Toxicology最新文献

{"title":"Benzene-induced hematotoxicity enhances the self-renewal ability of HSPCs in Mll-Af9 mice","authors":"Jin Zhou ,&nbsp;Pinpin Sui ,&nbsp;Jianxin Zhao ,&nbsp;Xiurong Cheng ,&nbsp;Tao Yu ,&nbsp;Shiwei Cui ,&nbsp;Xiangrong Song ,&nbsp;Caihong Xing","doi":"10.1016/j.tox.2025.154061","DOIUrl":"10.1016/j.tox.2025.154061","url":null,"abstract":"<div><div>Patients with benzene-induced leukemia undergo a continuous transformation from myelosuppression to malignant proliferation. However, the underlying mechanisms in this process remain unknown. Our previous studies have shown that the pathways involved in self-renewal capacity of bone marrow (BM) cells in <em>Mll-Af9</em> mice exposed to benzene for life are significantly activated after severe blood toxicity. In order to investigate the hematotoxicity effects of benzene on the self-renewal capacity of HSCs, <em>Mll-Af9</em> chimeric mice were exposed to benzene and hematological parameters were dynamically monitored after benzene exposure. Transcriptomic analysis were used to analyze different time points during benzene exposure and after competitive bone marrow transplantation (BMT). Results showed that despite severe hematotoxicity in mice, but the chimerism rate of <em>Mll-Af9</em> cells in peripheral blood (PB) cells was significantly increased after 10 weeks benzene exposure (<em>P</em> &lt; 0.001). After competitive BMT, the chimerism rate of <em>Mll-Af9</em> cells from 10 weeks benzene-exposed mice was gradually increased and significantly surpassed that of the control at 26 weeks of bone marrow reconstruction (benzene group 86 % VS control group 78 %, <em>P</em> = 0.03). Transcriptome analysis revealed that the expression levels of self-renewal related genes, such as Hox genes (<em>Hoxb4</em>, <em>Hoxa7</em>, <em>Hoxa10</em>), <em>Mecom</em> and <em>Ms4a</em> in BM cells of 10 weeks benzene-exposed mice were relatively higher compared to those in the control group, but no significant difference were observed. Interestingly, <em>Hoxa7</em>, <em>Hoxa10</em> and <em>Mecom</em> were significantly up-regulated at 26 weeks after bone marrow transplantation. In conclusion, our study suggests that abnormal expression of self-renewal-related genes may be potential early biomarkers for benzene-induced hematotoxicity. This hematotoxicity may contribute to the acquisition of evolutionary advantages by leukemic precursor cells and accelerate malignant transformation.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154061"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143024784","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":"Myocardial deposition of aluminum, arsenic, cadmium, and lead accelerates heart failure and alters UPRmt in humans","authors":"Tomo Svagusa ,&nbsp;Natalija Matic ,&nbsp;Vid Mirosevic ,&nbsp;Kresimir Maldini ,&nbsp;Mario Siljeg ,&nbsp;Davor Milicic ,&nbsp;Hrvoje Gasparovic ,&nbsp;Igor Rudez ,&nbsp;Marjan Urlic ,&nbsp;Tomislav Tokic ,&nbsp;Stjepan Ivankovic ,&nbsp;Duska Tjesic-Drinkovic ,&nbsp;Ana Sepac ,&nbsp;Danko Muller ,&nbsp;Marko Lucijanic ,&nbsp;Filip Svalina ,&nbsp;Lucija Gojmerac ,&nbsp;Katarina Zic ,&nbsp;Davor Baric ,&nbsp;Daniel Unic ,&nbsp;Filip Sedlic","doi":"10.1016/j.tox.2024.154033","DOIUrl":"10.1016/j.tox.2024.154033","url":null,"abstract":"<div><div>In the myocardium of control subjects and patients undergoing heart transplantation or left ventricular assist device implantation (LVAD), we analyzed concentrations of Al, As, Cd, Pb, and Ni using inductively coupled plasma mass spectrometry. Myocardial generation of oxidative-stress-induced lipid peroxidation was analyzed by quantifying concentration of 4-Hydroxynonenal (4-HNE) with ELISA and pro-apoptotic <em>DAPK2</em> gene expression was determined with quantitative RT-PCR. Compared to six control hearts, myocardial samples of 128 individuals undergoing heart transplantation or LVAD implantation exhibited a moderate increase in deposition of five tested non-essential elements, which was significantly increased only for Cd and cumulative deposition of Al, As, Cd, and Pb. Patients with higher cumulative deposition of Al, As, Cd, and Pb, underwent heart transplantation or LVAD implantation at a younger age than those with lower cumulative deposition, which was not observed in individual elements. Also, Al, As, and Ni exhibited a positive correlation with <em>DAPK2</em> expression. Moreover, Al, As, Cd, and Ni showed positive correlations and Pb negative correlations with several mitochondrial quality control (MQC) genes. None of the elements showed correlation with 4-HNE generation in the myocardium. There was no difference in tested non-essential element deposition between dilated and ischemic cardiomyopathy. In conclusion, patients with higher cumulative deposition of Al, As, Cd, and Pb in the myocardium underwent heart transplantation or LVAD implantation at a younger age, indicating that they may accelerate heart failure, which is associated with induction of <em>DAPK2</em> expression. Deposition of Al, As, Cd, Ni, and Pb also altered the expression of several MQC genes.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154033"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824500","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":"Engagement of peroxisome proliferator-activated receptor gamma (PPARγ) and mammalian target of rapamycin (mTOR) in the triclosan-induced disruption of Cyp450 enzyme activity in an in vitro model of mouse embryo fibroblasts (3T3-L1)","authors":"Konrad A. Szychowski ,&nbsp;Bartosz Skóra ,&nbsp;Anna K. Wójtowicz","doi":"10.1016/j.tox.2024.154031","DOIUrl":"10.1016/j.tox.2024.154031","url":null,"abstract":"<div><div>Triclosan (TCS) is commonly used worldwide due to its bactericidal and antifungal properties. There are data suggesting the involvement of aryl hydrocarbon receptors (AhR) and peroxisome proliferator-activated receptors (PPARγ). Since the effect of TCS on mouse fibroblasts has not been described so far, we decided to investigate the mechanism of action of this compound in the mouse embryonic fibroblast cell line (3T3-L1). Our results showed that high µM concentrations of TCS increased caspase-3 activity and decreased cell viability after 24-h exposure. The molecular analysis confirmed that 1 µM TCS decreased Ki67 mRNA expression and PCNA protein expression with a similar tendency to that of AhR. The analyses of mRNA levels after treatment with αNF or βNF alone and αNF in combination with TCS showed an increase in Ki67 mRNA expression. TCS alone increased AhR mRNA but had different effects on <em>Cyp1a1</em> and <em>Cyp1b1</em> expression. These results suggest the involvement of the PPARγ pathway in the inhibition of <em>Cyp1b1</em> by TCS. After the TCS exposure, we observed a decrease in PPARγ, and this effect was enhanced in the presence of an AhR agonist and antagonist. These results support the theory about the interaction between the AhR and PPARγ pathways. In the experiments, the strongest increase in PI3K protein expression was observed in the group treated simultaneously with TCS and βNF. Changes in the PI3K level were reflected in changes in the examined mTOR protein. TCS caused a decrease in both mTOR and Cyp1b1 after 24 hours, while opposite effects were observed after 48 hours. Given the crucial role of Cyp1b1, PPARγ, and mTOR in cellular metabolism, we can conclude that TCS is able to disrupt a number of cellular processes. Our data suggest that TCS reduces the metabolism of this xenobiotic in mouse preadipocytes.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154031"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142802143","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":"Environmental mycotoxins: A potential etiological factor for neurodegenerative diseases?","authors":"Tong Nie ,&nbsp;Jiefeng Li ,&nbsp;Li You ,&nbsp;Qinghua Wu","doi":"10.1016/j.tox.2025.154056","DOIUrl":"10.1016/j.tox.2025.154056","url":null,"abstract":"<div><div>Mycotoxins are potential environmental risk factors for neurodegenerative diseases. These toxins penetrate the central nervous system via a compromised blood-brain barrier, which may cause oxidative stress and neuroinflammation, these can also contribute to amyloid-beta (Aβ) plaque accumulation, Tau protein hyperphosphorylation, and neurofibrillary tangle formation. Mycotoxins also activate microglia, cause neuronal apoptosis, and disrupt central nervous system function. This study examines the evidence linking mycotoxin exposure to neurodegenerative disorders like Alzheimer's and Parkinson's diseases. We explore mechanisms such as oxidative stress, mitochondrial dysfunction, blood-brain barrier disruption, neuroinflammation, and direct neurotoxic effects. Epidemiological studies show regional variations in mycotoxin prevalence and corresponding neurodegenerative disease incidences, supporting this association. We also review current approaches to mitigate mycotoxin exposure and discuss the challenges and opportunities in developing strategies to prevent or slow neurodegenerative disease progression. This work highlights the need for increased awareness and research on mycotoxins as modifiable risk factors in neurological health.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154056"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143011520","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":"Comparing the cannabidiol-induced transcriptomic profiles in human and mouse Sertoli cells","authors":"Yuxi Li ,&nbsp;Xilin Li ,&nbsp;Patrick Cournoyer ,&nbsp;Supratim Choudhuri ,&nbsp;Lei Guo ,&nbsp;Si Chen","doi":"10.1016/j.tox.2025.154068","DOIUrl":"10.1016/j.tox.2025.154068","url":null,"abstract":"<div><div>Cannabidiol (CBD), a major cannabinoid found in <em>Cannabis sativa</em> L., has been used in the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex. Recently, concerns have been raised regarding the male reproductive toxicity of CBD in animal models, such as monkeys, rats, and mice. In our previous studies, we reported that CBD inhibited cell proliferation in both primary human Sertoli cells and mouse Sertoli TM4 cells. Transcriptomic analysis revealed that in primary human Sertoli cells CBD disrupted DNA replication, cell cycle, and DNA repair, ultimately causing cellular senescence. In this study, we further investigated the molecular changes induced by CBD in mouse Sertoli TM4 cells using RNA-sequencing analyses and compared the transcriptomic profile with that of primary human Sertoli cells. Our findings demonstrated that, unlike in primary human Sertoli cells, CBD did not induce cellular senescence but caused apoptosis in mouse Sertoli TM4 cells. Through transcriptomic data analysis in mouse Sertoli TM4 cells, immune and cellular stress responses were identified. Moreover, transcriptomic comparisons revealed major differences in molecular changes induced by CBD between mouse Sertoli TM4 and primary human Sertoli cells. This suggests that primary human Sertoli cells and mouse Sertoli cells may respond differently to CBD.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"512 ","pages":"Article 154068"},"PeriodicalIF":4.8,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143081139","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":"Corrigendum to “Inhibitory effects of parabens on human and rat 17β-hydroxysteroid dehydrogenase 1: Mechanisms of action and impact on hormone synthesis” Toxicology 506 (August) (2024) 153873","authors":"Zhuoqi Chen ,&nbsp;Chaochao Gong ,&nbsp;Yunbing Tang ,&nbsp;Yang Zhu ,&nbsp;Shaowei Wang ,&nbsp;Ren-shan Ge ,&nbsp;Yingfen Ying","doi":"10.1016/j.tox.2024.153991","DOIUrl":"10.1016/j.tox.2024.153991","url":null,"abstract":"","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"510 ","pages":"Article 153991"},"PeriodicalIF":4.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142628691","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":"Bisphenol A exposure during gestation and lactation in mice: Sex-specific consequences on oligodendrocytes and myelination","authors":"Vanessa Naffaa ,&nbsp;Juliette Van Steenwinckel ,&nbsp;Romain Magny ,&nbsp;Anne Regazzetti ,&nbsp;Céline Keime ,&nbsp;Pierre Gressens ,&nbsp;Olivier Laprévote ,&nbsp;Nicolas Auzeil ,&nbsp;Anne-Laure Schang","doi":"10.1016/j.tox.2024.154041","DOIUrl":"10.1016/j.tox.2024.154041","url":null,"abstract":"<div><div>Bisphenol A (BPA), a ubiquitous environmental endocrine disruptor, is suspected of disturbing brain development through largely unknown cellular and molecular mechanisms. In the central nervous system, oligodendrocytes are responsible for forming myelin sheaths, which enhance the propagation of action potentials along axons. Disruption of axon myelination can have lifelong consequences, making oligodendrocyte differentiation and myelination critical stages of brain development. In the present study, mice were exposed to BPA during gestation and lactation through drinking water at concentrations of 25 and 250 μg.L⁻¹. These doses, corresponding to estimated exposures of 4 μg.kg⁻¹.d⁻¹ and 40 μg.kg⁻¹.d⁻¹, respectively, led to disturbances in lipid remodeling associated with myelination in the offspring. Importantly, changes in myelin lipid composition were selectively observed in female mice and were transient, being visible only at post-natal day P15 but not at later stages (P30 and P60). In females exposed to BPA, myelin exhibited a lower proportion of phosphatidylcholines and higher proportions of other glycerophospholipid subclasses, thus resembling more mature myelin. Conversely, male myelin was not affected, likely due to its already more mature lipid composition. Additionally, transcriptomic analysis of female oligodendrocytes at P15 did not reveal any transcriptional changes in genes related to lipid metabolism, further suggesting post-transcriptional effects of BPA <em>via</em> chaperone-mediated protein folding and RNA splicing. In males, the altered genes were mainly associated with synaptic transmission. Finally, alterations in chromatin accessibility were also largely sex dependent and did not correlate with transcription, with the exception of the <em>Cwc22</em>. At this locus, BPA exposure increased chromatin accessibility in half of mice of both sexes, leading to an “unchanged/open” bimodal profile correlated with “unchanged/upregulated” gene expression. Together, these results open new insights into the sex-dependent mechanisms of BPA's effects on brain development.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"512 ","pages":"Article 154041"},"PeriodicalIF":4.8,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915587","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":"The crucial involvement of gamma-Mangostin and CYP1B1 in the mechanism underlying the toxicity caused by cigarette smoke extract: In silico and in vitro insights","authors":"Hao Lin ,&nbsp;Zijian Li ,&nbsp;Tao Zeng ,&nbsp;Ying Wang ,&nbsp;Lan Zhang","doi":"10.1016/j.tox.2024.154016","DOIUrl":"10.1016/j.tox.2024.154016","url":null,"abstract":"<div><div>Cigarette smoke extracts (CSE) contain harmful substances that significantly contribute to respiratory conditions. Previous studies have primarily focused on the presence of carcinogens in CSE. However, it should be noted that other compounds may also synergistically contribute to a greater impact. This study proposes an innovative collaboration between natural products in CSE and carcinogens to enhance CSE-induced acute toxicity. Bioinformatics analysis coupled with experimental validation have elucidated the pivotal role of CYP1B1 in CSE-induced acute toxicity. Inhibitors targeting CYP1B1 have demonstrated preferential cytotoxicity towards cells exhibiting elevated levels of CYP1B1 expression. Afterwards, we conducted a virtual screening of the CSE composition database to identify a potential inhibitor for CYP1B1. After analyzing docking scores and complex interaction modes, γ-mangostin emerged as a highly promising CYP1B1 inhibitor. Molecular docking and dynamics were used to elucidate the complex structure formed between γ-mangostin and CYP1B1. Further investigations suggest that γ-mangostin can synergistically interact with carcinogens in CSE, causing cellular harm and contributing significantly to acute toxicity induced by CSE. Furthermore, γ-mangostin showed increased affinity towards CYP1B1 variants L432V and N453S, suggesting that organisms with these genetic variations may be more susceptible to cell damage caused by CSE. These new perspectives enhance our understanding of the mechanism behind acute toxicity associated with CSE and offer new possibilities for improving preventive measures and treatment strategies.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"510 ","pages":"Article 154016"},"PeriodicalIF":4.8,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142759224","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":"Chronic exposure to polystyrene microplastics triggers osteoporosis by breaking the balance of osteoblast and osteoclast differentiation","authors":"Chun Pan ,&nbsp;Runyang Hong ,&nbsp;Kehan Wang ,&nbsp;Yujie Shi ,&nbsp;Zhencheng Fan ,&nbsp;Tingting Liu ,&nbsp;Hao Chen","doi":"10.1016/j.tox.2024.154017","DOIUrl":"10.1016/j.tox.2024.154017","url":null,"abstract":"<div><div>Plastic pollution is becoming more and more serious, and microplastics (MPs) formed by degradation from plastics significantly threaten the health of animals and humans. However, it remains unknown how MPs interfere with bone homeostasis by regulating the function of bone marrow mesenchymal stem cells (BMSCs). In order to simulate the toxic impacts of long-term low-dose MPs on the skeletal system, we constructed a 6-month drinking water model of mice exposed to MPs. We found that the bone microstructure in the femur of mice exposed to MPs was destroyed, the quantity of bone trabeculae decreased sharply and the bone mass decreased significantly, accompanied by the decrease of bone formation and the activation of osteoclasts. In addition, RNA sequencing showed NF-κB pathway was activated in MPs-treated BMSCs, manifested as significantly up-regulated inflammatory factors, accelerated the senescence of BMSCs, and inhibited their osteogenic differentiation and extracellular mineralization. Senescent BMSCs induced by MPs led to the overproduction of RANKL, which contributed to the production of more osteoclasts. Importantly, the administration of NF-κB inhibitors <em>in vivo</em> markedly diminished MPs-induced BMSCs senescence and impaired osteogenic differentiation. Meanwhile, the secretion of RANKL caused by MPs was reversed, and osteoclast formation was significantly reduced. In summary, our data innovatively reveal the core mechanism of MPs in bone balance. By promoting the NF-κB signaling pathway, it significantly accelerates the aging of BMSCs, causes a decrease in bone formation, and promotes osteoclast formation through RANKL.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"510 ","pages":"Article 154017"},"PeriodicalIF":4.8,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142747216","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":"Proteomic analysis of human iPSC-derived sympathetic neurons identifies proteostasis collapse as a molecular signature following subtoxic rotenone exposure","authors":"Tamar Gordon ,&nbsp;Mahmood Ali Saleh ,&nbsp;Metsada Pasmanik-Chor ,&nbsp;Gad D. Vatine ,&nbsp;Avraham Ashkenazi","doi":"10.1016/j.tox.2024.154015","DOIUrl":"10.1016/j.tox.2024.154015","url":null,"abstract":"<div><div>Rotenone is a toxic isoflavone and an inhibitor of the mitochondrial respiratory chain. Rotenone is commonly used due to its piscicidal and pesticidal properties. The peripheral nervous system (PNS) lacks protective barriers and is exposed to many environmental substances due to its long-reaching structure. A causal association between rotenone and human PNS dysfunction is currently a subject of investigation. Here, we treated human induced pluripotent stem cell (iPSC)-derived peripheral sympathetic neurons with a subtoxic dose of rotenone (10 µg/L) that is considered safe for human health and is permitted for environmental use. Indeed, no overt toxicity was observed in the human peripheral neurons and neurite morphology was intact in the treated neurons. Surprisingly, we detected significant changes in the proteome of rotenone-exposed sympathetic neurons with a signature of protein homeostasis (proteostasis) collapse. Screening the proteostasis modules of protein translation, proteolysis, and chaperones, revealed severe perturbations in clusters of autophagy regulators. Our proteomic profiling reveals compromised proteostasis as a consequence of low-dose non-toxic exposure to rotenone, which can disrupt the ability of the PNS to cope with proteotoxic stress. Exposed individuals may have varying degrees of tolerance to such vulnerabilities but they may eventually progress into peripheral neuropathies.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"510 ","pages":"Article 154015"},"PeriodicalIF":4.8,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740730","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}