Toxicology letters最新文献

{"title":"Studies on acute dermal toxicity and dermal absorption of a nanoform zinc oxide (ZnO; NM-111) in rats","authors":"Tanja Hansen ,&nbsp;Thomas Tillmann ,&nbsp;Karin Wiench ,&nbsp;Otto Creutzenberg","doi":"10.1016/j.toxlet.2025.04.011","DOIUrl":"10.1016/j.toxlet.2025.04.011","url":null,"abstract":"<div><div>In two studies, the dermal toxicity (limit test following OECD TG 402) and toxicokinetics (with [⁶⁵Zn]-tagged ZnO following OECD TG 427) of a nanostructured ZnO particle were characterized. The overall aim was to assess the risk of its systemic availability. Wistar rats were dermally treated once with 2000 mg ZnO/kg b.w. (limit test). – Male rats were treated topically with 2 mg/cm^{2 65}ZnO for 6 h. Necropsy was done after the end of the exposure period (6 h) and after 24 and 72 h to investigate dermal absorption of ⁶⁵ZnO. ZnO showed no clinical signs of toxicity in the limit test. – ⁶⁵ZnO was not significantly absorbed following deposition: In the group means, 62–76 % of the dose applied were recovered in the not absorbed fraction. The amount of ⁶⁵ZnO in the <em>stratum corneum</em> was found to be approx. 15 %, 8 % and 4.6 % after 6, 24 and 72 h, respectively. The ⁶⁵ZnO content in the remaining skin at the application site (viable skin + remaining <em>stratum corneum</em>) accounted for approx. 10 %, 16 % and 16 % after 6, 24 and 72 h (total on/in the skin 25 %, 24 % and 20.6 % after 6, 24 and 72 h). No relevant radioactivity was found in faeces, urine, cage wash, organ or tissue samples.</div><div>The acute dermal limit test with ZnO resulted in ‘Unclassified’ (globally harmonized system). – Radioactivity, representative of ⁶⁵ZnO, was not detected systemically after dermal application. Overall, the results indicate that ⁶⁵ZnO was not absorbed with subsequent translocation beyond the skin into the blood compartment.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"409 ","pages":"Pages 42-49"},"PeriodicalIF":2.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143924041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In silico and in vitro analysis of the genotoxic and mutagenic potential of STING modulators","authors":"Santosh Vishwakarma,&nbsp;Saketh S. Dinavahi,&nbsp;Kapil R. Nikam,&nbsp;Bibhuti Ranjan,&nbsp;Ramesh Rangaiah,&nbsp;M. Karunyaa,&nbsp;Anupreetha V,&nbsp;Arul Ramakrishnan,&nbsp;Saravanakumar Dhakshinamoorthy","doi":"10.1016/j.toxlet.2025.04.012","DOIUrl":"10.1016/j.toxlet.2025.04.012","url":null,"abstract":"<div><div>The STING pathway plays a crucial role in dsDNA homeostasis and has been implicated in several diseases, including cancer and autoimmune disorders. Consequently, efforts have been made to develop modulators (agonists and antagonists) of the STING pathway. However, it is imperative to clinically evaluate the mutagenic and genotoxic potential effects of these novel molecules. For this purpose, an exhaustive list of STING modulators was subjected to knowledge- and expert-based <em>in silico</em> mutagenicity evaluations. A few antagonists were predicted to be positive for mutagenicity by Derek, and a few agonists were predicted to be positive (moderate reliability) by Vega. Based on the varying results of the computational approaches (Derek and Vega) for prediction of mutagenicity, two of each STING agonists and antagonists were evaluated using the bacterial reverse mutation test (Ames test; with and without metabolic activation) at concentrations of 1.935–250 μg/well. Additionally, the compounds (5, 10, and 20 μM) were subjected to single-cell gel electrophoresis (comet) assay to evaluate DNA damage in HepG2 cells. <em>In silico</em> analysis predicted that multiple STING modulators are mutagenic. In addition, the Ames test results demonstrated that only C-178, a STING antagonist, is mutagenic, while the other antagonist (SN-001) and both agonists (CMA and SR-717) are not mutagenic at the concentrations evaluated. C-178 is mutagenic, even without metabolic activation. Although not significantly different, there was a dose-dependent increase in comet tail length with C-178, thereby confirming genotoxicity, even in mammalian cells. The other STING modulators were inactive as per the comet assay. In summary, although mutagenic potential is not chemical class-specific, our findings highlight the carcinogenic potential of STING modulators, such as the covalent binder C-178. Caution must be exercised when developing novel STING modulators to avoid toxicological liabilities. Additionally, knowledge- and expert-based <em>in silico</em> evaluation of mutagenicity could help quickly identify toxicological potential.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"409 ","pages":"Pages 21-29"},"PeriodicalIF":2.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143890877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced toxic effects of photoaged microplastics on the trophoblast cells","authors":"Yan Zhang ,&nbsp;Zijie Zhou ,&nbsp;Xiaoli Wang ,&nbsp;Shouhai Jiao ,&nbsp;Qingshan Zhang ,&nbsp;Shuai Bao ,&nbsp;Shuping Zhang ,&nbsp;Li Sun ,&nbsp;Xiaolu Li","doi":"10.1016/j.toxlet.2025.04.010","DOIUrl":"10.1016/j.toxlet.2025.04.010","url":null,"abstract":"<div><div>Microplastics (MPs) are emerging as a novel pollutant, raising significant concerns regarding their adverse effects on human health. Furthermore, MPs are susceptible to light-induced aging in the environment, which alters their physical characteristics and potentially alters their toxic effects. While previous studies have documented the retention of MPs in the placenta, the specific impacts of MPs, particularly aged MPs, on placental function remain poorly understood. In the current study, we utilized 1 µm polystyrene microplastics (PS-MPs), a widely used model for MPs, to evaluate the effects of photoaged MPs on the placenta. Following oral administration of PS-MPs beginning on embryonic day 3.5 (E3.5), we observed impaired fetal growth and damage to the placental labyrinth chorionic layer in the treated pregnant mice by embryonic day 13.5 (E13.5). The photoaged PS-MPs were generated by exposure to simulated lighting for 7 or 14 days, resulting in alterations to their physical properties. Notably, enhanced cytotoxicity in trophoblast cells was observed for photoaged PS-MPs compared to pristine PS-MPs. Mechanistically, the altered physical properties of PS-MPs, along with elevated lipid peroxidation, may contribute to the increased cytotoxicity of the photoaged MPs. Our findings provide new insights into the detrimental effects and underlying mechanisms of both MPs and, in particular, aged MPs on the placenta and embryonic development. These insights are crucial for assessing the risks posed by MPs to human pregnancy.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"409 ","pages":"Pages 32-41"},"PeriodicalIF":2.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The induction of quinone oxidoreductases NQO1 and NQO2 by clozapine: Potential implications for clozapine-induced agranulocytosis","authors":"Md Harunur Rashid ,&nbsp;Dinesh Babu ,&nbsp;Newton H. Tran ,&nbsp;Steven Lockhart ,&nbsp;Mohammed A. Alqahtani ,&nbsp;Mahmoud A. El-Ghiaty ,&nbsp;Ayman O.S. El-Kadi ,&nbsp;Pierre Chue ,&nbsp;Arno G. Siraki","doi":"10.1016/j.toxlet.2025.04.013","DOIUrl":"10.1016/j.toxlet.2025.04.013","url":null,"abstract":"<div><div>Clozapine exhibits superior efficacy in the management of treatment-resistant schizophrenia. However, clozapine is currently considered under-prescribed as it carries a risk of idiosyncratic drug reactions (including severe neutropenia or agranulocytosis). The mechanisms of clozapine-induced agranulocytosis mechanisms are evolving. Reports of polymorphisms with NADPH: Quinone Oxidoreductase 2 (NQO2) being associated with clozapine-induced agranulocytosis prompted the studies described herein. Clozapine is known to produce reactive, electrophilic metabolites. It is not known if the latter can interact with NQO2 or with NQO1, its more well-characterized isoform, as quinoid electrophiles do. We hypothesized that clozapine or its metabolites can induce both NQO1 and NQO2 expression via the Nrf2 signaling pathway, as observed with quinoid electrophiles. HL-60 cells were used in this study as they are similar to granulocytes/neutrophils and contain enzymes to metabolize clozapine. A UV-Vis spectrophotometric assay was performed to determine NQO1 and NQO2 enzymatic activity using selective substrates and inhibitors. Immunoblotting was used to investigate NQO1, NQO2, and Nrf2 protein expression. NQO1 and NQO2 gene expression was determined using RT-PCR. Clozapine treatment induced NQO1 and NQO2 enzyme activity, mRNA, and protein expression significantly more than vehicle control accompanied by translocation of the transcription factor, Nrf2, from cytoplasm to nucleus. A structurally related antipsychotic, quetiapine, did not show these effects. The upregulation of both NQO1 and NQO2 enzymatic activity, protein, and gene expression indicated that these enzymes may be involved in the biological response to clozapine toxicity. The translocation of the Nrf2 suggested that the Nrf2 signaling pathway is involved in these response pathways. Further studies are required to determine if NQO2 expression levels and activity are protective mechanisms against clozapine-induced agranulocytosis or if NQO2 levels are a prognostic risk factor for clozapine-induced agranulocytosis.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"409 ","pages":"Pages 50-60"},"PeriodicalIF":2.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143924042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic implications of low herbicide concentrations in hepatic cells: Insights into the individual and combined effects of 2,4-D, glyphosate, and AMPA","authors":"Leticia Cardoso Valente ,&nbsp;Luana Riechelmann-Casarin ,&nbsp;Rosemari Otton ,&nbsp;Flávia Karina Delella ,&nbsp;Luís Fernando Barbisan ,&nbsp;Guilherme Ribeiro Romualdo","doi":"10.1016/j.toxlet.2025.04.009","DOIUrl":"10.1016/j.toxlet.2025.04.009","url":null,"abstract":"<div><div>Glyphosate and 2,4-D are among the most widely used herbicides globally, leading to environmental presence, food contamination, and human contact. Investigations based on current toxicological limits or populational-based herbicide exposures are warranted, and <em>in vitro</em> bioassays provide useful tools for toxicological screening. Thus, this study evaluated the transcriptomic implications of non-cytotoxic exposures to glyphosate, its metabolite aminomethylphosphonic acid (AMPA), or 2,4-D - or to their mixes - on hepatic cells. The half maximal effective concentration (IC50) of each herbicide was calculated (cell viability) in human hepatic C3A cells and 1000-fold lower concentrations were used for transcriptomic analysis (RNA-Seq) after 48 h exposure, resembling current toxicological limits and considering herbicide water levels (glyphosate: 0.95 µg/mL; AMPA: 3.7 µg/mL; 2,4-D: 0.56 µg/mL). Glyphosate exposure enriched MAPK-related biological processes (upregulated <em>TNF, FOS, IGF1</em>, and <em>PDGFB</em>), and downregulated genes associated with lipid metabolism (<em>CD36</em> and <em>PPARA</em>). Many AMPA exposure-related differentially expressed genes (DEGs, such as <em>PFKFB3</em>, <em>HK2, and ALDOA)</em> were associated with glucose metabolic pathways. Glyphosate and its metabolite yielded a common molecular signature, as illustrated by principal component analysis and the function of 212 shared DEGs. The exposure to 2,4-D was associated with the JNK cascade and the solute carrier family annotations. The herbicide mixtures had a discrete effect on enhancing the impact of individual herbicides, although important epithelial-mesenchymal transition genes were exclusively modified by the mixes (<em>COL11A2, LOXL3, SNAI1</em>). Altogether, our data reveals new perspectives on the short-term molecular effects of herbicide exposure in liver cells, emphasizing potential avenues for further exploration.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"409 ","pages":"Pages 1-11"},"PeriodicalIF":2.9,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143888133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative toxicity of eleven bisphenol analogs in the nematode Caenorhabditis elegans","authors":"Sang Eun Ha ,&nbsp;Myon Hee Lee ,&nbsp;Sung Min Han ,&nbsp;Sung-hwan Kim ,&nbsp;Moonjung Hyun ,&nbsp;Jeong Doo Heo","doi":"10.1016/j.toxlet.2025.04.008","DOIUrl":"10.1016/j.toxlet.2025.04.008","url":null,"abstract":"<div><div>Bisphenol analogs are widely used as industrial substitutes for Bisphenol A (BPA) and are included in water bottles, food containers, and receipts commonly encountered daily. However, there are currently no specific regulations on these substitute substances, and reports on their harmful effects are also lacking. In this study, we examined the toxicity of eleven bisphenol analogs, including BPAP, BPB, BPC, BPC2, BPE, BPG, BPM, BPP, BPPH, BPZ, and TBBPA at 1 mM concentration using the <em>C. elegans</em> model. Our findings revealed that several bisphenol analogs, most notably BPB, BPC, BPE, and BPG, significantly increased lethality in embryonic and L1 larval stages. Additionally, developmental delays were observed with BPAP, BPB, BPC, and BPG, with a reduced fraction of animals reaching adulthood. Regarding reproductive toxicity, we found that BPAP, BPB, BPC, BPC2, and BPG reduced egg production. Furthermore, exposure to the analogs significantly shortened the lifespan of <em>C. elegans</em>, particularly with BPAP, BPB, BPC, and BPG, raising concerns about their potential impact on aging. This study suggests their potential harmful effects on development, reproduction, and longevity.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"409 ","pages":"Pages 12-20"},"PeriodicalIF":2.9,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143890875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fecal metabonomics combined with 16S rRNA gene sequencing to study the mechanisms of cantharidin-induced hepatotoxicity","authors":"Lijuan Xiong ,&nbsp;Jialu Zou ,&nbsp;Kexin Lin ,&nbsp;Xiaohong Zhang ,&nbsp;Caiying Yan ,&nbsp;Yanmei He ,&nbsp;Jianyong Zhang","doi":"10.1016/j.toxlet.2025.04.006","DOIUrl":"10.1016/j.toxlet.2025.04.006","url":null,"abstract":"<div><div>Cantharidin (CTD) serves as the principal bioactive compound in traditional Chinese medicine <em>Mylabris</em>, commonly employed in cancer treatment. Nevertheless, the clinical application of CTD is partly restricted by hepatotoxicity, and the toxicology mechanism is not fully elucidated. This study aims to explore the potential mechanism of CTD-induced hepatoxicity by targeted metabolomics-based UPLC-QTOF-MS/MS analysis and 16S rRNA sequencing. Studies have shown that the administration of CTD could lead to elevated serum biochemical indices including ALT and AST. Notably, dilatation of the liver central vein, hepatocellular necrosis, and slight vacuoles in rats were observed after CTD intervention. Fecal metabolomics found CTD could up-regulate 10 and down-regulate 33 metabolites, and metabolic pathway enrichment found that CTD could disrupt 2 metabolic pathways, including Arginine biosynthesis metabolism and β-Alanine metabolism. 16S rRNA gene sequencing analysis showed that CTD could increase the abundance of <em>Turicibacter and Clostridium sensu stricto 1</em>, but decrease the amounts of <em>Prevotella 1</em>. Our correlation analyses showed that alterations in the gut microbiota induced by CTD in rats may have impacted changes in the associated hepatic amino acid metabolism pathway. And the mechanism of action of CTD-induced hepatotoxicity may be related to inflammation, oxidative stress, impaired glucose metabolism and reduced hepatic glycogen storage. These findings will offer novel insights for the prevention and treatment of CTD-induced hepatotoxicity.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"408 ","pages":"Pages 65-76"},"PeriodicalIF":2.9,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exposure to pesticides and cognitive function in school-age children of the Bolivar department (Colombia)","authors":"Maria Quintana-Mejia ,&nbsp;Flor Palacio-Herrera ,&nbsp;Jesus Olivero-Verbel ,&nbsp;Karina Caballero-Gallardo","doi":"10.1016/j.toxlet.2025.04.007","DOIUrl":"10.1016/j.toxlet.2025.04.007","url":null,"abstract":"<div><div>Joining efforts to address the interactions between social and environmental determinants of cognitive functioning allows the identification of structural barriers that guide government plans towards the fulfillment of the 2030 Agenda. This study examined the pesticide exposure and cognitive function in school-age children between the ages of 6–12 years old from Magangue, Achi, and Arjona (reference site) in the Bolivar Department (Colombia). A total of 323 school-age children participated in the study. A cross-sectional examination was conducted, including the measurement of blood serum pesticide concentrations using a gas chromatography–mass spectrometer (GC–MS) and cognitive function was assessed employing the Wechsler Intelligence Scale for Children, 4th edition. A comprehensive questionnaire was used to collect demographic information and exposure profiles. A total of fourteen organophosphate pesticides and 2 carbamates in human blood serum were detected. In Magangue, pesticides were quantified in 91 % of the participants, and in Achi in 34 %. At the comparison site, the results showed the presence of these pesticides in less than 2 % of the total samples analyzed. Interaction effects were observed between parental education, number of pesticides detected (&gt;LOD), IQ, and verbal comprehension index, which could generate alterations in reasoning, problem solving, memory and verbal comprehension. Interaction effects were observed between parental education, the number of pesticides detected, sum of pesticide concentrations detected in blood divided by the reported LD₅₀ of each chemical (ΣCPN/LD), and very low scores on the perceptual reasoning index, indicating compromised performance in abstract, logical, and analytical reasoning tasks. These findings underscore the magnitude of pesticide exposure as a public health concern, emphasizing the need for longitudinal studies to establish causal relationships between social determinants and neurotoxicant exposure as predictors of human development. The results contribute to governmental public health strategies aimed at protecting vulnerable populations and raising awareness of the risks associated with toxic exposures.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"408 ","pages":"Pages 105-118"},"PeriodicalIF":2.9,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143887870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of the gut microbiome in the associations between lead exposure and child neurodevelopment","authors":"Amanda C. Wylie ,&nbsp;Nicolas Murgueitio ,&nbsp;Alexander L. Carlson ,&nbsp;Rebecca C. Fry ,&nbsp;Cathi B. Propper","doi":"10.1016/j.toxlet.2025.04.004","DOIUrl":"10.1016/j.toxlet.2025.04.004","url":null,"abstract":"<div><div>Lead is highly toxic to the developing brain. Given its persistence in the environment, new intervention strategies are needed to mitigate the impacts of lead on child neurodevelopment. The gut microbiome, referring to the bacteria and microorganisms residing in the gastrointestinal system, may be a viable target for intervention. This short review summarizes recent evidence linking the gut-brain axis to child developmental outcomes. We explore how lead-induced effects to the gut microbiome could indirectly affect child neurodevelopment, such that disrupting or offsetting this mediating process could buffer the effects of lead on child developmental outcomes. Unexpected findings with respect to child microbiota diversity and child cognitive and behavioral outcomes as well as lead exposure and adult microbiota diversity are discussed. When possible, we draw connections between observed changes to relative bacterial abundance, proposed bacterial functions, and downstream effects to brain development. We also explore how the gut microbiome might modify the toxicity of lead by impeding the uptake of lead across the gastrointestinal tract or through indirect mechanisms in such ways that the gut microbiome does not fit within a mediating pathway. In this case, promoting the buffering capacity of the gut microbiome may reduce the impacts of lead on child neurodevelopment. The goal of this short review is to bring attention to the potential role of the gut microbiome in the associations between lead exposure and child neurodevelopment with an eye towards intervention.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"408 ","pages":"Pages 95-104"},"PeriodicalIF":2.9,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143867936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synergistic cardiotoxic effects of captagon and azithromycin in rat via oxidative stress, apoptosis and upregulation of the PI3K/AKT/NF-kB pathway","authors":"Shaimaa A. Shehata ,&nbsp;Noha M. Abd El-Fadeal ,&nbsp;Islam Omar Abdel Fattah ,&nbsp;Abeer M. Hagras ,&nbsp;Enas M.A. Mostafa ,&nbsp;Mohamed M. Abdel-Daim ,&nbsp;Mohamed A. Abdelshakour ,&nbsp;Eman Kolieb ,&nbsp;Asmaa K.K. Abdelmaogood ,&nbsp;Youssef M. Rabee ,&nbsp;Khadiga M. Abdelrahman","doi":"10.1016/j.toxlet.2025.04.002","DOIUrl":"10.1016/j.toxlet.2025.04.002","url":null,"abstract":"<div><div>Fenethylline (Captagon) is a blend of amphetamine and theophylline that functions as a stimulant, while azithromycin (AZ) is a commonly prescribed macrolide antibiotic. The co-usage of illicit substances and therapeutic drugs can result in substantial health risk especially cardiotoxicity. This study aimed to assess cardiotoxicity effects of Captagon (Capta) and Azithromycin/Captagon interaction in adult male rats. Forty-two animals were assigned into 6 groups: Group I (Control) and group II (AZ (30 mg/kg/day) starting from the 14th day of the experiment and for 2 weeks. Group III (Capta10 mg/kg/day), group IV (Capta20 mg/kg/day), group V (AZ+Capta10) and group VI (AZ+Capta20) daily 28 days. Electrocardiogram (ECG), cardiac enzymes, oxidative stress markers, inflammatory genes expression, histopathological and immunohistochemical changes were assessed. Administration of AZ and Capta alone or in combination cause cardiotoxicity. This was indicated by elevated LDH and CTNI levels, ECG changes as increased HR, prolonged QT interval and elevated ST segment accompanied by cardiac histopathological changes. There was a significant reduction in antioxidants SOD, GSH, TAC, and catalase, alongside a significant rise in oxidative stress MDA and NO. Significant rise of ERK, TNF-α, NF-ҡB, PI3K/AKT, Il-1β and IL-6, in both the Capta20 and AZ+Capta groups in dose dependent manner. The Coadministration of AZ and Capta20 produced intense immunoexpression of caspase-3 and BAX and wide areas of negative reactivity for Bcl-2. Coadministration of AZ and Capta induced cardiotoxicity through oxidative stress, inflammation, and apoptosis pathways. It is important to educate healthcare providers and patients about the potential harmful interactions.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"408 ","pages":"Pages 77-94"},"PeriodicalIF":2.9,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859581","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}