Pub Date : 2025-02-01DOI: 10.1016/j.tox.2025.154045
Miao Guo , Ming-Yue Qiu , Lin Zeng , Ya-Xiong Nie , Ya-Ling Tang , Yan Luo , Hong-Feng Gu
Although it has been confirmed that acid-sensing ion channel 1 (ASIC1) plays a critical role in acidosis-induced neuronal injury and death, its underlying mechanisms remain largely unclear. In the present study, we investigated the involvement of ASIC1 in acidosis-induced neuronal death and its underlying mechanisms in HT22 neurons. The neurons were cultured in acidic medium to mimic extracellular acidosis. Cell viability and death, autophagy, ASIC1 expression, and the phosphorylation of Akt and mTOR were evaluated. Our results demonstrated that acidosis markedly increased the cell death rate, which was profoundly reversed by 3-MA (an autophagy inhibitor) but exacerbated by rapamycin (an autophagy activator). Moreover, our results indicated that acidosis induced excessive autophagy by increasing the expression and translocation of ASIC1, and decreasing the phosphorylation of the Akt and mTOR proteins. Intriguingly, inhibiting the activation of ASIC1 with its blocker PcTx-1 not only significantly decreased acidosis-induced neurotoxicity but also markedly compromised acidosis-induced autophagy and Akt/mTOR signaling inactivation, as evidenced by a decrease in the neuronal death rate, LC3Ⅱ/LC3Ⅰ ratio, and autophagosome number as well as p62 degradation and an increase in the phosphorylation of Akt and mTOR. Collectively, these results indicate that acidosis exerts its cytotoxic effects on HT22 neurons by inducing autophagic cell death through the ASIC1-related Akt/mTOR signaling pathway.
{"title":"Acidosis induces autophagic cell death through ASIC1-mediated Akt/mTOR signaling in HT22 neurons","authors":"Miao Guo , Ming-Yue Qiu , Lin Zeng , Ya-Xiong Nie , Ya-Ling Tang , Yan Luo , Hong-Feng Gu","doi":"10.1016/j.tox.2025.154045","DOIUrl":"10.1016/j.tox.2025.154045","url":null,"abstract":"<div><div>Although it has been confirmed that acid-sensing ion channel 1 (ASIC1) plays a critical role in acidosis-induced neuronal injury and death, its underlying mechanisms remain largely unclear. In the present study, we investigated the involvement of ASIC1 in acidosis-induced neuronal death and its underlying mechanisms in HT22 neurons. The neurons were cultured in acidic medium to mimic extracellular acidosis. Cell viability and death, autophagy, ASIC1 expression, and the phosphorylation of Akt and mTOR were evaluated. Our results demonstrated that acidosis markedly increased the cell death rate, which was profoundly reversed by 3-MA (an autophagy inhibitor) but exacerbated by rapamycin (an autophagy activator). Moreover, our results indicated that acidosis induced excessive autophagy by increasing the expression and translocation of ASIC1, and decreasing the phosphorylation of the Akt and mTOR proteins. Intriguingly, inhibiting the activation of ASIC1 with its blocker PcTx-1 not only significantly decreased acidosis-induced neurotoxicity but also markedly compromised acidosis-induced autophagy and Akt/mTOR signaling inactivation, as evidenced by a decrease in the neuronal death rate, LC3Ⅱ/LC3Ⅰ ratio, and autophagosome number as well as p62 degradation and an increase in the phosphorylation of Akt and mTOR. Collectively, these results indicate that acidosis exerts its cytotoxic effects on HT22 neurons by inducing autophagic cell death through the ASIC1-related Akt/mTOR signaling pathway.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154045"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932549","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 : 2025-02-01DOI: 10.1016/j.tox.2025.154051
Geun-Young Kim , Suji Kim , Kihong Park , Hyun-Joung Lim , Won-Ho Kim
Gasoline exhaust particles (GEP) are risk factors for cardiovascular disease. Activating transcription factor 3 (ATF3) is a transcription factor known to form a heterodimer with AP-1 transcription factors for its target gene expression. However, the involvement of ATF3 in GEP-induced gene expression in human umbilical vein endothelial cells (HUVECs) has not been investigated. In this study, we found that GEP, at IC50 value of 59 μg/ml, induced the expression of ATF3, which led to the expression of matrix metalloproteinase 1 (MMP1) in HUVECs. GEP induce an interaction between c-Jun and ATF3, and c-Jun depletion attenuates GEP-induced MMP1 expression. Depletion of NADPH oxidase 4 (Nox4) suppressed GEP-induced reactive oxygen species (ROS) generation and the subsequent upregulation of ATF3 and MMP1, suggesting that Nox4-derived ROS play a role as upstream regulators of GEP-induced ATF3 expression and MMP1 upregulation. Furthermore, Nox4 depletion attenuated the interaction between ATF3 and c-Jun and their binding to the AP-1 binding site of the MMP1 promoter. Taken together, these findings demonstrate that GEP induce the expression of MMP1 by generating Nox4-dependent ROS, which subsequently increase ATF3 expression and its interaction with c-Jun. This leads to their binding to the promoter region of MMP1 and its transcription. These findings suggest that Nox4-derived ROS and ATF3 are critical for GEP-induced MMP1 expression.
{"title":"Gasoline exhaust particles induce MMP1 expression via Nox4-derived ROS-ATF3-linked pathway in human umbilical vein endothelial cells","authors":"Geun-Young Kim , Suji Kim , Kihong Park , Hyun-Joung Lim , Won-Ho Kim","doi":"10.1016/j.tox.2025.154051","DOIUrl":"10.1016/j.tox.2025.154051","url":null,"abstract":"<div><div>Gasoline exhaust particles (GEP) are risk factors for cardiovascular disease. Activating transcription factor 3 (ATF3) is a transcription factor known to form a heterodimer with AP-1 transcription factors for its target gene expression. However, the involvement of ATF3 in GEP-induced gene expression in human umbilical vein endothelial cells (HUVECs) has not been investigated. In this study, we found that GEP, at IC<sub>50</sub> value of 59 μg/ml, induced the expression of ATF3, which led to the expression of matrix metalloproteinase 1 (MMP1) in HUVECs. GEP induce an interaction between c-Jun and ATF3, and c-Jun depletion attenuates GEP-induced MMP1 expression. Depletion of NADPH oxidase 4 (Nox4) suppressed GEP-induced reactive oxygen species (ROS) generation and the subsequent upregulation of ATF3 and MMP1, suggesting that Nox4-derived ROS play a role as upstream regulators of GEP-induced ATF3 expression and MMP1 upregulation. Furthermore, Nox4 depletion attenuated the interaction between ATF3 and c-Jun and their binding to the AP-1 binding site of the MMP1 promoter. Taken together, these findings demonstrate that GEP induce the expression of MMP1 by generating Nox4-dependent ROS, which subsequently increase ATF3 expression and its interaction with c-Jun. This leads to their binding to the promoter region of MMP1 and its transcription. These findings suggest that Nox4-derived ROS and ATF3 are critical for GEP-induced MMP1 expression.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154051"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967050","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}
Malathion is an organophosphate compound widely used as an insecticide in the agriculture sector and is toxic to humans and other mammals. Although several studies have been conducted at different levels in different animal models. But there is no work has been conducted on the toxicological correlation from cellular to behavioral level in surviving species model. Addressing this gap through further research is essential for a comprehensive understanding of malathion's impact on biological systems, facilitating better risk assessment and management strategies.
Current research systemically evaluated the effects of malathion on the central nervous system and peripheral immune cells using immunological techniques in the BALB/c mice models. For this, animals were placed inside an inhalation chamber containing malathion (dose of 89.5 mg/ml/m3) for a specific exposure time. The group exposed for 6 minutes has shown a significant change in plasma-neurotransmitter (serotonin, dopamine) levels and decreased expression of Tyrosine hydroxylase in striatum and SNPC region of brain. The depolarized mitochondria and increased level of cleaved caspase-3 level and mature neurons in DG, CA1 and CA3 were also observed in the brain. Peripheral blood analysis illustrated a decrease in total leukocyte count and an increased level of early apoptosis at the same time point. From neurobehavioral results a significant locomotor hyperactivity, restlessness, and risk-taking behavior was observed. Taken together, results from the current study indicate that exposure to malathion at prolonged time durations induces neuronal and immune cell toxicity, and its toxicity may be mediated via changes in neurotransmitter levels and metabolite concentrations.
{"title":"From cell to organ: Exploring the toxicological correlation of organophosphorus compounds in living system","authors":"Pooja Yadav , Ashrit Nair , Raman Chawla , Subhajit Ghosh , Mohd Aleem , Bhupendra Singh Butola , Navneet Sharma , Haider Ali Khan","doi":"10.1016/j.tox.2025.154049","DOIUrl":"10.1016/j.tox.2025.154049","url":null,"abstract":"<div><div>Malathion is an organophosphate compound widely used as an insecticide in the agriculture sector and is toxic to humans and other mammals. Although several studies have been conducted at different levels in different animal models. But there is no work has been conducted on the toxicological correlation from cellular to behavioral level in surviving species model. Addressing this gap through further research is essential for a comprehensive understanding of malathion's impact on biological systems, facilitating better risk assessment and management strategies.</div><div>Current research systemically evaluated the effects of malathion on the central nervous system and peripheral immune cells using immunological techniques in the BALB/c mice models. For this, animals were placed inside an inhalation chamber containing malathion (dose of 89.5 mg/ml/m<sup>3</sup>) for a specific exposure time. The group exposed for 6 minutes has shown a significant change in plasma-neurotransmitter (serotonin, dopamine) levels and decreased expression of Tyrosine hydroxylase in striatum and SNPC region of brain. The depolarized mitochondria and increased level of cleaved caspase-3 level and mature neurons in DG, CA1 and CA3 were also observed in the brain. Peripheral blood analysis illustrated a decrease in total leukocyte count and an increased level of early apoptosis at the same time point. From neurobehavioral results a significant locomotor hyperactivity, restlessness, and risk-taking behavior was observed. Taken together, results from the current study indicate that exposure to malathion at prolonged time durations induces neuronal and immune cell toxicity, and its toxicity may be mediated via changes in neurotransmitter levels and metabolite concentrations.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154049"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972204","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}
Cadmium is a heavy metal risk factor for various cardiovascular diseases, such as atherosclerosis. In atherosclerotic lesions, hyaluronan, a glycosaminoglycan consisting of β4-glucuronic acid-β3-N-acetylglucosamine disaccharides repeats, is highly accumulated, regulating signal transduction, cell migration, and angiogenesis. Hyaluronan is synthesized by hyaluronan synthase (HAS)1-3 in the plasma membrane and secreted into the extracellular space. Hyaluronan derived from HAS3 promotes inflammatory responses. Recently, we found that cadmium elongates chondroitin/dermatan sulfate chains in vascular endothelial cells and that glycosaminoglycan sugar chains are potential targets for the vascular toxicity of cadmium. Therefore, hyaluronan, a glycosaminoglycan sugar chain, may also affected by cadmium; however, this has not yet been clarified. In this study, we aimed to analyze the effect of cadmium on hyaluronan synthesis using cultured aortic endothelial cells. Cadmium at a concentration of 2 µM upregulated hyaluronan synthesis in the medium and specifically induced HAS3 mRNA and protein expression. However, cadmium-mediated HAS3 induction was abolished by the inhibition of the c-Jun N-terminal kinase (JNK)–c-Jun pathway. Moreover, JNK inhibition prevented the increase in hyaluronan levels in the medium. These results revealed that the JNK–c-Jun pathway was involved in HAS3-mediated hyaluronan synthesis by cadmium in vascular endothelial cells, suggesting that endothelial HAS3 induction contributes to atherosclerotic lesion formation by promoting inflammatory responses.
镉是导致动脉粥样硬化等多种心血管疾病的重金属危险因素。在动脉粥样硬化病变中，透明质酸是一种由β4-葡萄糖醛酸-β3- n -乙酰氨基葡萄糖胺双糖重复序列组成的糖胺聚糖，它高度积累，调节信号转导、细胞迁移和血管生成。透明质酸是由质膜中的透明质酸合成酶（HAS）1-3合成并分泌到细胞外空间。来源于HAS3的透明质酸促进炎症反应。最近，我们发现镉延长了血管内皮细胞中的软骨素/硫酸皮聚糖链，而糖胺聚糖链是镉血管毒性的潜在靶点。因此，糖胺聚糖糖链透明质酸也可能受到镉的影响；然而，这一点尚未得到澄清。在这项研究中，我们旨在分析镉对培养的主动脉内皮细胞透明质酸合成的影响。浓度为2µM的镉上调了培养基中透明质酸的合成，并特异性诱导了HAS3 mRNA和蛋白的表达。然而，镉介导的HAS3诱导被c-Jun n -末端激酶(JNK)-c-Jun通路的抑制所消除。此外，JNK抑制阻止了培养基中透明质酸水平的增加。这些结果表明，JNK-c-Jun通路参与了镉在血管内皮细胞中介导的HAS3介导的透明质酸合成，提示内皮HAS3诱导通过促进炎症反应参与动脉粥样硬化病变的形成。
{"title":"Cadmium promotes hyaluronan synthesis by inducing hyaluronan synthase 3 expression in cultured vascular endothelial cells via the c-Jun N-terminal kinase–c-Jun pathway","authors":"Misaki Shirai , Takato Hara , Toshiyuki Kaji , Chika Yamamoto","doi":"10.1016/j.tox.2025.154062","DOIUrl":"10.1016/j.tox.2025.154062","url":null,"abstract":"<div><div>Cadmium is a heavy metal risk factor for various cardiovascular diseases, such as atherosclerosis. In atherosclerotic lesions, hyaluronan, a glycosaminoglycan consisting of β4-glucuronic acid-β3-<em>N</em>-acetylglucosamine disaccharides repeats, is highly accumulated, regulating signal transduction, cell migration, and angiogenesis. Hyaluronan is synthesized by hyaluronan synthase (HAS)1-3 in the plasma membrane and secreted into the extracellular space. Hyaluronan derived from HAS3 promotes inflammatory responses. Recently, we found that cadmium elongates chondroitin/dermatan sulfate chains in vascular endothelial cells and that glycosaminoglycan sugar chains are potential targets for the vascular toxicity of cadmium. Therefore, hyaluronan, a glycosaminoglycan sugar chain, may also affected by cadmium; however, this has not yet been clarified. In this study, we aimed to analyze the effect of cadmium on hyaluronan synthesis using cultured aortic endothelial cells. Cadmium at a concentration of 2 µM upregulated hyaluronan synthesis in the medium and specifically induced HAS3 mRNA and protein expression. However, cadmium-mediated HAS3 induction was abolished by the inhibition of the c-Jun N-terminal kinase (JNK)–c-Jun pathway. Moreover, JNK inhibition prevented the increase in hyaluronan levels in the medium. These results revealed that the JNK–c-Jun pathway was involved in HAS3-mediated hyaluronan synthesis by cadmium in vascular endothelial cells, suggesting that endothelial HAS3 induction contributes to atherosclerotic lesion formation by promoting inflammatory responses.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154062"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143010919","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 : 2025-02-01DOI: 10.1016/j.tox.2024.154040
Megan E. Cull , Louise M. Winn
Bisphenol A (BPA) is an organic synthetic chemical used worldwide. Billions of pounds of BPA are produced annually through industrial processes to be used in commercial products, making human exposure to BPA ubiquitous. Concerns have been raised due to the potential adverse health effects of BPA, specifically in vulnerable populations, such as pregnant persons and children. BPA is an endocrine-disrupting chemical, and through this function has been linked to reproductive toxicity. We review BPA’s historical and current use, health and safety concerns and regulations, sources of exposure, and evidence for male and female reproductive toxicity. Evidence from epidemiological and animal studies idenfity that low- and high-exposure levels of BPA (prenatal, postnatal and adulthood exposure) can adversely affect male and female fertility and reproductive organs. While the cause of BPA-induced reproductive toxicity is not fully understood, we discuss BPA’s estrogenic and androgenic activity, and its ability to disrupt the hypothalamic-pituitary-gonadal axis as a potential associated mechanism. There are significant differences in tolerable daily intakes of BPA set by global agencies, making interpretation of previous and emerging research findings challenging and inconsistent. Although BPA is deemed toxic by some government agencies, most do not currently consider it a health risk due to low populational exposure levels. However, we highlight evidence that even at acute, low exposure, BPA can adversely affect reproductive function. We recommend continuing research into the adverse effects of BPA on human health and revisiting the regulatory measures of BPA to limit exposure and promote public awareness of its potential to cause reproductive toxicity.
{"title":"Bisphenol A and its potential mechanism of action for reproductive toxicity","authors":"Megan E. Cull , Louise M. Winn","doi":"10.1016/j.tox.2024.154040","DOIUrl":"10.1016/j.tox.2024.154040","url":null,"abstract":"<div><div>Bisphenol A (BPA) is an organic synthetic chemical used worldwide. Billions of pounds of BPA are produced annually through industrial processes to be used in commercial products, making human exposure to BPA ubiquitous. Concerns have been raised due to the potential adverse health effects of BPA, specifically in vulnerable populations, such as pregnant persons and children. BPA is an endocrine-disrupting chemical, and through this function has been linked to reproductive toxicity. We review BPA’s historical and current use, health and safety concerns and regulations, sources of exposure, and evidence for male and female reproductive toxicity. Evidence from epidemiological and animal studies idenfity that low- and high-exposure levels of BPA (prenatal, postnatal and adulthood exposure) can adversely affect male and female fertility and reproductive organs. While the cause of BPA-induced reproductive toxicity is not fully understood, we discuss BPA’s estrogenic and androgenic activity, and its ability to disrupt the hypothalamic-pituitary-gonadal axis as a potential associated mechanism. There are significant differences in tolerable daily intakes of BPA set by global agencies, making interpretation of previous and emerging research findings challenging and inconsistent. Although BPA is deemed toxic by some government agencies, most do not currently consider it a health risk due to low populational exposure levels. However, we highlight evidence that even at acute, low exposure, BPA can adversely affect reproductive function. We recommend continuing research into the adverse effects of BPA on human health and revisiting the regulatory measures of BPA to limit exposure and promote public awareness of its potential to cause reproductive toxicity.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154040"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142898459","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 : 2025-02-01DOI: 10.1016/j.tox.2024.154035
M. Marraudino , S. Nasini , C. Porte , B. Bonaldo , E. Macchi , G. Ponti , M. Keller , S. Gotti
Genistein (GEN) is a phytoestrogen with oestrogen-like activity found in many plants. Classified as an endocrine disruptor, GEN is potentially hazardous, particularly during developmental stages. It induces alterations in anxious behaviour, fertility, and energy metabolism, alongside modifications in specific brain circuits. As the serotonin (5-HT) system is critically involved in many of these behaviours, we hypothesised that some of GEN’s behavioural effects might results from disruptions in the development of the 5-HT system. To test this, we examined the impact of early postnatal exposure to GEN at a dose of 50 mg/kg body weight, mimicking the exposure level of infants consuming soy-based formulas, on anxiety-related behaviours and 5-HT neuronal populations in the raphe nucleus. Male and female CD1 mice were treated orally with GEN or a vehicle during the first 8 days of life. On postnatal day 60, one cohort underwent anxiety behaviour testing, while another was euthanised for immunohistochemical analysis. Behavioural testing revealed that male control mice exhibited higher anxiety levels than females, whereas GEN exposure produced sex-specific effects: anxiolytic in males and anxiogenic in females. Immunohistochemical analysis of the raphe nuclei demonstrated significant alterations in 5-HT neuronal numbers in GEN-treated animals. Specifically, GEN exposure affected dorsal and median raphe 5-HT neuronal populations in a sexually dimorphic manner, with females showing a reduction and males an increase in 5-HT neurones compared to controls. These findings indicate that the regulation of anxiety-related behaviours and the 5-HT system are key targets of early phytoestrogen exposure at levels comparable to those in soy-based infant formulas.
{"title":"Infant mice fed soy-based formulas exhibit alterations in anxiety-like behaviours and the 5-HT system","authors":"M. Marraudino , S. Nasini , C. Porte , B. Bonaldo , E. Macchi , G. Ponti , M. Keller , S. Gotti","doi":"10.1016/j.tox.2024.154035","DOIUrl":"10.1016/j.tox.2024.154035","url":null,"abstract":"<div><div>Genistein (GEN) is a phytoestrogen with oestrogen-like activity found in many plants. Classified as an endocrine disruptor, GEN is potentially hazardous, particularly during developmental stages. It induces alterations in anxious behaviour, fertility, and energy metabolism, alongside modifications in specific brain circuits. As the serotonin (5-HT) system is critically involved in many of these behaviours, we hypothesised that some of GEN’s behavioural effects might results from disruptions in the development of the 5-HT system. To test this, we examined the impact of early postnatal exposure to GEN at a dose of 50 mg/kg body weight, mimicking the exposure level of infants consuming soy-based formulas, on anxiety-related behaviours and 5-HT neuronal populations in the raphe nucleus. Male and female CD1 mice were treated orally with GEN or a vehicle during the first 8 days of life. On postnatal day 60, one cohort underwent anxiety behaviour testing, while another was euthanised for immunohistochemical analysis. Behavioural testing revealed that male control mice exhibited higher anxiety levels than females, whereas GEN exposure produced sex-specific effects: anxiolytic in males and anxiogenic in females. Immunohistochemical analysis of the raphe nuclei demonstrated significant alterations in 5-HT neuronal numbers in GEN-treated animals. Specifically, GEN exposure affected dorsal and median raphe 5-HT neuronal populations in a sexually dimorphic manner, with females showing a reduction and males an increase in 5-HT neurones compared to controls. These findings indicate that the regulation of anxiety-related behaviours and the 5-HT system are key targets of early phytoestrogen exposure at levels comparable to those in soy-based infant formulas.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154035"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872047","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}
Hexafluoropropylene oxide dimer acid (HFPO-DA), which belongs to the class of perfluoroalkyl ether carboxylic acid (PFECA), is a new alternative to perfluorooctanoic acid (PFOA). However, whether HFPO-DA is a safer alternative to PFOA in neonates remains unclear. In this study, we evaluated neonatal hepatic toxicity on postnatal days 9–10 by orally exposing pregnant CD-1 mice to 0.3 or 3.0 mg/kg/day (low or high doses) of HFPO-DA or PFOA from gestation days 15–17. The results showed that exposure of pregnant mice to HFPO-DA and PFOA induced similar phenotypic effects, including significant decreases in neonatal body weight (BW) and significant increases in liver weight relative to BW in the high-dose. Notably, HFPO-DA exposure significantly decreased in neonatal BW in the low-dose group, whereas PFOA did not. Comprehensive gene expression analysis revealed significant alterations in 408 and 1402 differentially expressed genes (DEGs) in the liver of neonates from the low- and high-dose HFPO-DA groups, respectively, while PFOA significantly altered 0 and 292 DEGs in the corresponding groups. Gene set enrichment analysis indicated that the DEGs induced by HFPO-DA and PFOA were enriched in pathway related to “PPAR signaling”, “fatty acid metabolism”, and “biological oxidations”. In addition, transactivation assays revealed that mouse (m)PPARα and mPPARγ activity of HFPO-DA exceeds that of PFOA and molecular docking simulations analysis predicted that the binding conformation differ between PFOA and HFPO-DA. Overall, our findings demonstrate that HFPO-DA consistently affected neonatal phenotypes, liver gene expression and the molecular initiating events involving PPARα/γ, at lower concentrations than PFOA.
{"title":"Comparative study on gene expression profiles in the liver of male neonatal mice prenatally exposed to PFOA and its alternative HFPO-DA","authors":"Wataru Murase , Atsuhito Kubota , Ryo Hakota , Ayaka Yasuda , Atsuko Ikeda , Koji Nakagawa , Ryota Shizu , Kouichi Yoshinari , Hiroyuki Kojima","doi":"10.1016/j.tox.2025.154048","DOIUrl":"10.1016/j.tox.2025.154048","url":null,"abstract":"<div><div>Hexafluoropropylene oxide dimer acid (HFPO-DA), which belongs to the class of perfluoroalkyl ether carboxylic acid (PFECA), is a new alternative to perfluorooctanoic acid (PFOA). However, whether HFPO-DA is a safer alternative to PFOA in neonates remains unclear. In this study, we evaluated neonatal hepatic toxicity on postnatal days 9–10 by orally exposing pregnant CD-1 mice to 0.3 or 3.0 mg/kg/day (low or high doses) of HFPO-DA or PFOA from gestation days 15–17. The results showed that exposure of pregnant mice to HFPO-DA and PFOA induced similar phenotypic effects, including significant decreases in neonatal body weight (BW) and significant increases in liver weight relative to BW in the high-dose. Notably, HFPO-DA exposure significantly decreased in neonatal BW in the low-dose group, whereas PFOA did not. Comprehensive gene expression analysis revealed significant alterations in 408 and 1402 differentially expressed genes (DEGs) in the liver of neonates from the low- and high-dose HFPO-DA groups, respectively, while PFOA significantly altered 0 and 292 DEGs in the corresponding groups. Gene set enrichment analysis indicated that the DEGs induced by HFPO-DA and PFOA were enriched in pathway related to “PPAR signaling”, “fatty acid metabolism”, and “biological oxidations”. In addition, transactivation assays revealed that mouse (m)PPARα and mPPARγ activity of HFPO-DA exceeds that of PFOA and molecular docking simulations analysis predicted that the binding conformation differ between PFOA and HFPO-DA. Overall, our findings demonstrate that HFPO-DA consistently affected neonatal phenotypes, liver gene expression and the molecular initiating events involving PPARα/γ, at lower concentrations than PFOA.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154048"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142955603","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 : 2025-02-01DOI: 10.1016/j.tox.2025.154061
Jin Zhou , Pinpin Sui , Jianxin Zhao , Xiurong Cheng , Tao Yu , Shiwei Cui , Xiangrong Song , Caihong Xing
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 Mll-Af9 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, Mll-Af9 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 Mll-Af9 cells in peripheral blood (PB) cells was significantly increased after 10 weeks benzene exposure (P < 0.001). After competitive BMT, the chimerism rate of Mll-Af9 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 %, P = 0.03). Transcriptome analysis revealed that the expression levels of self-renewal related genes, such as Hox genes (Hoxb4, Hoxa7, Hoxa10), Mecom and Ms4a 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, Hoxa7, Hoxa10 and Mecom 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.
{"title":"Benzene-induced hematotoxicity enhances the self-renewal ability of HSPCs in Mll-Af9 mice","authors":"Jin Zhou , Pinpin Sui , Jianxin Zhao , Xiurong Cheng , Tao Yu , Shiwei Cui , Xiangrong Song , 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> < 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}
Pub Date : 2025-02-01DOI: 10.1016/j.tox.2024.154033
Tomo Svagusa , Natalija Matic , Vid Mirosevic , Kresimir Maldini , Mario Siljeg , Davor Milicic , Hrvoje Gasparovic , Igor Rudez , Marjan Urlic , Tomislav Tokic , Stjepan Ivankovic , Duska Tjesic-Drinkovic , Ana Sepac , Danko Muller , Marko Lucijanic , Filip Svalina , Lucija Gojmerac , Katarina Zic , Davor Baric , Daniel Unic , Filip Sedlic
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 DAPK2 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 DAPK2 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 DAPK2 expression. Deposition of Al, As, Cd, Ni, and Pb also altered the expression of several MQC genes.
{"title":"Myocardial deposition of aluminum, arsenic, cadmium, and lead accelerates heart failure and alters UPRmt in humans","authors":"Tomo Svagusa , Natalija Matic , Vid Mirosevic , Kresimir Maldini , Mario Siljeg , Davor Milicic , Hrvoje Gasparovic , Igor Rudez , Marjan Urlic , Tomislav Tokic , Stjepan Ivankovic , Duska Tjesic-Drinkovic , Ana Sepac , Danko Muller , Marko Lucijanic , Filip Svalina , Lucija Gojmerac , Katarina Zic , Davor Baric , Daniel Unic , 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}
Pub Date : 2025-02-01DOI: 10.1016/j.tox.2024.154031
Konrad A. Szychowski , Bartosz Skóra , Anna K. Wójtowicz
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 Cyp1a1 and Cyp1b1 expression. These results suggest the involvement of the PPARγ pathway in the inhibition of Cyp1b1 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.
{"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 , Bartosz Skóra , 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}
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