Toxicology最新文献

{"title":"Bioinformatics identification of shared signaling pathways and core targets linking Benzo[a]pyrene exposure to HCC progression","authors":"Yong-Le Li ,&nbsp;Rong He ,&nbsp;Meng Tang ,&nbsp;Jing-Yi Lan ,&nbsp;Guo-Yang Liu ,&nbsp;Li-He Jiang","doi":"10.1016/j.tox.2025.154129","DOIUrl":"10.1016/j.tox.2025.154129","url":null,"abstract":"<div><div>With the increasing prevalence of environmental pollutants, there is growing concern about the potential effects of these substances in major diseases such as liver cancer. Previous studies have suggested that various chemicals, such as benzo[<em>a</em>]pyrene(BaP), produced by burning carbon containing fuels, may negatively affect liver health, but the exact mechanisms remain unclear. This study aimed to explore the potential molecular mechanisms of BaP in the progression of liver cancer. Through an exhaustive study of databases such as ChEMBL, SwissTargetPrediction, STITCH and TCGA, we identified 169 potential targets that are closely related to BaP and liver cancer. Next, we conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses using the clusterProfiler package to study the biological functions and important pathways of potential targets induced by BaP, which showed that these targets were associated with mitochondrial function, cellular energy metabolism and REDOX reactions. The protein interaction (PPI) network was constructed using the STRING database and Cytoscape software to identify the core targets UBA52, NDUFS8, CYP1A2, NDUFS1 and CYP3A4. The interaction between BaP and these core proteins was further analyzed via molecular docking using the CB-Dock2 database, demonstrating high binding stability, which suggests their critical role in BaP-induced hepatocellular carcinoma (HCC) toxicity. Subsequently, we found significant differences in the expression of five core genes (UBA52, NDUFS8, CYP1A2, NDUFS1, CYP3A4) in HCC, and significant correlation between UBA52, NDUFS8 and CYP3A4 and survival of HCC patients. Single-cell sequencing analysis showed that the expression of UBA52 gene was particularly pronounced in the three immune cells.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"514 ","pages":"Article 154129"},"PeriodicalIF":4.8,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143737923","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":"Dicyclohexyl phthalate derails trophoblast function and lipid metabolism through NDRG1 by targeting PPARα:RXRα","authors":"Yu Zhang ,&nbsp;Yanqing Geng ,&nbsp;Yan Zhang ,&nbsp;Yidan Ma ,&nbsp;Xin Yin ,&nbsp;Zhuxiu Chen ,&nbsp;Xinyi Mu ,&nbsp;Rufei Gao ,&nbsp;Xuemei Chen ,&nbsp;Fangfang Li ,&nbsp;Junlin He","doi":"10.1016/j.tox.2025.154124","DOIUrl":"10.1016/j.tox.2025.154124","url":null,"abstract":"<div><div>Phthalates (PAEs) can impair trophoblast cell and subsequent placental development, adversely affecting pregnancy. The effects of dicyclohexyl phthalate (DCHP), the main PAE homologue in urban household dust, on trophoblast function and placental development are unknown. In this study, we investigated the effects and potential mechanisms of DCHP on trophoblast function and placental development by constructing in vitro trophoblast (10, 20, 30 μM) and in vivo mouse pregnancy (25, 50, 100 mg/kg bw) exposure models. We found that exposure to DCHP during pregnancy led to the accumulation of placental lipid droplets and foetal weight gain. Consistently, DCHP induced the uptake of fatty acids by HTR-8/SVneo cells, leading to intracellular lipid droplet accumulation and mitochondrial dysfunction while inhibiting cell migration and invasion. This suggests that metabolic processes can serve as important links for environmental pollutants to interfere with bodily functions. Knocking down N-myc Downstream-Regulated Gene 1 (NDRG1) can alleviate lipid metabolism abnormalities caused by DCHP exposure while restoring cell migration and invasion abilities. Further research has found that the enhanced transcriptional activity of PPARα:RXRα is an important molecular initiating event for the role of DCHP, which promotes the transcription of downstream target gene NDRG1 by binding to PPARα:RXRα. These findings fill the research gap regarding the effects and related mechanisms of DCHP exposure on the placenta, help explore prevention and treatment strategies for DCHP reproductive toxicity, and provide new insights into toxicological research on environmental pollutants.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"514 ","pages":"Article 154124"},"PeriodicalIF":4.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143737922","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":"Investigating the functional role of BUB1B in aflatoxin B1-associated hepatocarcinogenesis","authors":"Hayam Hamdy ,&nbsp;Wafaa A. Aly ,&nbsp;Eyad Elkord","doi":"10.1016/j.tox.2025.154127","DOIUrl":"10.1016/j.tox.2025.154127","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, stemming from a complex interplay of genetic, environmental, and lifestyle factors. Aflatoxin B1 (AFB1), a prevalent food contaminant, is a known HCC risk factor, but its molecular mechanisms remain incompletely understood. This study investigated the contribution of BUB1B, a crucial spindle assembly checkpoint regulator, in AFB1-induced hepatocyte malignant transformation, we assessed AFB1's impact on cell proliferation, viability, cell cycle regulation, and BUB1B expression. BUB1B knockdown via siRNA revealed its role in epithelial-mesenchymal transition (EMT), cell motility, and proliferation. AFB1 exposure significantly altered cell proliferation and cell cycle dynamics, correlating with increased BUB1B expression. Furthermore, we identified a significant interaction between BUB1B and the IL12A-JAK2/STAT4 signaling pathway, suggesting a mechanism for immune evasion and tumor progression. These findings highlight BUB1B's critical role in AFB1-induced hepatocarcinogenesis and establish its potential target for HCC. Further research is needed to fully elucidate the underlying molecular mechanisms and explore the therapeutic implications of BUB1B inhibition in HCC treatment.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"514 ","pages":"Article 154127"},"PeriodicalIF":4.8,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143725647","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":"T-2 toxin induces anemia via disrupting erythroid commitment and differentiation","authors":"Yan Li ,&nbsp;Jingxin Zhang ,&nbsp;Longzhen Zhao ,&nbsp;Peijun Jia ,&nbsp;Yazhe Zhen ,&nbsp;Huan Zhang ,&nbsp;Yuanlin Xu ,&nbsp;Shijie Zhang","doi":"10.1016/j.tox.2025.154126","DOIUrl":"10.1016/j.tox.2025.154126","url":null,"abstract":"<div><div>T-2 toxin, a stable and highly toxic secondary metabolite produced by <em>Fusarium</em>, is known to have strong cytotoxicity and threaten multiple systems. However, its effect on the hematopoietic system and the mechanisms of anemia induction remains unclear. Here, we establish the acute T-2 toxin poisoning mouse model at concentrations ranging between 0.5 and 4 mg/kg. Our results show that T-2 toxin exposure causes severe anemia in mice, as indicated by significant reductions in red blood cell count and hemoglobin levels. Further analysis indicates that T-2 toxin profoundly disrupts the homeostasis of hematopoietic stem cells and their commitment to the erythroid lineage and subsequent erythroid differentiation, thus significantly inhibiting the formation of erythroblasts and reticulocytes. In humans, cells are exposed to T-2 toxin at concentrations of 0.25–1 ng/mL for 13 days. T-2 toxin strongly inhibits erythropoiesis and promotes the formation of abnormal nucleated erythroblasts. Mechanistically, high concentration of T-2 toxin induces apoptosis, while lower levels arrest the cell cycle at the G1/S phase. Overall, our findings reveal the hematotoxic effects of T-2 toxin and shed light on the mechanisms underlying T-2 toxin induced anemia, providing valuable guidance for developing strategies to mitigate T-2 toxin poisoning.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"514 ","pages":"Article 154126"},"PeriodicalIF":4.8,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731721","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":"Identification of key genes linking bisphenols exposure and breast cancer","authors":"Zhen Wang ,&nbsp;Meng Cao ,&nbsp;Tian Gao ,&nbsp;Xinyue Xu ,&nbsp;Weihua Yu ,&nbsp;Jiangzheng Liu ,&nbsp;Rui Liu ,&nbsp;Xiaodi Zhang ,&nbsp;Fei Li ,&nbsp;Chunxu Hai","doi":"10.1016/j.tox.2025.154123","DOIUrl":"10.1016/j.tox.2025.154123","url":null,"abstract":"<div><div>Breast cancer (BC) is one of the most common types of cancer and is caused by the complex interplay of genetic and environmental factors, such as an unhealthy lifestyle, family history of illness, reproductive factors, and ageing. However, increasing evidence has revealed that manufactured organic pollutants such as bisphenols are closely related to BC. Bisphenols exposure can promote the progression of BC through multiple complicated and variable molecular mechanisms. Reanalysis of existing data on this topic may reveal molecular markers with clinical value. In this study, we identified four key genes [keratin 14 (<em>KRT14</em>), keratin 5 (<em>KRT5</em>), acyl-CoA synthetase long chain family member 1 (<em>ACSL1</em>) and matrix metallopeptidase 1 (<em>MMP1</em>)] related to both bisphenols exposure and BC by employing the Comparative Toxicogenomics Database (CTD) and The Cancer Genome Atlas Cervical Cancer (TCGA-CESC) dataset; notably, <em>KRT14</em> expression exhibited the most significant difference between tumour and normal tissues. Further analysis of the functions and biological processes associated with <em>KRT14</em> and related regulatory molecules revealed that bisphenols exposure induces BC-promoting characteristics and aggressive behaviour-related signaling pathways, such as the steroid biosynthesis, Forkhead box (<em>FOXO</em>) and prolactin signaling pathways. To confirm the expression and biological effects of <em>KRT14</em>, we conducted relevant experiments. In vitro studies revealed that bisphenols such as bisphenol A (BPA) exposure significantly affected the proliferation, migration, and invasion of MCF-7 cells by inhibiting <em>KRT14</em> expression. Similarly, we also observed a decrease in KRT14 expression in BPA induced abnormal breast tissue in mice. In summary, our study revealed potential genes and pathways associated with bisphenols exposure in BC.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"514 ","pages":"Article 154123"},"PeriodicalIF":4.8,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143697690","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":"Parabens exposure and its impact on diabesity: a review","authors":"Ana Ramalho ,&nbsp;Abel Vale ,&nbsp;Félix Carvalho ,&nbsp;Eduarda Fernandes ,&nbsp;Marisa Freitas","doi":"10.1016/j.tox.2025.154125","DOIUrl":"10.1016/j.tox.2025.154125","url":null,"abstract":"<div><div>Parabens are a family of alkyl esters of 4-hydroxybenzoic acid. The most commonly used include methylparaben, ethylparaben, propylparaben, and butylparaben. These compounds have been reported to disrupt the endocrine system and are believed to affect the central nervous, immune, and reproductive systems, as well as lipid homeostasis, glucose levels, and thyroid function. Given these effects, parabens pose potential health risks, including their possible link to conditions like diabesity - a term describing the dual condition of type 2 diabetes mellitus and obesity. This review explores current literature on how parabens may influence key mechanisms in diabesity, such as gluconeogenesis, glycogenolysis, adipogenesis, insulin resistance, and inflammation. Understanding their role in these metabolic pathways is critical for assessing their contribution to the diabesity epidemic and guiding future research for minimizing their harmful health impacts.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154125"},"PeriodicalIF":4.8,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711366","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":"Mice mortality induced by dexmedetomidine is non-alpha2-adrenergic receptor-dependent","authors":"Xiaoxuan Wang ,&nbsp;Yulei Li ,&nbsp;Jiye Yin ,&nbsp;Jiaqi Wang ,&nbsp;Peilan Zhou ,&nbsp;Ruibin Su","doi":"10.1016/j.tox.2025.154122","DOIUrl":"10.1016/j.tox.2025.154122","url":null,"abstract":"<div><div>Dexmedetomidine (DMED) is widely used in sedative anesthetics in clinical settings. Currently, there are no therapeutic interventions available for the lethal toxicity induced by DMED. Administered at doses ranging from 25 to 100 mg/kg intraperitoneally (i.p.), DMED exhibited a dose-dependent fatality in mice. The 50 % lethal dose (LD50) was determined to be 48.5 mg/kg within 24 h and 44.8 mg/kg within 7 days. Alpha2-adrenergic receptor antagonists, namely yohimbine and atipamezole, demonstrated no mitigating effect on the lethal toxicity induced by DMED at the dose of 44.8 mg/kg. Conversely, the administration of atipamezole and yohimbine increased the mortality associated with DMED. By contrast, the imidazoline receptor antagonist idazoxan and the opioid receptor antagonist naloxone significantly attenuated the mortality induced by DMED, thereby prolonging the median survival time following administration of DMED at 44.8 mg/kg (i.p.). Furthermore, the immune modulator imiquimod, calcium sensitizer levosimendan, and TAAR1 antagonist RO5212773 decreased acute mortality without impacting chronic mortality induced by DMED. Histopathological analysis revealed characteristic lung alterations, including capillary hemorrhage, widened alveolar septa, fusion of pulmonary alveoli, and inflammatory cell infiltrate upon DMED exposure. Pretreatment with idazoxan or naloxone inhibited these pathological changes induced by DMED, while atipamezole or yohimbine pretreatment exacerbated lung damage. Elevated levels of serum creatine kinase and myoglobin were noted following DMED administration. However, pretreatment with idazoxan or naloxone decreased the rise of serum creatine kinase and myoglobin. Collectively, these results highlighted the involvement of imidazoline receptors and opioid receptor in DMED mortality.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"514 ","pages":"Article 154122"},"PeriodicalIF":4.8,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674582","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":"Optimization of the drug-induced cholestasis index based on advanced modeling for predicting liver toxicity","authors":"Annika Drees ,&nbsp;Vahid Nassiri ,&nbsp;Andrés Tabernilla ,&nbsp;Jan Serroyen ,&nbsp;Emmanuel Gustin ,&nbsp;Bruna dos Santos Rodrigues ,&nbsp;Darren Michael Moss ,&nbsp;Ann De Smedt ,&nbsp;Mathieu Vinken ,&nbsp;Freddy Van Goethem ,&nbsp;Julen Sanz-Serrano","doi":"10.1016/j.tox.2025.154119","DOIUrl":"10.1016/j.tox.2025.154119","url":null,"abstract":"<div><div>Cholestatic drug-induced liver injury (cDILI) is a frequent reason for drug failure and withdrawal during premarketing and postmarketing stages of drug development. Strategies for reliable detection of cDILI in early drug development are therefore urgently needed. The drug-induced cholestasis index (DICI) concept was previously introduced as a tool for assessing the cholestatic potential of drug candidates. DICI is calculated as the ratio between the viability values obtained in drug-treated liver cells in the presence and absence of bile acids. The present in vitro study was set up to investigate the applicability of DICI in a novel high-throughput and large sample setting. Furthermore, the improvement of the predictivity of the DICI by introduction of advanced modeling was explored. Fifty-eight well-documented drugs were selected and categorized as drugs inducing cDILI, non-cholestatic DILI (ncDILI), and not inducing DILI (non-DILI). Cultures of human hepatoma HepaRG cells in 3D spheroid configuration were exposed to 9 half-log concentrations of each drug for 1, 3 and 7 days in the absence or presence of a concentrated mixture of human bile acids. The highest concentration of each drug was based on solubility and the maximum concentrations in human plasma (total Cmax). DICI values were computed for all drugs and time points. In addition, the area under the curve ratio and the occurrence of a trend in the cytotoxicity profiles were included as modeling descriptors. As such, 3 time-related scenarios were considered upon modeling, while categories were modeled on a nominal or an ordinal scale. Applying DICI with a cut-off value of 0.8 resulted in a high sensitivity for the cDILI class, but in turn, a low sensitivity for the non- DILI class. From the 28 predictive models generated, the best performing models integrated all descriptors and the ordinal scale for either the 7-day time point from a 3-time-point model or the 3-day time point. While these models were unable to accurately identify ncDILI drugs, the 7-day time point identified 84 % of the cDILI drugs and the 3-day time point correctly identified 94 % of non-DILI drugs. Based on the obtained results, it can be concluded that the reported DICI modeling provides an optimized approach that could be applied in an integrated DILI testing strategy</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"514 ","pages":"Article 154119"},"PeriodicalIF":4.8,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143664554","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":"Thallium induces metallothionein gene expression in Huh-7 human hepatoma cells","authors":"Toshihiko Aki,&nbsp;Takeshi Funakoshi,&nbsp;Kana Unuma","doi":"10.1016/j.tox.2025.154121","DOIUrl":"10.1016/j.tox.2025.154121","url":null,"abstract":"<div><div>Thallium (Tl) is one of the most toxic heavy metals and is found ubiquitously in the earth’s crust. To investigate the cellular responses to and against Tl cytotoxicity, we conducted DNA microarray analysis using three human cell lines of different origins: SH-SY5Y (neuroblast-derived), HEK293T (embryonic kidney-derived), and Huh-7 (hepatoma-derived) cells. All of the ten genes that showed the highest inductions in Huh-7 cells treated with 60 µM Tl₂SO₄ for 72 hours are metallothionein (MT) genes. The induction of the MT genes appears specific to Huh-7 cells; increases of 50–140-fold in the ten MT genes were observed in Huh-7 cells, while the increases were less than 4-fold in HEK293T and SH-SY5Y cells by microarray analysis. Investigation of the pathway responsible for Tl₂SO₄-induced MT expression in Huh-7 cells revealed that the RNA interference-mediated forced downregulation of MTF1 transcription factor resulted in the suppression of Tl₂SO₄-induced MT gene expressions, but not Tl₂SO₄-induced cell death, suggesting that MTF1-mediated MT gene expression is insufficient to protect Huh-7 cells against death by Tl₂SO₄. In contrast, the knockdown of nrf1 worsened Tl₂SO₄-induced cell death without suppressing MT gene expressions. These results indicate that MT gene induction in response to Tl₂SO₄ is mediated at least in part by MTF1 in Huh-7 cells. Nevertheless, MT gene induction through MTF1 seems insufficient to prevent the cell death caused by Tl₂SO₄. Nrf1 appears to be involved in protection against Tl₂SO₄ toxicity through mechanisms other than MT gene induction.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"514 ","pages":"Article 154121"},"PeriodicalIF":4.8,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143642961","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":"Subacute exposure of male adolescent rats to 2,2′,5,5′-tetrachlorobiphenyl-4-ol via a polymeric implant causes gene expression changes in the brain and metabolomic disruption in serum","authors":"Hui Wang ,&nbsp;Amanda J. Bullert ,&nbsp;Morgan J. Linahon ,&nbsp;Michael E. Dailey ,&nbsp;Jonathan A. Doorn ,&nbsp;Aloysius J. Klingelhutz ,&nbsp;James A. Ankrum ,&nbsp;Hans-Joachim Lehmler","doi":"10.1016/j.tox.2025.154120","DOIUrl":"10.1016/j.tox.2025.154120","url":null,"abstract":"<div><div>Polychlorinated biphenyls (PCBs) remain an environmental health concern due to their persistence and ongoing release from legacy and emerging sources. 2,2′,5,5′-Tetrachlorobiphenyl (PCB52), a PCB congener frequently detected in the environment and human blood, is oxidized to 2,2′,5,5′-tetrachlorobiphenyl-4-ol (4−52). The neurotoxicity of this hydroxylated (OH-PCB) metabolite remains poorly characterized. In this study, we exposed 4-week-old male Sprague Dawley rats to 4–52 via a polymeric implant drug delivery system grafted in the subcutaneous cavity at 4–52 concentrations of 0 %, 1 %, 5 %, and 10 % in the implant (w/w) for 28 days. Metabolomic analyses were performed in the serum. RNA sequencing, immunofluorescence, and dopamine (DA) measurement with electrochemical detection were used to characterize the effects of 4–52 on the striatum and cerebellum, brain regions implicated in PCB neurotoxicity. Serum metabolomic analysis revealed disruptions in the \"arginine biosynthesis\" pathway following 4–52 exposure. Exposure to 4–52 caused moderate transcriptomic changes in pathways related to \"oxidative phosphorylation\" and \"neuroactive ligand-receptor interactions.\" Immunofluorescence showed no significant alterations in microglial, astrocytic, or apoptotic biomarkers. In the medium dose group, the levels of the DA metabolite DOPAL (3,4-dihydroxyphenylacetaldehyde) were significantly reduced in the striatum. Subsequent multi-omics network analysis identified interactions among OH-PCBs, endogenous metabolites, and the transcriptome. For example, levels of glutamic acid, aspartic acid, choline, and glycerophosphocholine negatively correlated with 4–52 in the striatum. Expression levels of heat shock protein (HSP) family genes, <em>Hsp90b1</em>, <em>Hspa8</em>, and <em>Hspa5</em>, positively correlated with serum metabolites, including proline, 1-methylguanidine, and methionine sulfoxide. These findings identify novel biomarkers and targets of 4–52-induced neurotoxicity.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"514 ","pages":"Article 154120"},"PeriodicalIF":4.8,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143650850","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}