolong Huang ,&nbsp;Kai Lian ,&nbsp;Peng Duan ,&nbsp;Qi Jiang","doi":"10.1016/j.cbi.2025.111633","DOIUrl":"10.1016/j.cbi.2025.111633","url":null,"abstract":"<div><div>Esketamine (ESK), a novel intravenous general anesthetic, extensively utilized in obstetric and pediatric anesthesia. However, the potential <em>in vivo</em> toxicity of ESK to growth and development has not been comprehensively evaluated. In this study, we employed a zebrafish model to investigate the developmental toxicity and behavioral alterations induced by ESK in zebrafish embryos. Based on the 24-h lethal concentration 50 % (LC₅₀) value of 271.9 μg/mL, fertilized embryos were exposed to ESK at concentrations of 50, 100, 150, 200, and 250 μg/mL for a duration of 24 h (from 2 to 26 h post-fertilization). The findings indicated that ESK exposure resulted in delayed hatching, increased mortality, and elevated malformation rates. Developmental anomalies, such as reduced body length, delayed yolk absorption, decreased heart rate, and an increased distance between the sinus venosus and bulbus arteriosus (SV-BA) were observed in zebrafish embryos and larvae following ESK exposure. Moreover, Exposure to ESK resulted in notable behavioral alterations, including decreased movement distance and average speed at 96 h post-fertilization (hpf). Histopathological analyses further demonstrated impaired brain development. RNA sequencing data revealed significant disruptions in the cell cycle, neuroactive ligand-receptor interaction, adrenergic signaling in cardiomyocytes, and calcium signaling pathways. These findings indicate that ESK induces both cardiotoxicity and neurotoxicity in zebrafish larvae. This study elucidates the potential mechanisms underlying the developmental toxic effects of embryonic exposure to ESK in zebrafish larvae, offering valuable insights for ecological risk assessment and potential implications for human health.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"419 ","pages":"Article 111633"},"PeriodicalIF":4.7,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}