Experimental animal models are crucial for elucidating the pathophysiology of liver injuries and for assessing new hepatoprotective agents. Drugs and chemicals such as acetaminophen, isoniazid, valproic acid, ethanol, carbon tetrachloride (CCl4), dimethylnitrosamine (DMN), and thioacetamide (TAA) are metabolized by the CYP2E1 enzyme, producing hepatotoxic metabolites that lead to both acute and chronic liver injuries. In experimental settings, acetaminophen (centrilobular necrosis), carbamazepine (centrilobular necrosis and inflammation), sodium valproate (necrosis, hydropic degeneration and mild inflammation), methotrexate (sinusoidal congestion and inflammation), and TAA (centrilobular necrosis and inflammation) are commonly used to induce various types of acute liver injuries. Repeated and intermittent low-dose administration of CCl4, TAA, and DMN activates quiescent hepatic stellate cells, transdifferentiating them into myofibroblasts, which results in abnormal extracellular matrix production and fibrosis induction, more rapidly with DMN and CCL4 than TAA (DMN > CCl4 > TAA). Regarding toxicity and mortality, CCl4 is more toxic than DMN and TAA (CCl4 > DMN > TAA). Models used to induce metabolic dysfunction-associated liver disease (MAFLD) vary, but MAFLD's multifactorial nature driven by factors like obesity, fatty liver, dyslipidaemia, type II diabetes, hypertension, and cardiovascular disease makes it challenging to replicate human metabolic dysfunction-associated steatohepatitis accurately. From an experimental point of view, the degree and pattern of liver injury are influenced by various factors, including the type of hepatotoxic agent, exposure duration, route of exposure, dosage, frequency of administration, and the animal model utilized. Therefore, there is a pressing need for standardized protocols and regulatory guidelines to streamline the selection of animal models in preclinical studies.
{"title":"Preclinical liver toxicity models: Advantages, limitations and recommendations.","authors":"Devaraj Ezhilarasan, Sivanesan Karthikeyan, Mustapha Najimi, Paramasivan Vijayalakshmi, Ganapathy Bhavani, Muthukrishnan Jansi Rani","doi":"10.1016/j.tox.2024.154020","DOIUrl":"10.1016/j.tox.2024.154020","url":null,"abstract":"<p><p>Experimental animal models are crucial for elucidating the pathophysiology of liver injuries and for assessing new hepatoprotective agents. Drugs and chemicals such as acetaminophen, isoniazid, valproic acid, ethanol, carbon tetrachloride (CCl<sub>4</sub>), dimethylnitrosamine (DMN), and thioacetamide (TAA) are metabolized by the CYP2E1 enzyme, producing hepatotoxic metabolites that lead to both acute and chronic liver injuries. In experimental settings, acetaminophen (centrilobular necrosis), carbamazepine (centrilobular necrosis and inflammation), sodium valproate (necrosis, hydropic degeneration and mild inflammation), methotrexate (sinusoidal congestion and inflammation), and TAA (centrilobular necrosis and inflammation) are commonly used to induce various types of acute liver injuries. Repeated and intermittent low-dose administration of CCl<sub>4</sub>, TAA, and DMN activates quiescent hepatic stellate cells, transdifferentiating them into myofibroblasts, which results in abnormal extracellular matrix production and fibrosis induction, more rapidly with DMN and CCL<sub>4</sub> than TAA (DMN > CCl<sub>4</sub> > TAA). Regarding toxicity and mortality, CCl<sub>4</sub> is more toxic than DMN and TAA (CCl<sub>4</sub> > DMN > TAA). Models used to induce metabolic dysfunction-associated liver disease (MAFLD) vary, but MAFLD's multifactorial nature driven by factors like obesity, fatty liver, dyslipidaemia, type II diabetes, hypertension, and cardiovascular disease makes it challenging to replicate human metabolic dysfunction-associated steatohepatitis accurately. From an experimental point of view, the degree and pattern of liver injury are influenced by various factors, including the type of hepatotoxic agent, exposure duration, route of exposure, dosage, frequency of administration, and the animal model utilized. Therefore, there is a pressing need for standardized protocols and regulatory guidelines to streamline the selection of animal models in preclinical studies.</p>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":" ","pages":"154020"},"PeriodicalIF":4.8,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142786856","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 : 2024-11-30DOI: 10.1016/j.tox.2024.154019
Rashida Hameed, Divyabharathi R, Krishna Kumar Yadav, Prasenjit Debbarma, Shiv Vendra Singh, Amir Ibrahim Ali Arabi, Adeel Abbas, Shubham Anil Durgude, Mir Waqas Alam, Chongqing Wang
In today's fast-paced technological era, multifaceted technological advancements in our contemporary lifestyle are surging the use of electronic devices, which are significantly piling e-waste and posing environmental concerns. This stock of e-waste is expected to keep rising up to 50 mt year-1. Formal recycling of such humongous waste is a major challenge, especially in developing nations. Mishandling of e-waste poses serious threats to human health, soil, and water ecosystem, threatening ecological and environmental sustainability. Complex matrix of resourceful materials comprising valuable metals like gold, silver, and copper, and hazardous substances such as lead, mercury, cadmium, and brominated flame retardants make its judicious management even more crucial. Potential toxic elements such as Pb, Cd, Cr, As, and Hg, as well as plastic/microplastics, nanoparticles are prevalent in components like batteries, cathode ray tubes, circuit boards, glass and plastic components which are known to cause neurological, renal, and developmental damage in humans. Effective and sustainable management of these requires a comprehensive understanding of their sources, environmental behavior, and toxicological impacts. This review explores potential approached for sustainable e-waste recycling (recycling of glass, plastic, rare earth metals, and base metals), and resource recycling through pyrometallurgy, hydrometallurgy, biometallurgy, biohydrometallurgy, bioleaching and biodegradation plastic alongside challenges and prospects.
{"title":"A review on sustainable management strategies for navigating the piling e-waste crisis and associated environmental threats.","authors":"Rashida Hameed, Divyabharathi R, Krishna Kumar Yadav, Prasenjit Debbarma, Shiv Vendra Singh, Amir Ibrahim Ali Arabi, Adeel Abbas, Shubham Anil Durgude, Mir Waqas Alam, Chongqing Wang","doi":"10.1016/j.tox.2024.154019","DOIUrl":"10.1016/j.tox.2024.154019","url":null,"abstract":"<p><p>In today's fast-paced technological era, multifaceted technological advancements in our contemporary lifestyle are surging the use of electronic devices, which are significantly piling e-waste and posing environmental concerns. This stock of e-waste is expected to keep rising up to 50 mt year<sup>-1</sup>. Formal recycling of such humongous waste is a major challenge, especially in developing nations. Mishandling of e-waste poses serious threats to human health, soil, and water ecosystem, threatening ecological and environmental sustainability. Complex matrix of resourceful materials comprising valuable metals like gold, silver, and copper, and hazardous substances such as lead, mercury, cadmium, and brominated flame retardants make its judicious management even more crucial. Potential toxic elements such as Pb, Cd, Cr, As, and Hg, as well as plastic/microplastics, nanoparticles are prevalent in components like batteries, cathode ray tubes, circuit boards, glass and plastic components which are known to cause neurological, renal, and developmental damage in humans. Effective and sustainable management of these requires a comprehensive understanding of their sources, environmental behavior, and toxicological impacts. This review explores potential approached for sustainable e-waste recycling (recycling of glass, plastic, rare earth metals, and base metals), and resource recycling through pyrometallurgy, hydrometallurgy, biometallurgy, biohydrometallurgy, bioleaching and biodegradation plastic alongside challenges and prospects.</p>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":" ","pages":"154019"},"PeriodicalIF":4.8,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142772632","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 : 2024-11-29DOI: 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}
Skin toxicities are the most common adverse effects of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). While EGFR-TKIs induce pyroptosis in lung cancer cells through Gasdermin E (GSDME) activation, it is unknown whether they can similarly affect skin cells. In this study, we used immunohistochemistry to demonstrate that in acneiform rash, the N-terminus of GSDME (GSDME-N) is predominantly expressed in the basal layer of the follicular epithelium and sebocytes, while it is absent in the interfollicular epidermis. In contrast, in cases of xerosis or secondary eczematous rash, GSDME-N was significantly expressed in the basal layer of the interfollicular epidermis and weakly or partially positive in the follicular epithelium. Bright-field microscopy of HaCaT and SZ95 cells treated with afatinib revealed cell swelling and large bubble formation, while scanning electron microscopy showed a reduction in microvilli and membrane pores formation. Transmission electron microscopy further revealed multiple membrane pores and decreased cytoplasmic density. Importantly, we found that GSDME is cleaved during afatinib-induced pyroptosis via caspase-3 activation. ELISA analysis further confirmed that afatinib-treated cells released elevated levels of HMGB1 and IL-1α. Meanwhile, inhibition of caspase-3 activity or knockdown of GSDME both suppressed afatinib-induced pyroptosis, while GSDME elimination did not affect caspase-3 activation. These results indicate that afatinib-induced pyroptosis in keratinocytes and sebocytes is mediated by the caspase-3/GSDME pathway. Our findings suggest that GSDME-dependent pyroptosis in HaCaT and SZ95 cells contributes to the development of acneiform rash and xerosis, highlighting the need for further investigation into the underlying mechanisms.
皮肤毒性是表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）最常见的不良反应。虽然EGFR-TKIs通过激活Gasdermin E （GSDME）诱导肺癌细胞焦亡，但它们是否能类似地影响皮肤细胞尚不清楚。在本研究中，我们使用免疫组织化学方法证明，在痘样皮疹中，GSDME的n端（GSDME- n）主要在滤泡上皮和皮脂细胞的基底层表达，而在滤泡间表皮中不存在。相反，在干燥或继发性湿疹皮疹的病例中，GSDME-N在滤泡间表皮的基底层显著表达，在滤泡上皮中弱或部分阳性。经阿法替尼处理的HaCaT和SZ95细胞在亮场显微镜下显示细胞肿胀和大泡形成，扫描电镜显示微绒毛和膜孔形成减少。透射电镜进一步显示多个膜孔和降低的细胞质密度。重要的是，我们发现GSDME在阿法替尼诱导的焦亡过程中通过caspase-3激活被切割。ELISA分析进一步证实，阿法替尼处理的细胞释放的HMGB1和IL-1α水平升高。同时，抑制caspase-3活性或敲低GSDME均能抑制阿法替尼诱导的焦亡，而消除GSDME不影响caspase-3的激活。这些结果表明，阿法替尼诱导的角质形成细胞和皮脂细胞的焦亡是通过caspase-3/GSDME途径介导的。我们的研究结果表明，HaCaT和SZ95细胞中gsdme依赖性的焦亡有助于痤疮样皮疹和干燥的发展，强调需要进一步研究其潜在机制。
{"title":"EGFR-TKIs induce acneiform rash and xerosis via Caspase-3/GSDME-mediated pyroptosis of keratinocytes and sebocytes.","authors":"Huiling Zhu, Qiuyun She, Hongmei Li, Ning Zhang, Weining Huang, Yingping Xu, Zhongrong Liu, Yunsheng Liang","doi":"10.1016/j.tox.2024.154018","DOIUrl":"10.1016/j.tox.2024.154018","url":null,"abstract":"<p><p>Skin toxicities are the most common adverse effects of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). While EGFR-TKIs induce pyroptosis in lung cancer cells through Gasdermin E (GSDME) activation, it is unknown whether they can similarly affect skin cells. In this study, we used immunohistochemistry to demonstrate that in acneiform rash, the N-terminus of GSDME (GSDME-N) is predominantly expressed in the basal layer of the follicular epithelium and sebocytes, while it is absent in the interfollicular epidermis. In contrast, in cases of xerosis or secondary eczematous rash, GSDME-N was significantly expressed in the basal layer of the interfollicular epidermis and weakly or partially positive in the follicular epithelium. Bright-field microscopy of HaCaT and SZ95 cells treated with afatinib revealed cell swelling and large bubble formation, while scanning electron microscopy showed a reduction in microvilli and membrane pores formation. Transmission electron microscopy further revealed multiple membrane pores and decreased cytoplasmic density. Importantly, we found that GSDME is cleaved during afatinib-induced pyroptosis via caspase-3 activation. ELISA analysis further confirmed that afatinib-treated cells released elevated levels of HMGB1 and IL-1α. Meanwhile, inhibition of caspase-3 activity or knockdown of GSDME both suppressed afatinib-induced pyroptosis, while GSDME elimination did not affect caspase-3 activation. These results indicate that afatinib-induced pyroptosis in keratinocytes and sebocytes is mediated by the caspase-3/GSDME pathway. Our findings suggest that GSDME-dependent pyroptosis in HaCaT and SZ95 cells contributes to the development of acneiform rash and xerosis, highlighting the need for further investigation into the underlying mechanisms.</p>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":" ","pages":"154018"},"PeriodicalIF":4.8,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142751678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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}
Pub Date : 2024-11-17DOI: 10.1016/j.tox.2024.154000
Malene Lislien , Eliska Kuchovska , Julia Kapr , Nur Duale , Jill Mari Andersen , Hubert Dirven , Oddvar Myhre , Ellen Fritsche , Katharina Koch , Marcin W. Wojewodzic
The safety and developmental neurotoxicity (DNT) potential of chemicals remain critically understudied due to limitations of current in vivo testing guidelines, which are low throughput, resource-intensive, and hindered by species differences that limit their relevance to human health. To address these issues, robust New Approach Methodologies (NAMs) using deeply characterized cell models are essential. This study presents the comprehensive transcriptomic characterization of two advanced human-induced pluripotent stem cell (hiPSC)-derived models: a 2D adherent and a 3D neurosphere model of human neural progenitor cells (hiNPCs) differentiated up to 21 days. Using high-throughput RNA sequencing, we compared gene expression profiles of 2D and 3D models at three developmental stages (3, 14, and 21 days of differentiation). Both models exhibit maturation towards post-mitotic neurons, with the 3D model maturing faster and showing a higher prevalence of GABAergic neurons, while the 2D model is enriched with glutamatergic neurons. Both models demonstrate broad applicability domains, including excitatory and inhibitory neurons, astrocytes, and key endocrine and especially the understudied cholinergic receptors. Comparison with human fetal brain samples confirms their physiological relevance. This study provides novel in-depth applicability insights into the temporal and dimensional aspects of hiPSC-derived neural models for DNT testing. The complementary use of these two models is highlighted: the 2D model excels in synaptogenesis assessment, while the 3D model is particularly suited for neural network formation as observed as well in previous functional studies with these models. This research marks a significant advancement in developing human-relevant, high-throughput DNT assays for regulatory purposes.
{"title":"Transcriptomic characterization of 2D and 3D human induced pluripotent stem cell-based in vitro models as New Approach Methodologies for developmental neurotoxicity testing","authors":"Malene Lislien , Eliska Kuchovska , Julia Kapr , Nur Duale , Jill Mari Andersen , Hubert Dirven , Oddvar Myhre , Ellen Fritsche , Katharina Koch , Marcin W. Wojewodzic","doi":"10.1016/j.tox.2024.154000","DOIUrl":"10.1016/j.tox.2024.154000","url":null,"abstract":"<div><div>The safety and developmental neurotoxicity (DNT) potential of chemicals remain critically understudied due to limitations of current <em>in vivo</em> testing guidelines, which are low throughput, resource-intensive, and hindered by species differences that limit their relevance to human health. To address these issues, robust New Approach Methodologies (NAMs) using deeply characterized cell models are essential. This study presents the comprehensive transcriptomic characterization of two advanced human-induced pluripotent stem cell (hiPSC)-derived models: a 2D adherent and a 3D neurosphere model of human neural progenitor cells (hiNPCs) differentiated up to 21 days. Using high-throughput RNA sequencing, we compared gene expression profiles of 2D and 3D models at three developmental stages (3, 14, and 21 days of differentiation). Both models exhibit maturation towards post-mitotic neurons, with the 3D model maturing faster and showing a higher prevalence of GABAergic neurons, while the 2D model is enriched with glutamatergic neurons. Both models demonstrate broad applicability domains, including excitatory and inhibitory neurons, astrocytes, and key endocrine and especially the understudied cholinergic receptors. Comparison with human fetal brain samples confirms their physiological relevance. This study provides novel in-depth applicability insights into the temporal and dimensional aspects of hiPSC-derived neural models for DNT testing. The complementary use of these two models is highlighted: the 2D model excels in synaptogenesis assessment, while the 3D model is particularly suited for neural network formation as observed as well in previous functional studies with these models. This research marks a significant advancement in developing human-relevant, high-throughput DNT assays for regulatory purposes.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"510 ","pages":"Article 154000"},"PeriodicalIF":4.8,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648807","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}
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