Pub Date : 2025-02-01DOI: 10.1016/j.tox.2025.154056
Tong Nie , Jiefeng Li , Li You , Qinghua Wu
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.
{"title":"Environmental mycotoxins: A potential etiological factor for neurodegenerative diseases?","authors":"Tong Nie , Jiefeng Li , Li You , 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}
Pub Date : 2025-01-31DOI: 10.1016/j.tox.2025.154068
Yuxi Li , Xilin Li , Patrick Cournoyer , Supratim Choudhuri , Lei Guo , Si Chen
Cannabidiol (CBD), a major cannabinoid found in Cannabis sativa 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.
{"title":"Comparing the cannabidiol-induced transcriptomic profiles in human and mouse Sertoli cells","authors":"Yuxi Li , Xilin Li , Patrick Cournoyer , Supratim Choudhuri , Lei Guo , 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}
Pub Date : 2025-01-01DOI: 10.1016/j.tox.2024.153991
Zhuoqi Chen , Chaochao Gong , Yunbing Tang , Yang Zhu , Shaowei Wang , Ren-shan Ge , Yingfen Ying
{"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 , Chaochao Gong , Yunbing Tang , Yang Zhu , Shaowei Wang , Ren-shan Ge , 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}
Pub Date : 2024-12-30DOI: 10.1016/j.tox.2024.154041
Vanessa Naffaa , Juliette Van Steenwinckel , Romain Magny , Anne Regazzetti , Céline Keime , Pierre Gressens , Olivier Laprévote , Nicolas Auzeil , Anne-Laure Schang
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 via 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 Cwc22. 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.
双酚A （BPA）是一种普遍存在的环境内分泌干扰物，被怀疑通过未知的细胞和分子机制干扰大脑发育。在中枢神经系统中，少突胶质细胞负责形成髓鞘，髓鞘能促进动作电位沿轴突的传播。轴突髓鞘形成的破坏可以产生终生的后果，使少突胶质细胞分化和髓鞘形成成为大脑发育的关键阶段。本研究采用25 μg. l -1和250μg.L-1双酚a浓度的饮用水，对妊娠期和哺乳期小鼠进行双酚a暴露。这些剂量相当于4μg.kg-1的估计暴露量。D-1和40μg.kg-1。D-1分别导致与后代髓鞘形成相关的脂质重塑紊乱。重要的是，在雌性小鼠中选择性地观察到髓磷脂脂质组成的变化，并且是短暂的，仅在出生后P15天可见，而在后期（P30和P60）则不可见。在暴露于BPA的雌性中，髓磷脂表现出较低比例的磷脂酰胆碱和较高比例的其他甘油磷脂亚类，因此类似于更成熟的髓磷脂。相反，男性髓磷脂不受影响，可能是由于其脂质成分已经更成熟。此外，对P15期雌性少突胶质细胞的转录组学分析未发现脂质代谢相关基因的转录变化，进一步表明BPA通过伴侣蛋白介导的蛋白质折叠和RNA剪接发挥转录后作用。在雄性中，改变的基因主要与突触传递有关。最后，除了Cwc22外，染色质可及性的改变也在很大程度上依赖于性别，与转录无关。在这个位点，BPA暴露增加了一半雌雄小鼠的染色质可及性，导致“不变/开放”双峰谱与“不变/上调”基因表达相关。总之，这些结果为双酚a对大脑发育影响的性别依赖机制提供了新的见解。
{"title":"Bisphenol A exposure during gestation and lactation in mice: Sex-specific consequences on oligodendrocytes and myelination","authors":"Vanessa Naffaa , Juliette Van Steenwinckel , Romain Magny , Anne Regazzetti , Céline Keime , Pierre Gressens , Olivier Laprévote , Nicolas Auzeil , 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<sup>−1</sup>. These doses, corresponding to estimated exposures of 4 μg.kg<sup>−1</sup>.d<sup>−1</sup> and 40 μg.kg<sup>−1</sup>.d<sup>−1</sup>, 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}
Pub Date : 2024-11-29DOI: 10.1016/j.tox.2024.154016
Hao Lin , Zijian Li , Tao Zeng , Ying Wang , Lan Zhang
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.
{"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 , Zijian Li , Tao Zeng , Ying Wang , 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}
Pub Date : 2024-11-27DOI: 10.1016/j.tox.2024.154017
Chun Pan , Runyang Hong , Kehan Wang , Yujie Shi , Zhencheng Fan , Tingting Liu , Hao Chen
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 in vivo 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.
{"title":"Chronic exposure to polystyrene microplastics triggers osteoporosis by breaking the balance of osteoblast and osteoclast differentiation","authors":"Chun Pan , Runyang Hong , Kehan Wang , Yujie Shi , Zhencheng Fan , Tingting Liu , 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}
Pub Date : 2024-11-26DOI: 10.1016/j.tox.2024.154015
Tamar Gordon , Mahmood Ali Saleh , Metsada Pasmanik-Chor , Gad D. Vatine , Avraham Ashkenazi
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.
{"title":"Proteomic analysis of human iPSC-derived sympathetic neurons identifies proteostasis collapse as a molecular signature following subtoxic rotenone exposure","authors":"Tamar Gordon , Mahmood Ali Saleh , Metsada Pasmanik-Chor , Gad D. Vatine , 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}
Pub Date : 2024-11-23DOI: 10.1016/j.tox.2024.154014
Jui-Ming Liu , Shing-Hwa Liu , Shih-Chang Fu , Wei-Cheng Lai , Kai-Min Fang , Ken-An Lin , Jun-An Ke , Chun-Ying Kuo , Chin-Chuan Su , Ya-Wen Chen
Tetrabromobisphenol A (TBBPA), a brominated flame retardant (BFR), has been implicated as the neurotoxic effects in mammalian. However, the exact mechanisms underlying TBBPA-induced neurotoxicity remain unclear. In the present study, Neuro-2a cells, a mouse neural crest-derived cell line, were used to examine the mechanism of TBBPA-induced neuronal cytotoxicity. TBBPA exposure caused alterations in cell viability and mitochondrial membrane potential (MMP) and induction of apoptotic events, such as increased apoptotic cell population and cleaved caspase-3, −7, −9, and poly (ADP-ribose) polymerase (PARP) protein expression). TBBPA exposure triggered CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) activation. Transfection with CHOP-specific small interfering RNA (siRNA) obviously prevented the expression of CHOP protein and markedly attenuated MMP loss, and caspase-3 and −7 activation in TBBPA-exposed Neuro-2a cells. In addition, TBBPA exposure significantly evoked the phosphorylation of c-Jun N-terminal kinase (JNK), extracellular-signal regulated kinase1/2 (ERK1/2), p38-mitogen-activated protein kinase (p38-MAPK), and AMP-activated protein kinase (AMPK)α proteins. Pretreatment of cells with pharmacological inhibitors of p38-MAPK (SB203580) and AMPK (compound C), but not inhibitors of JNK (SP600125) or ERK1/2 (PD98059), effectively prevented the increase in caspase-3 activity, MMP loss, and activated CHOP and cleaved caspase-3 and −7 protein expression in TBBPA-treated cells. Notably, transfection with either p38α-MAPK- or AMPKα1/2-specific siRNAs markedly attenuated the expression of CHOP, and cleaved caspase-3 and −7. Interestingly, transfection with each siRNA significantly reduced the TBBPA-induced phosphorylation of p38-MAPK and AMPKα proteins. Collectively, these findings suggest that CHOP activation-mediated mitochondria-dependent apoptosis contributes to TBBPA-induced neurotoxicity. An interdependent p38-MAPK and AMPKα signaling-regulated apoptotic pathway may provide new insights into the mechanism understanding TBBPA-elicited neurotoxicity.
{"title":"Tetrabromobisphenol A induced p38-MAPK/AMPKα activation downstream-triggered CHOP signal contributing to neuronal apoptosis and death","authors":"Jui-Ming Liu , Shing-Hwa Liu , Shih-Chang Fu , Wei-Cheng Lai , Kai-Min Fang , Ken-An Lin , Jun-An Ke , Chun-Ying Kuo , Chin-Chuan Su , Ya-Wen Chen","doi":"10.1016/j.tox.2024.154014","DOIUrl":"10.1016/j.tox.2024.154014","url":null,"abstract":"<div><div>Tetrabromobisphenol A (TBBPA), a brominated flame retardant (BFR), has been implicated as the neurotoxic effects in mammalian. However, the exact mechanisms underlying TBBPA-induced neurotoxicity remain unclear. In the present study, Neuro-2a cells, a mouse neural crest-derived cell line, were used to examine the mechanism of TBBPA-induced neuronal cytotoxicity. TBBPA exposure caused alterations in cell viability and mitochondrial membrane potential (MMP) and induction of apoptotic events, such as increased apoptotic cell population and cleaved caspase-3, −7, −9, and poly (ADP-ribose) polymerase (PARP) protein expression). TBBPA exposure triggered CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) activation. Transfection with CHOP-specific small interfering RNA (siRNA) obviously prevented the expression of CHOP protein and markedly attenuated MMP loss, and caspase-3 and −7 activation in TBBPA-exposed Neuro-2a cells. In addition, TBBPA exposure significantly evoked the phosphorylation of c-Jun N-terminal kinase (JNK), extracellular-signal regulated kinase1/2 (ERK1/2), p38-mitogen-activated protein kinase (p38-MAPK), and AMP-activated protein kinase (AMPK)α proteins. Pretreatment of cells with pharmacological inhibitors of p38-MAPK (SB203580) and AMPK (compound C), but not inhibitors of JNK (SP600125) or ERK1/2 (PD98059), effectively prevented the increase in caspase-3 activity, MMP loss, and activated CHOP and cleaved caspase-3 and −7 protein expression in TBBPA-treated cells. Notably, transfection with either p38α-MAPK- or AMPKα1/2-specific siRNAs markedly attenuated the expression of CHOP, and cleaved caspase-3 and −7. Interestingly, transfection with each siRNA significantly reduced the TBBPA-induced phosphorylation of p38-MAPK and AMPKα proteins. Collectively, these findings suggest that CHOP activation-mediated mitochondria-dependent apoptosis contributes to TBBPA-induced neurotoxicity. An interdependent p38-MAPK and AMPKα signaling-regulated apoptotic pathway may provide new insights into the mechanism understanding TBBPA-elicited neurotoxicity.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"510 ","pages":"Article 154014"},"PeriodicalIF":4.8,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142705530","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}
The aim of this study was to apply a network toxicology strategy to investigate the potential toxicity and the molecular mechanisms underlying the aging-induced toxicity of acetyl tributyl citrate (ATBC). Utilizing the ChEMBL, SwissTargetPrediction, and CellAge databases, we identified 32 potential targets associated with ATBC exposure and aging. Subsequent optimization by STRING and Cytoscape software highlighted 11 core targets, including EGFR, STAT3, and BCL-2. A comprehensive analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways revealed that core targets of ATBC-induced senescence were predominantly enriched in pathways related to the positive regulation of cell proliferation, telomere shortening, cancer, and cellular senescence. Among these pathways, we selected four core genes of the cellular senescence pathway (MAPK14, CDK2, MDM2, and PIK3CA) for molecular docking with Autodock, which confirmed the high binding affinity between ATBC and the core targets. In conclusion, these findings indicate that ATBC may contribute to human aging by modulating the positive regulation of cell proliferation, the telomere shortening pathway, the cancer-related pathway, and the cellular senescence pathway. This study establishes a theoretical basis for exploring the molecular mechanisms of human aging induced by ATBC, alongside a systematic and effective framework for researchers to assess the potential toxicity of various chemical products.
{"title":"Efficient analysis of toxicity and mechanisms of Acetyl tributyl citrate on aging with network toxicology and molecular docking strategy","authors":"Qiu Zheng , Qingping Peng , Jianlin Shen , Huan Liu","doi":"10.1016/j.tox.2024.154009","DOIUrl":"10.1016/j.tox.2024.154009","url":null,"abstract":"<div><div>The aim of this study was to apply a network toxicology strategy to investigate the potential toxicity and the molecular mechanisms underlying the aging-induced toxicity of acetyl tributyl citrate (ATBC). Utilizing the ChEMBL, SwissTargetPrediction, and CellAge databases, we identified 32 potential targets associated with ATBC exposure and aging. Subsequent optimization by STRING and Cytoscape software highlighted 11 core targets, including EGFR, STAT3, and BCL-2. A comprehensive analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways revealed that core targets of ATBC-induced senescence were predominantly enriched in pathways related to the positive regulation of cell proliferation, telomere shortening, cancer, and cellular senescence. Among these pathways, we selected four core genes of the cellular senescence pathway (MAPK14, CDK2, MDM2, and PIK3CA) for molecular docking with Autodock, which confirmed the high binding affinity between ATBC and the core targets. In conclusion, these findings indicate that ATBC may contribute to human aging by modulating the positive regulation of cell proliferation, the telomere shortening pathway, the cancer-related pathway, and the cellular senescence pathway. This study establishes a theoretical basis for exploring the molecular mechanisms of human aging induced by ATBC, alongside a systematic and effective framework for researchers to assess the potential toxicity of various chemical products.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"510 ","pages":"Article 154009"},"PeriodicalIF":4.8,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695804","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}
Pub Date : 2024-11-17DOI: 10.1016/j.tox.2024.153998
Laura Micheli , David Balayssac , Jérôme Busserolles , Cristelle Dalbos , Laetitia Prival , Damien Richard , Mercedes Quintana , Lorenzo Di Cesare Mannelli , Alessandra Toti , Clara Ciampi , Carla Ghelardini , Katerina Vlasakova , Warren E. Glaab , Yang Hu , Irena Loryan , Olivier Perrault , Mohamed Slaoui , Kuno Wuersch , Eric Johnson , Wilfried Frieauff , Diethilde Theil
Peripheral nervous system (PNS) toxicity assessment in non-clinical safety studies is challenging and relies mostly on histopathological assessment. The present work aims to identify blood-based biomarkers that could detect peripheral neuropathy in rats upon exposure to neurotoxic compounds. Three anticancer agents (oxaliplatin, cisplatin, paclitaxel) and a developmental compound (NVS-1) were assessed in male rats (Wistar Han). Clinical and/or functional endpoints (i.e., electronic Von Frey, Cold Plate, and Paw Pressure tests) and blood biomarkers (i.e., neurofilament light chain (NfL), neurofilament heavy chain (NF-H), microtubule-associated protein Tau (Tau), neuron specific enolase (NSE), vascular endothelial growth factor A (VEGFA), and glial fibrillary acidic protein (GFAP)) were assessed. Drug exposure and histopathological evaluations were conducted on selected nervous tissues. Oxaliplatin, cisplatin and paclitaxel treatment resulted in a significant decrease of nociceptive thresholds. Clinical signs suggestive of PNS toxicity were observed with NVS-1. NfL was consistently increased in the NVS-1 study and correlated with moderate microscopic findings in dorsal root ganglia (DRG). Only minimal microscopic findings were observed in oxaliplatin-treated animals, whereas no treatment-related microscopic findings were observed in animals treated with cisplatin and paclitaxel. For all compounds, exposure was confirmed in the PNS tissues. Clinical and functional changes were observed with all the compounds evaluated. NfL levels in plasma proved to be the most sensitive indicator of PNS toxicities, capturing moderate nervous degeneration in DRG. A combined approach that includes both functional assessments and biomarker measurements offers a more comprehensive evaluation than histopathological analysis alone when monitoring drug-induced neurotoxicity in rat models.
{"title":"The challenge to identify sensitive safety biomarkers of peripheral neurotoxicity in the rat: A collaborative effort across industry and academia (IMI NeuroDeRisk project)","authors":"Laura Micheli , David Balayssac , Jérôme Busserolles , Cristelle Dalbos , Laetitia Prival , Damien Richard , Mercedes Quintana , Lorenzo Di Cesare Mannelli , Alessandra Toti , Clara Ciampi , Carla Ghelardini , Katerina Vlasakova , Warren E. Glaab , Yang Hu , Irena Loryan , Olivier Perrault , Mohamed Slaoui , Kuno Wuersch , Eric Johnson , Wilfried Frieauff , Diethilde Theil","doi":"10.1016/j.tox.2024.153998","DOIUrl":"10.1016/j.tox.2024.153998","url":null,"abstract":"<div><div>Peripheral nervous system (PNS) toxicity assessment in non-clinical safety studies is challenging and relies mostly on histopathological assessment. The present work aims to identify blood-based biomarkers that could detect peripheral neuropathy in rats upon exposure to neurotoxic compounds. Three anticancer agents (oxaliplatin, cisplatin, paclitaxel) and a developmental compound (NVS-1) were assessed in male rats (Wistar Han). Clinical and/or functional endpoints (i.e., electronic Von Frey, Cold Plate, and Paw Pressure tests) and blood biomarkers (i.e., neurofilament light chain (NfL), neurofilament heavy chain (NF-H), microtubule-associated protein Tau (Tau), neuron specific enolase (NSE), vascular endothelial growth factor A (VEGFA), and glial fibrillary acidic protein (GFAP)) were assessed. Drug exposure and histopathological evaluations were conducted on selected nervous tissues. Oxaliplatin, cisplatin and paclitaxel treatment resulted in a significant decrease of nociceptive thresholds. Clinical signs suggestive of PNS toxicity were observed with NVS-1. NfL was consistently increased in the NVS-1 study and correlated with moderate microscopic findings in dorsal root ganglia (DRG). Only minimal microscopic findings were observed in oxaliplatin-treated animals, whereas no treatment-related microscopic findings were observed in animals treated with cisplatin and paclitaxel. For all compounds, exposure was confirmed in the PNS tissues. Clinical and functional changes were observed with all the compounds evaluated. NfL levels in plasma proved to be the most sensitive indicator of PNS toxicities, capturing moderate nervous degeneration in DRG. A combined approach that includes both functional assessments and biomarker measurements offers a more comprehensive evaluation than histopathological analysis alone when monitoring drug-induced neurotoxicity in rat models.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"510 ","pages":"Article 153998"},"PeriodicalIF":4.8,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648805","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}
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