Journal of Applied Toxicology最新文献_第7页

Intestinal Bacterial Dysbiosis and Liver Fibrosis in Mice Through Gut-Liver Axis and NLRP3 Inflammatory Pathway Caused by Fine Particulate Matter 细颗粒物致小鼠肠-肝轴和NLRP3炎症通路肠道细菌生态失调与肝纤维化

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-02-20 DOI: 10.1002/jat.4767

Pengfei Fu, Mei Zhang, Lirong Bai, Shanshan Chen, Wenqi Chen, Zhiping Li, Jianwei Yue, Chuan Dong, Ruijin Li

{"title":"Intestinal Bacterial Dysbiosis and Liver Fibrosis in Mice Through Gut-Liver Axis and NLRP3 Inflammatory Pathway Caused by Fine Particulate Matter","authors":"Pengfei Fu, Mei Zhang, Lirong Bai, Shanshan Chen, Wenqi Chen, Zhiping Li, Jianwei Yue, Chuan Dong, Ruijin Li","doi":"10.1002/jat.4767","DOIUrl":"10.1002/jat.4767","url":null,"abstract":"<div>\u0000 \u0000 Fine particulate matter (PM2.5) is associated with risks of liver diseases and intestinal bacterial dysbiosis, in which the gut-liver axis regulation mechanisms induced by PM2.5 exposure are still limited so far. In this study, after 12 weeks of exposure to atmospheric PM2.5 (64 μg/m3) and clean air in winter in Taiyuan, China, we collected liver and intestinal tissues and serum in male mice to perform toxicology experiments. The results showed that PM2.5 significantly exacerbated the pathological injury in the liver and intestine and liver fibrosis in mice, along with elevated levels of pro-inflammatory cytokines and lipopolysaccharide (LPS) levels in the serum. PM2.5 caused abnormal liver function and activated TLR4/NF-κB/NLRP3 pathway in mouse liver. PM2.5 also significantly inhibited the expression of intestinal mucosal tight junction proteins such as ZO-1 and occludin. Besides, from 16S rRNA gene sequencing results in intestinal and fecal samples, we found that PM2.5 decreased the diversity and abundance of intestinal bacteria, along with reducing Shannon, Chao1 and Ace indices and increasing Simpson indices. Principal component analysis (PCA) showed that mice's intestinal bacterial composition and β-diversity in the PM2.5-exposed group significantly differed from the control group. KEGG pathway analyzed key functional genes and metabolic pathways in important mouse bacterial communities in the PM2.5-exposed group. It suggested that PM2.5 exposure exacerbates liver fibrosis in mice via the NLRP3 pathway. PM2.5 caused intestinal mucosal injury, intestinal bacterial disorders and increased LPS levels, leading to the activation of inflammatory pathways, which can exacerbate liver fibrosis via the gut-liver axis.\u0000 </div>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"45 6","pages":"1030-1042"},"PeriodicalIF":2.7,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Mechanism of Bisphenol S-Induced Atherosclerosis Elucidated Based on Network Toxicology, Molecular Docking, and Machine Learning 基于网络毒理学、分子对接和机器学习的双酚s诱导动脉粥样硬化机制研究

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-02-20 DOI: 10.1002/jat.4768

Bing Guo, Xuan He

{"title":"The Mechanism of Bisphenol S-Induced Atherosclerosis Elucidated Based on Network Toxicology, Molecular Docking, and Machine Learning","authors":"Bing Guo, Xuan He","doi":"10.1002/jat.4768","DOIUrl":"10.1002/jat.4768","url":null,"abstract":"<div>\u0000 \u0000 The increasing prevalence of environmental pollutants has raised public concern about their potential role in diseases such as atherosclerosis (AS). Existing studies suggest that chemicals, including bisphenol S (BPS), may adversely affect cardiovascular health, but the specific mechanisms remain unclear. This study aims to elucidate the effects of BPS on AS and the underlying mechanisms. Through an extensive search of databases such as ChEMBL, STITCH, SwissTargetPrediction, SuperPred, SEA, and GEO, we identified 34 potential targets related to BPS-induced AS. A target network was constructed using the STRING platform and Cytoscape software. GO and KEGG functional enrichment analysis using the DAVID database revealed that BPS may promote the occurrence of AS by interfering with critical biological processes such as glutathione metabolism, nitrogen metabolism, and tyrosine metabolism. This was followed by the selection of 4 core targets—aminopeptidase n (ANPEP), alcohol dehydrogenase 5 (ADH5), lysosomal pro-x carboxypeptidase (PRCP), and microsomal glutathione s-transferase 1 (MGST1)—using five machine learning methods. These core targets play a pivotal role in BPS-induced AS. Furthermore, molecular docking confirmed the tight binding between BPS and these core targets. In conclusion, this study provides a theoretical framework for understanding the molecular mechanisms of BPS-induced AS and contributes scientific evidence for the development of prevention and treatment strategies for cardiovascular diseases triggered by BPS exposure.\u0000 </div>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"45 6","pages":"1043-1055"},"PeriodicalIF":2.7,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Subchronic Inhalation of TiO2 Nanoparticles Leads to Deposition in the Lung and Alterations in Erythrocyte Morphology in Mice 亚慢性吸入TiO2纳米颗粒导致小鼠肺沉积和红细胞形态改变。

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-02-11 DOI: 10.1002/jat.4759

Pavel Kulich, Soňa Marvanová, Radim Skoupý, Miša Škorič, Jan Vysloužil, Omar Šerý, Pavel Mikuška, Lukáš Alexa, Pavel Coufalík, Kamil Křůmal, Pavel Moravec, Zbyněk Večeřa, Miroslav Machala

{"title":"Subchronic Inhalation of TiO2 Nanoparticles Leads to Deposition in the Lung and Alterations in Erythrocyte Morphology in Mice","authors":"Pavel Kulich, Soňa Marvanová, Radim Skoupý, Miša Škorič, Jan Vysloužil, Omar Šerý, Pavel Mikuška, Lukáš Alexa, Pavel Coufalík, Kamil Křůmal, Pavel Moravec, Zbyněk Večeřa, Miroslav Machala","doi":"10.1002/jat.4759","DOIUrl":"10.1002/jat.4759","url":null,"abstract":"TiO2 nanoparticles (NPs) are extensively used in various applications, highlighting the importance of ongoing research into their effects. This work belongs among rare whole-body inhalation studies investigating the effects of TiO2 NPs on mice. Unlike previous studies, the concentration of TiO2 NPs in the inhalation chamber (130.8 μg/m3) was significantly lower. This 11-week study on mice confirmed in vivo the presence of TiO2 NPs in lung macrophages and type II pneumocytes including their intracellular localization by using the electron microscopy and the state-of-the-art methods detecting NPs' chemical identity/crystal structure, such as the energy-dispersed X-ray spectroscopy (EDX), cathodoluminescence (CL), and detailed diffraction pattern analysis using powder nanobeam diffraction (PNBD). For the first time in inhalation study in vivo, the alterations in erythrocyte morphology with evidence of echinocytes and stomatocytes, accompanied by iron accumulation in spleen, liver, and kidney, are reported following NP's exposure. Together with the histopathological evidence of hyperaemia in the spleen and kidney, and haemosiderin presence in the spleen, the finding of NPs containing iron might suggest the increased decomposition of damaged erythrocytes. The detection of TiO2 NPs on erythrocytes through CL analysis confirmed their potential systemic availability. On the contrary, TiO2 NPs were not confirmed in other organs (spleen, liver, and kidney); Ti was detected only in the kidney near the detection limit.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"45 6","pages":"1004-1018"},"PeriodicalIF":2.7,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jat.4759","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Development of Yellow Mealworm (Tenebrio molitor) as a Cheap and Simple Model to Evaluate Acute Toxicity, Locomotor Activity Changes, and Metabolite Profile Alterations Induced by Nanoplastics of Different Sizes 黄粉虫（tenbrio molitor）的发展作为一种廉价和简单的模型来评估不同尺寸纳米塑料引起的急性毒性、运动活性变化和代谢物谱变化。

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-02-09 DOI: 10.1002/jat.4764

Miao Sun, Xiaomei Zhao, Sihuan Luo, Miao Jiang, Qing Liu, Yi Cao

{"title":"The Development of Yellow Mealworm (Tenebrio molitor) as a Cheap and Simple Model to Evaluate Acute Toxicity, Locomotor Activity Changes, and Metabolite Profile Alterations Induced by Nanoplastics of Different Sizes","authors":"Miao Sun, Xiaomei Zhao, Sihuan Luo, Miao Jiang, Qing Liu, Yi Cao","doi":"10.1002/jat.4764","DOIUrl":"10.1002/jat.4764","url":null,"abstract":"<div>\u0000 \u0000 Due to the wide uses of plastic products, nanoplastics are ubiquitous contaminants in the environment. Hence, extensive studies used various models to evaluate the toxicity of nanoplastics. In the present study, we developed yellow mealworm (Tenebrio molitor) as an alternative model to investigate the acute toxicity of nanoplastics. Our results showed that microinjection with 500 mg/kg nanoplastics significantly increased death rate of yellow mealworms after 24 or 48 h, with 100 nm particles being more effective compared with 20 nm ones. Meanwhile, dose-dependent increase of death rate was observed in yellow mealworms after injection with 2–200 mg/kg 100 nm nanoplastics. Exposure to 2 mg/kg 100 nm but not 20 nm nanoplastics also led to hyperactivity of yellow mealworms. Both types of nanoplastics altered metabolite profiles, that 20 nm nanoplastics significantly up-regulated and down-regulated 9 and 12 metabolites, whereas 100 nm nanoplastics significantly up-regulated and down-regulated 16 and 25 metabolites, respectively. Enrichment analysis revealed that 100 nm but not 20 nm nanoplastics significantly affected alpha-linolenic acid metabolism (ko00592) and purine metabolism (ko00230). For the metabolites belonging to these pathways, 100 nm nanoplastics significantly up-regulated stearidonic acid but down-regulated guanine. Combined, these results revealed size-dependent effects of nanoplastics on acute toxicity, hyperactivity and metabolite profile changes in yellow mealworms. These results also indicated the potential uses of yellow mealworms as a cheap and simple model to evaluate the toxicity of nanoplastics.\u0000 </div>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"45 6","pages":"994-1003"},"PeriodicalIF":2.7,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Toll-Like Receptors in Pentachlorophenol- and Dibutyltin-Induced Production of Pro-Inflammatory Cytokines, Interleukin (IL)-1β, and IL-6, by Human Immune Cells toll样受体在五氯酚和二丁基汀诱导的促炎性细胞因子，白细胞介素(IL)-1β和IL-6的产生中的作用。

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-02-06 DOI: 10.1002/jat.4762

Aleshia Seaton-Terry, Zinia Hunter, Meaghan Lewis, Sophia Fisher, Ellie Bray, Brian Townsend, Saleban Gabure, Latoya Daniel, Margaret Whalen

{"title":"Toll-Like Receptors in Pentachlorophenol- and Dibutyltin-Induced Production of Pro-Inflammatory Cytokines, Interleukin (IL)-1β, and IL-6, by Human Immune Cells","authors":"Aleshia Seaton-Terry, Zinia Hunter, Meaghan Lewis, Sophia Fisher, Ellie Bray, Brian Townsend, Saleban Gabure, Latoya Daniel, Margaret Whalen","doi":"10.1002/jat.4762","DOIUrl":"10.1002/jat.4762","url":null,"abstract":"<div>\u0000 \u0000 Pentachlorophenol (PCP) and dibutyltin dichloride (DBT) contaminate the environment due to their diverse applications. PCP has been found from 0.26 to 5 μM in the serum of exposed individuals and at an average of 0.15 μM in the unexposed. DBT has been detected in human blood at levels up to 0.3 μM. Exposure to these contaminants is linked to pathological conditions including cancer. Interleukin-1 beta (IL-1β) and IL-6 are pro-inflammatory cytokines that when produced inappropriately can cause chronic inflammation, which is linked to pathologies including autoimmune diseases and cancer. PCP and DBT have been shown to increase the production of IL-1β and IL-6 by immune cells in a MAP kinase (MAPK) dependent process. Toll-like receptors (TLRs) activate the signaling pathways linked to MAPK that lead to production of these cytokines. This study demonstrates that PCP-induced production of IL-1β and IL-6 is dependent on TLR4 and TLR8, and independent of TLR1/2, TLR2, and TLR3. Additionally, DBT-induced IL-6 production depends on TLR1/2, whereas IL-1β production does not. Blocking the TLR-linked adapter protein, MyD88, lead to a loss of both PCP and DBT stimulation of IL-1β and IL-6. These findings indicate that both PCP and DBT interact with selected TLRs as part of their mechanisms of elevating the levels of critical pro-inflammatory cytokines, which may contribute to chronic inflammation and its related pathologies.\u0000 </div>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"45 6","pages":"976-993"},"PeriodicalIF":2.7,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Oxidative Stress in Kidney of Zebrafish due to Individual and Combined Exposure to Amoxicillin, Arsenic, and Fluoride: Involving Nrf2-Keap1-ARE Pathway 单独或联合暴露于阿莫西林、砷和氟化物导致的斑马鱼肾脏氧化应激：涉及Nrf2-Keap1-ARE通路

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-02-05 DOI: 10.1002/jat.4763

Sunanda Mukherjee, Shehnaz Islam, Olivia Sarkar, Ansuman Chattopadhyay

{"title":"Oxidative Stress in Kidney of Zebrafish due to Individual and Combined Exposure to Amoxicillin, Arsenic, and Fluoride: Involving Nrf2-Keap1-ARE Pathway","authors":"Sunanda Mukherjee, Shehnaz Islam, Olivia Sarkar, Ansuman Chattopadhyay","doi":"10.1002/jat.4763","DOIUrl":"10.1002/jat.4763","url":null,"abstract":"<div>\u0000 \u0000 Toxic manifestations of different antibiotics and metal compounds have been studied comprehensively in the last decades; however, their co-toxicity on aquatic organisms is poorly investigated. This study aimed to evaluate the oxidative stress imposed on zebrafish kidney tissue when exposed to amoxicillin (AMX, 10 μg/L) alone or in combination with 50 μg/L of As2O3 (equivalent to 37.87 μg/L of As) and/or 15 mg/L of NaF (equivalent to 6.8 mg/L of F) for 15 days. We observed increased levels of cellular ROS, MDA, and GSH along with increased activity of CAT enzyme in all the treated groups. Disrupted histoarchitecture, including degeneration of tubular cells, vacuolation, and necrotic spots, was indicative of oxidative damage. mRNA expression of stress responsive genes like nrf2, gpx1, hsp70, keap1, nqo1, cat, and ho1 corroborated the data. Translocation of Nrf2 from cytoplasm to nucleus and its subsequent expression was higher for all the treated groups. Moreover, the mixture effects of AMX + As + F were more severe than the other combinations, while unique exposure with AMX had minimum effects. Highlighting the involvement of the Nrf2-Keap1-ARE pathway, these findings make us aware of the synergistic response of AMX, As, and F in the ecosystem, putting forward a great threat to humankind.\u0000 </div>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"45 6","pages":"964-975"},"PeriodicalIF":2.7,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effects of Non-Feeding on Development in a Teleost, Minami-Medaka, Oryzias latipes: Identification of Eleutheroembryonic Stage for Potential Alternative Regulatory Toxicology Tests Along the 3R Principles 不摄食对硬骨鱼（Minami-Medaka, Oryzias latipes）发育的影响：根据3R原则确定拟真胚胎阶段的潜在替代调节毒理学试验。

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-01-30 DOI: 10.1002/jat.4757

Taijun Myosho, Makoto Kashima, Taisen Iguchi, Tohru Kobayashi

{"title":"Effects of Non-Feeding on Development in a Teleost, Minami-Medaka, Oryzias latipes: Identification of Eleutheroembryonic Stage for Potential Alternative Regulatory Toxicology Tests Along the 3R Principles","authors":"Taijun Myosho, Makoto Kashima, Taisen Iguchi, Tohru Kobayashi","doi":"10.1002/jat.4757","DOIUrl":"10.1002/jat.4757","url":null,"abstract":"<div>\u0000 \u0000 Fish in the eleutheroembryonic life stage are defined as embryos or hatched fry before external self-feeding begins, and this stage is not classified as a protected life stage according to the EU (Directive 2010/63/EU) because of its alignment with the 3R principles (replacement, reduction, and refinement). In Minami-medaka (Oryzias latipes), the eleutheroembryonic stage is considered to extend until hatching, according to OECD TG210, whereas no supporting evidence to identify this stage has yet been reported. To clarify the medaka eleutheroembryonic stage, we investigated the effects of non-feeding on survival, growth, and gene expression in the NIES-R, Hd-rR, and d-rR strains. Non-feeding did not affect survival up to 6 days post-hatching (dph) in any strain, with survival rates exceeding 80%. However, non-feeding beyond 8 dph reduced the survival rates to below 50% at 30 dph. Fish growth, measured as total length, was not significantly affected by non-feeding up to 6 dph, except for the Hd-rR. Analysis of differentially expressed genes (DEGs) in response to non-feeding revealed that autophagy-related DEGs (wipi2, wdr45, wipi1, atg14, and map1lc3b) were found from 43 autophagy-related genes. map1lc3b and the other DEGs were upregulated after 4 and 6 days of non-feeding, respectively. However, the effect of non-feeding up to 6 dph was rescued by feeding. Together, the medaka fry < 6 dph were considered to be in the eleutheroembryonic stage for at least up to 4 dph, suggesting that hatched fry can be used to evaluate chemical toxicity and endocrine-disrupting activity according to the 3R principles.\u0000 </div>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"45 6","pages":"935-947"},"PeriodicalIF":2.7,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143065976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Environmental Aromatic Amine Induces Pulmonary Arterial Hypertension Associated With Estrogen Signaling and Serpine1 环境芳胺诱导肺动脉高压与雌激素信号和丝氨酸1相关

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-01-30 DOI: 10.1002/jat.4758

Ashlyn C. Harmon, Michelle A. Carroll-Turpin, Merilyn H. Jennings, Tomislav Jelesijevic, Philip Ebenezer, Ankit Aryal, Qingzhao Yu, Joseph Francis, Tammy R. Dugas

{"title":"Environmental Aromatic Amine Induces Pulmonary Arterial Hypertension Associated With Estrogen Signaling and Serpine1","authors":"Ashlyn C. Harmon, Michelle A. Carroll-Turpin, Merilyn H. Jennings, Tomislav Jelesijevic, Philip Ebenezer, Ankit Aryal, Qingzhao Yu, Joseph Francis, Tammy R. Dugas","doi":"10.1002/jat.4758","DOIUrl":"https://doi.org/10.1002/jat.4758","url":null,"abstract":"<div>\u0000 \u0000 4,4′-Diaminodiphenylmethane (DAPM) is an aromatic amine used in the industrial synthesis of polyurethane. In rats, acute DAPM exposure induces biliary epithelial cell injury in the liver, but subchronic exposure promotes a female-specific pulmonary arterial hypertension (PAH). PAH in humans is four times more prevalent in women than men. To shed light on mechanisms explaining the female selectivity of PAH in humans, we examined molecular pathways underlying DAPM-induced PAH in female rats. Intersections between DAPM-mediated hepatic injury and DAPM-induced PAH were also interrogated. Intact compared to ovariectomized female rats were gavaged once weekly for 12 weeks with DAPM or vehicle. Morphometric analysis in lung sections was used to quantify PAH pathology. mRNA from liver were assessed for DAPM-induced alterations in genes associated with aryl hydrocarbon receptor, estrogen response, and endothelin-1 signaling. mRNA from pulmonary arteries were subjected to transcript profiling, and pathways associated with differentially expressed genes were mapped. First, DAPM-induced PAH was exacerbated by ovariectomy. Although DAPM-mediated liver injury per se was not correlated with its induction of PAH, increases in levels of the potent vasoconstrictor endothelin-1 were exacerbated by ovariectomy and were correlated with increased expression of Edn1 in the liver. In pulmonary arteries, transcript profiling revealed that DAPM and ovariectomy interacted to dysregulate estrogen receptor, VEGF, PI3K/AKT, endothelin-1, glucocorticoid receptor, IL-17A, and idiopathic pulmonary fibrosis signaling. One of the most dysregulated genes associated with both DAPM and estrogen status was Serpine1.\u0000 </div>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"45 6","pages":"948-963"},"PeriodicalIF":2.7,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143925995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Thyroid Endocrine Disrupting Potential of Fluoxetine in Zebrafish Larvae 氟西汀对斑马鱼幼体甲状腺内分泌的干扰作用。

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-01-28 DOI: 10.1002/jat.4755

Jin Huang, Kunyun Liu, Shan Chen, Huijia Tang, Ruiwen Li, Xianzheng Wang, Heying Sun

{"title":"Thyroid Endocrine Disrupting Potential of Fluoxetine in Zebrafish Larvae","authors":"Jin Huang, Kunyun Liu, Shan Chen, Huijia Tang, Ruiwen Li, Xianzheng Wang, Heying Sun","doi":"10.1002/jat.4755","DOIUrl":"10.1002/jat.4755","url":null,"abstract":"<div>\u0000 \u0000 Fluoxetine (FLX), a typical selective serotonin reuptake inhibitors, has been frequently detected in aquatic environment and wild fish. However, little is known about its effect on thyroid endocrine system. In the present study, zebrafish (Danio rerio) embryos were exposed to 1, 3, 10, and 30 μg/L of FLX for 6 days. Chemical analysis demonstrated that FLX and its metabolic product (nonfluoxetine, NFLX) were accumulated in zebrafish larvae. The exposure resulted in decreased thyroid hormones (THs) levels, indicating thyroid endocrine disruption. Moreover, thyroid-stimulating hormone (TSH) content was significantly inhibited in a concentration-dependent manner after exposure to FLX. Gene transcription in the hypothalamic–pituitary–thyroid (HPT) axis was further examined, and the results showed that the genes encoding corticotrophin-releasing hormone (crh) and thyrotropin-releasing hormone (trh) were significantly up-regulated as a compensatory mechanism for the decreased TH contents accompanied with decreased tshβ mRNA expression. In addition, genes involved in thyroid hormone synthesis (sodium/iodide symporter, nis, thyroglobulin, tg) and transport (transthyretin, ttr) were down-regulated after exposure to FLX in a concentration-dependent manner. The increased gene transcription of deiodinases (dio2) and uridinediphosphate-glucuronosyltransferase (ugt1ab) might be responsible for the decrease of TH contents. In addition, a significant inhibition in thyroid hormone receptors (trα and trβ) gene expression was observed upon treatment with FLX. All these results demonstrated that FLX could alter THs and TSH content as well as gene transcription in the HPT axis, exerting an endocrine disruption of the thyroid system in zebrafish larvae.\u0000 </div>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"45 6","pages":"916-924"},"PeriodicalIF":2.7,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Preclinical Toxicological Assessment of 2-(Benzoxazol-2-yl)[(2-hydroxynaphthyl)diazenyl]phenol Derivatives for Blue Light and UV Radiation Photoprotection Applications 2-（苯并恶唑-2-基）[（2-羟基萘基）二氮基]苯酚衍生物用于蓝光和紫外线光防护的临床前毒理学评估。

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-01-28 DOI: 10.1002/jat.4756

Karen Sousa, Dione Silva Corrêa, João Denis Medeiros de Oliveira, Gabriel Beilfuss Rieth, Juliana da Silva, Ingrid Maliszewski Paczkowski, Leandra Franciscato Campo, Ivana Grivicich, Jaqueline Nascimento Picada

{"title":"Preclinical Toxicological Assessment of 2-(Benzoxazol-2-yl)[(2-hydroxynaphthyl)diazenyl]phenol Derivatives for Blue Light and UV Radiation Photoprotection Applications","authors":"Karen Sousa, Dione Silva Corrêa, João Denis Medeiros de Oliveira, Gabriel Beilfuss Rieth, Juliana da Silva, Ingrid Maliszewski Paczkowski, Leandra Franciscato Campo, Ivana Grivicich, Jaqueline Nascimento Picada","doi":"10.1002/jat.4756","DOIUrl":"10.1002/jat.4756","url":null,"abstract":"<div>\u0000 \u0000 The widespread use of electronic devices has led to increased blue light exposure, highlighting the need for effective radiation blockers with blue light protection. Two synthetic 2-(2′-hydroxyphenyl)benzoxazole derivatives named azo-4′-benzoxazole and azo-5′-benzoxazole have shown an unprecedented blue light absorption capacity but had not been subjected to a safety evaluation. This study aimed to evaluate the cytotoxic, genotoxic, and mutagenic activities of these compounds. The cytotoxic and genotoxic activities were evaluated using MTT assay and comet assay in L929 fibroblast cells. Salmonella/microsome assay and micronucleus test were performed to detect gene and chromosomal mutations. The IC50 was 87.9 μg/mL for azo-4′-benzoxazole and 79.5 μg/mL for azo-5′-benzoxazole. In the Salmonella/microsome assay, the azo-5′-benzoxazole compound induced frameshift mutations in the TA97a strain in the presence of metabolic activation (S9 mix), while azo-4′-benzoxazole did not show mutagenic activities in all five strains tested. The azo-5′-benzoxazole showed genotoxic and mutagenic effects in L929 cells that were probably associated to the cleavage of azo-5′ into its analogs 2-(4′-amino-2′-hydroxyphenyl)benzoxazole and 2-amino-1-naphthol. In conclusion, the azo-substituted group at the 5′ position of the phenyl ring appears to have greater toxicological risks than substituents at the 4′ position of 2-(phenyl)benzoxazole. The findings warrant further preclinical studies to ensure the safety of these compounds for use as blue light filters.\u0000 </div>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"45 6","pages":"925-934"},"PeriodicalIF":2.7,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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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