Pub Date : 2025-10-09DOI: 10.1016/j.toxlet.2025.111742
Richa Soni , Santasabuj Das , Gopal Shankar Sahni , Dweipayan Goswami , Deepak Verma , Bikash Das , Palak Parmar
Every year, annual outbreaks of AES occur in lychee-growing regions: previously healthy children suddenly succumb to Acute Encephalitis Syndrome (AES). Initial suspicions pointed towards the seemingly innocent lychee fruit and its inherent toxins, Hypoglycin A and MCPG. However, the toxin-alone hypothesis is challenged by the fact that lychees are safely consumed globally. This discrepancy suggests that the development of severe illness is not caused by the toxins alone but requires specific host vulnerabilities, such as malnutrition, and co-factors like the consumption of unripe fruit on an empty stomach. This has prompted the consideration of alternative hypotheses. These include the role of pesticide contamination in orchards, potential bat-borne viral infections, and environmental stressors that may shift with seasons and geography. The striking differences in illness patterns observed in Bihar (India), Bangladesh, and Vietnam further complicate the picture. Moreover, documented reports of children falling ill with AES without any reported lychee consumption cast doubt on a singular explanation. This review delves into the heart of this enduring medical enigma, critically dissecting the compelling arguments and critical caveats surrounding each potential cause. This review critically evaluates the evidence for the multifaceted theories behind lychee-associated AES and challenges established assumptions. The analysis indicates a multifactorial etiology is responsible for this recurring childhood tragedy.
{"title":"Is lychee-associated encephalopathy in children a straightforward case of toxicity or a complex metabolic and environmental cascade?","authors":"Richa Soni , Santasabuj Das , Gopal Shankar Sahni , Dweipayan Goswami , Deepak Verma , Bikash Das , Palak Parmar","doi":"10.1016/j.toxlet.2025.111742","DOIUrl":"10.1016/j.toxlet.2025.111742","url":null,"abstract":"<div><div>Every year, annual outbreaks of AES occur in lychee-growing regions: previously healthy children suddenly succumb to Acute Encephalitis Syndrome (AES). Initial suspicions pointed towards the seemingly innocent lychee fruit and its inherent toxins, Hypoglycin A and MCPG. However, the toxin-alone hypothesis is challenged by the fact that lychees are safely consumed globally. This discrepancy suggests that the development of severe illness is not caused by the toxins alone but requires specific host vulnerabilities, such as malnutrition, and co-factors like the consumption of unripe fruit on an empty stomach. This has prompted the consideration of alternative hypotheses. These include the role of pesticide contamination in orchards, potential bat-borne viral infections, and environmental stressors that may shift with seasons and geography. The striking differences in illness patterns observed in Bihar (India), Bangladesh, and Vietnam further complicate the picture. Moreover, documented reports of children falling ill with AES without any reported lychee consumption cast doubt on a singular explanation. This review delves into the heart of this enduring medical enigma, critically dissecting the compelling arguments and critical caveats surrounding each potential cause. This review critically evaluates the evidence for the multifaceted theories behind lychee-associated AES and challenges established assumptions. The analysis indicates a multifactorial etiology is responsible for this recurring childhood tragedy.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111742"},"PeriodicalIF":2.9,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145259214","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 : 2025-10-07DOI: 10.1016/j.toxlet.2025.111741
Chenglong Zhang , Ruiqin Yang , Shuai Liu , Peng Li , Fei Guo
Exposure to methanethiol (MT) presents a significant challenge in public healthcare and could be a concern in the context of terrorist attacks. Therefore, reliable verification procedures for MT intoxication are essential for forensic, toxicological, and clinical purposes. We developed and validated a bioanalytical method for the simultaneous detection and identification of biomarkers indicative of MT exposure. Neat human serum albumin (HSA) and human plasma were incubated with MT to form adducts, which served as references. Subsequently, HSA and human plasma were subjected to proteolysis using two proteases, resulting in the formation of disulfide adducts detected as adducts of the single amino acid cysteine (MT-Cys), the dipeptide cysteine-proline (MT-Cys34Pro), and the tripeptides aspartic acid-isoleucine-cysteine (AspIleCys514-MT) and cysteine-proline-phenylalanine (MT-Cys34ProPhe). The adducts were analyzed using a sensitive ultra-performance liquid chromatography-quadrupole exactive orbitrap-high resolution mass spectrometry (UPLC-Q Exactive Orbitrap-HRMS) method operating in full scan mass spectrometry (Full MS) and parallel reaction monitoring (PRM) mode. Time- and concentration-dependent adduct formation during exposure was investigated. The limits of detection (LODs) for the adducts ranged from 20 ng/mL to 2 μg/mL, corresponding to the MT concentrations in plasma. Adducts at Cys34 exhibited the lowest LOD (20 ng/mL MT in plasma), the fastest adduct formation (20 min), and superior stability in plasma at 37 °C. The applicability of the method was demonstrated by the successful detection of adducts in sample from MT-poisoned patient, establishing the method as a reliable bioanalytical procedure for forensic and toxicological analysis.
{"title":"Human serum albumin-adduct biomarkers to prove human poisoning with methanethiol","authors":"Chenglong Zhang , Ruiqin Yang , Shuai Liu , Peng Li , Fei Guo","doi":"10.1016/j.toxlet.2025.111741","DOIUrl":"10.1016/j.toxlet.2025.111741","url":null,"abstract":"<div><div>Exposure to methanethiol (MT) presents a significant challenge in public healthcare and could be a concern in the context of terrorist attacks. Therefore, reliable verification procedures for MT intoxication are essential for forensic, toxicological, and clinical purposes. We developed and validated a bioanalytical method for the simultaneous detection and identification of biomarkers indicative of MT exposure. Neat human serum albumin (HSA) and human plasma were incubated with MT to form adducts, which served as references. Subsequently, HSA and human plasma were subjected to proteolysis using two proteases, resulting in the formation of disulfide adducts detected as adducts of the single amino acid cysteine (MT-Cys), the dipeptide cysteine-proline (MT-Cys<sup>34</sup>Pro), and the tripeptides aspartic acid-isoleucine-cysteine (<em>Asp</em>IleCys<sup>514</sup>-MT) and cysteine-proline-phenylalanine (MT-Cys<sup>34</sup>ProPhe). The adducts were analyzed using a sensitive ultra-performance liquid chromatography-quadrupole exactive orbitrap-high resolution mass spectrometry (UPLC-Q Exactive Orbitrap-HRMS) method operating in full scan mass spectrometry (Full MS) and parallel reaction monitoring (PRM) mode. Time- and concentration-dependent adduct formation during exposure was investigated. The limits of detection (LODs) for the adducts ranged from 20 ng/mL to 2 μg/mL, corresponding to the MT concentrations in plasma. Adducts at Cys<sup>34</sup> exhibited the lowest LOD (20 ng/mL MT in plasma), the fastest adduct formation (20 min), and superior stability in plasma at 37 °C. The applicability of the method was demonstrated by the successful detection of adducts in sample from MT-poisoned patient, establishing the method as a reliable bioanalytical procedure for forensic and toxicological analysis.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111741"},"PeriodicalIF":2.9,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252766","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}
Since the adoption of the ICH M7 guidelines in 2014, pharmaceutical industries have been mandated to screen all reagents and chemicals used in drug synthesis for genotoxicity. Genotoxic impurities (GTIs) have the potential to induce mutations in DNA, which may lead to cancer. Unlike routine impurities, the threshold for controlling GTIs is extremely low. Imipramine hydrochloride (IH) is a commonly used antidepressant; however, the genotoxicity of both the drug and their impurities remain unknown. In this study, we systematically investigate the raw materials, intermediates, and known impurities involved in the synthesis pathway of IH for their potential genotoxicity. We employed in silico prediction tools to evaluate the toxicity of the impurities, intermediates, and raw materials used in the synthesis of IH, in accordance with ICH M7 guidelines. In silico prediction results revealed two specific impurities, 2,2-dinitro-1,2-diphenylethane (DNB) and 2,2-amino-1,2-diphenylethane (DAB), as potentially genotoxic. Furthermore, molecular docking and simulation studies were conducted to evaluate the specific interactions of these impurities with DNA. The results demonstrated consistent interactions of these impurities with the dG-rich region of the DNA duplex, particularly at the minor groove. Both in silico predictions and molecular docking studies corroborated the genotoxic nature of these impurities. As part of our risk assessment and control strategy, we developed and validated an HPLC-UV method in accordance with ICH guidelines to identify both GTIs in the final active pharmaceutical ingredient (API) of imipramine. This study will assist manufacturers of IH in controlling these genotoxic impurities to ensure its safe consumption.
{"title":"In silico toxicity assessment and trace level quantification of potential genotoxic impurities in imipramine hydrochloride.","authors":"Vighnesh Pradeep Nalawade, Ravindra Kulkarni, Faiz Hussain Sayyed, Nitin Rathod, Sateesh Bandaru, Sonali Ramgopal Mahule","doi":"10.1016/j.toxlet.2025.08.002","DOIUrl":"10.1016/j.toxlet.2025.08.002","url":null,"abstract":"<p><p>Since the adoption of the ICH M7 guidelines in 2014, pharmaceutical industries have been mandated to screen all reagents and chemicals used in drug synthesis for genotoxicity. Genotoxic impurities (GTIs) have the potential to induce mutations in DNA, which may lead to cancer. Unlike routine impurities, the threshold for controlling GTIs is extremely low. Imipramine hydrochloride (IH) is a commonly used antidepressant; however, the genotoxicity of both the drug and their impurities remain unknown. In this study, we systematically investigate the raw materials, intermediates, and known impurities involved in the synthesis pathway of IH for their potential genotoxicity. We employed in silico prediction tools to evaluate the toxicity of the impurities, intermediates, and raw materials used in the synthesis of IH, in accordance with ICH M7 guidelines. In silico prediction results revealed two specific impurities, 2,2-dinitro-1,2-diphenylethane (DNB) and 2,2-amino-1,2-diphenylethane (DAB), as potentially genotoxic. Furthermore, molecular docking and simulation studies were conducted to evaluate the specific interactions of these impurities with DNA. The results demonstrated consistent interactions of these impurities with the dG-rich region of the DNA duplex, particularly at the minor groove. Both in silico predictions and molecular docking studies corroborated the genotoxic nature of these impurities. As part of our risk assessment and control strategy, we developed and validated an HPLC-UV method in accordance with ICH guidelines to identify both GTIs in the final active pharmaceutical ingredient (API) of imipramine. This study will assist manufacturers of IH in controlling these genotoxic impurities to ensure its safe consumption.</p>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":" ","pages":"77-84"},"PeriodicalIF":2.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144800292","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}
Neonicotinoids are high affinity agonists of insect Nicotinic Acetyl Choline Receptors (nAChRs) resulting in insect paralysis and death. Although they are assumed to have relatively low affinity towards mammalian and other non-insect nAChRs, studies have shown that they can cause neuro-endocrine toxicity, immunotoxicity and endocrine toxicity. Moreover, as a result of bioaccumulation the levels of neonicotinoids can be even traced in non-farming population at an significant level. KCHN2 gene encodes ERG1 or hERG or KV11.1 which is responsible for Ikr current. Multiple chemical molecules can block this KV11.1-alpha sub unit and can result in prolongation of QT interval causing Drug induced Long QT Syndrome (DI-LQTS). This could potentially trigger Torsades de Pointes (TdP), a unique form of the premature ventricular complex which are spontaneous in origin and often result in Sudden Cardiac Death (SCD). Imidacloprid (IMI) is highly bioavailable and undergoes biotransformation by cytochrome p450 monooxygenases (CYP) and aldehyde oxidases (AOX) forming Desnitro-Imidacloprid (DNI) and Imidacloprid-Olefin (IOL). Interestingly, acute poisoning with IMI can result in cardiac features such as ventricular tachyarrhythmias with severe hypotension. Nonetheless, despite of the evidence regarding the toxic bioaccumulation of neonicotinoids, a little is known about their cardiovascular toxicity. Henceforth, the current study aims to understand the effect of imidacloprid and its major metabolites on hERG (KV11.1) channel blockade using molecular docking studies. Findings of the study highlighted that IMI, DNI and IOL can potentially bind to residues like Tyr652 and Phe656 in the pore forming domain and can cause hERG (KV 11.1) blockade.
{"title":"Imidacloprid and its major metabolites blocks the alpha subunit of the human hERG (KV11.1) channel: Evidence from in-silico and fluorescence polarization studies.","authors":"Vankadoth Umakanth Naik, Ajay Godwin Potnuri, Swati Sharma, Ayyappa Mandla, Dharamvir Singh Arya","doi":"10.1016/j.toxlet.2025.08.001","DOIUrl":"10.1016/j.toxlet.2025.08.001","url":null,"abstract":"<p><p>Neonicotinoids are high affinity agonists of insect Nicotinic Acetyl Choline Receptors (nAChRs) resulting in insect paralysis and death. Although they are assumed to have relatively low affinity towards mammalian and other non-insect nAChRs, studies have shown that they can cause neuro-endocrine toxicity, immunotoxicity and endocrine toxicity. Moreover, as a result of bioaccumulation the levels of neonicotinoids can be even traced in non-farming population at an significant level. KCHN2 gene encodes ERG1 or hERG or KV11.1 which is responsible for Ikr current. Multiple chemical molecules can block this KV11.1-alpha sub unit and can result in prolongation of QT interval causing Drug induced Long QT Syndrome (DI-LQTS). This could potentially trigger Torsades de Pointes (TdP), a unique form of the premature ventricular complex which are spontaneous in origin and often result in Sudden Cardiac Death (SCD). Imidacloprid (IMI) is highly bioavailable and undergoes biotransformation by cytochrome p450 monooxygenases (CYP) and aldehyde oxidases (AOX) forming Desnitro-Imidacloprid (DNI) and Imidacloprid-Olefin (IOL). Interestingly, acute poisoning with IMI can result in cardiac features such as ventricular tachyarrhythmias with severe hypotension. Nonetheless, despite of the evidence regarding the toxic bioaccumulation of neonicotinoids, a little is known about their cardiovascular toxicity. Henceforth, the current study aims to understand the effect of imidacloprid and its major metabolites on hERG (KV11.1) channel blockade using molecular docking studies. Findings of the study highlighted that IMI, DNI and IOL can potentially bind to residues like Tyr652 and Phe656 in the pore forming domain and can cause hERG (KV 11.1) blockade.</p>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":" ","pages":"68-76"},"PeriodicalIF":2.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812441","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 : 2025-10-01DOI: 10.1016/j.toxlet.2025.111735
Qiang Shi , Laura K. Schnackenberg , Lijun Ren , Katy S. Papineau , Jessica J.H. Oliphant , Mark I. Avigan , Lorna Ewart , John FK. Sauld , Emily Dai , Paul C. Brown , Karen L. Davis Bruno , Frederic Moulin , Gonçalo Gamboa da Costa , Tucker A. Patterson , Nakissa Sadrieh
Liver-on-a-chip (liver-chip) is designed to better maintain in vitro-cultured hepatic cells and improve the prediction of drug-induced liver injury (DILI). Albumin, urea, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) are proposed translational biomarkers for the prediction of DILI using liver microphysiological systems (MPS), including liver-chip. However, the performance of commonly-used assays for these biomarkers in liver MPS may vary. While using the Emulate® liver-chip, we observed that the activity of ALT, but not AST, measured using the extensively validated International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Reference Procedure, spontaneously and remarkably decreased in the perfusing medium after 24 h. Furthermore, ALT and AST activity remained largely below the detection limit (5 U/L) after acetaminophen treatment when their protein concentrations were increased by approximately 20-fold, as determined by an enzyme-linked immunosorbent assay (ELISA). The protein concentrations of ALT and AST, but not activity, showed good correlation with LDH activity, which was nearly eliminated after a freeze-thaw cycle. For viability of non-parenchymal cells, an unusually high background signal, largely attributable to CultureBoost and fetal bovine serum in the perfusion medium, prevented the use of LDH activity assays; however, LDH ELISA appeared to be a useful alternative. Of two widely used urea assays, the enzymatic approach was profoundly affected by medium supplements, wherein sample dilution increased the limit of detection, making it impossible to observe drug-induced urea inhibition. By contrast, the chemical assay offered adequate and improved specificity and sensitivity. For albumin, an ELISA had to be adopted, since routinely used dye-binding methods were not sensitive enough. These findings provide a plausible explanation for some controversies in the literature and highlight the significance of establishing reliable and reproducible assays for translational DILI biomarkers in liver MPS.
{"title":"Challenges and solutions in measuring commonly used biomarkers for drug-induced liver injury in a liver-on-a-chip platform","authors":"Qiang Shi , Laura K. Schnackenberg , Lijun Ren , Katy S. Papineau , Jessica J.H. Oliphant , Mark I. Avigan , Lorna Ewart , John FK. Sauld , Emily Dai , Paul C. Brown , Karen L. Davis Bruno , Frederic Moulin , Gonçalo Gamboa da Costa , Tucker A. Patterson , Nakissa Sadrieh","doi":"10.1016/j.toxlet.2025.111735","DOIUrl":"10.1016/j.toxlet.2025.111735","url":null,"abstract":"<div><div>Liver-on-a-chip (liver-chip) is designed to better maintain in vitro-cultured hepatic cells and improve the prediction of drug-induced liver injury (DILI). Albumin, urea, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) are proposed translational biomarkers for the prediction of DILI using liver microphysiological systems (MPS), including liver-chip. However, the performance of commonly-used assays for these biomarkers in liver MPS may vary. While using the Emulate® liver-chip, we observed that the activity of ALT, but not AST, measured using the extensively validated International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Reference Procedure, spontaneously and remarkably decreased in the perfusing medium after 24 h. Furthermore, ALT and AST activity remained largely below the detection limit (5 U/L) after acetaminophen treatment when their protein concentrations were increased by approximately 20-fold, as determined by an enzyme-linked immunosorbent assay (ELISA). The protein concentrations of ALT and AST, but not activity, showed good correlation with LDH activity, which was nearly eliminated after a freeze-thaw cycle. For viability of non-parenchymal cells, an unusually high background signal, largely attributable to CultureBoost and fetal bovine serum in the perfusion medium, prevented the use of LDH activity assays; however, LDH ELISA appeared to be a useful alternative. Of two widely used urea assays, the enzymatic approach was profoundly affected by medium supplements, wherein sample dilution increased the limit of detection, making it impossible to observe drug-induced urea inhibition. By contrast, the chemical assay offered adequate and improved specificity and sensitivity. For albumin, an ELISA had to be adopted, since routinely used dye-binding methods were not sensitive enough. These findings provide a plausible explanation for some controversies in the literature and highlight the significance of establishing reliable and reproducible assays for translational DILI biomarkers in liver MPS.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111735"},"PeriodicalIF":2.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145221471","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 : 2025-10-01DOI: 10.1016/j.toxlet.2025.111740
Zhinan Jin , Shenghui Cheng , Baoyue Liu , Yixuan Liu , Yanming Wei , Xuliang Hao , Huifang Li
Gardenia jasminoides, as a widely used traditional Chinese medicine, excessive consumption of it may lead to severe liver injury. As the main hepatotoxic component in Gardenia jasminoides, the specific mechanism by which geniposide (GE) causes liver injury remains elusive. In this study, we conducted a systematic investigation of the effects of GE on bile acid (BA) metabolism and related signal transduction and inflammatory pathways in healthy Sprague-Dawley (SD) rats after oral administration of a 13-fold clinical equivalent dose (450 mg/kg) for 5 days. It is noteworthy that GE administration altered the content and composition of BAs and disrupted BA metabolism. At the same time, the expressions of farnesoid X receptor (FXR) and its downstream proteins bile salt export pump (BSEP) and sodium taurocholate cotransporting polypeptide (NTCP) are significantly inhibited. In addition, the inhibition of FXR will increase the signal transduction of the protein kinase R-like endoplasmic reticulum kinase (PERK)-thioredoxin-interacting protein (TXNIP)-nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome axis, thereby triggering cysteine protease-1 (caspase-1), leading to the release of inflammatory factors and worsening liver injury. The addition of the FXR agonist obeticholic acid (OCA) effectively reversed the expressions of the above proteins and mRNA, and alleviated the liver injury caused by GE by restoring BAs homeostasis and regulating the inflammatory pathway. Conclusion: GE causes severe liver injury by affecting bile acid metabolism and inflammatory pathways, and the inhibition of FXR is a crucial factor.
{"title":"Geniposide induces hepatotoxicity via the bile acid-induced activation of NLRP3 inflammasome and regulation of the FXR/PERK/TXNIP pathway","authors":"Zhinan Jin , Shenghui Cheng , Baoyue Liu , Yixuan Liu , Yanming Wei , Xuliang Hao , Huifang Li","doi":"10.1016/j.toxlet.2025.111740","DOIUrl":"10.1016/j.toxlet.2025.111740","url":null,"abstract":"<div><div><em>Gardenia jasminoides</em>, as a widely used traditional Chinese medicine, excessive consumption of it may lead to severe liver injury. As the main hepatotoxic component in <em>Gardenia jasminoides</em>, the specific mechanism by which geniposide (GE) causes liver injury remains elusive. In this study, we conducted a systematic investigation of the effects of GE on bile acid (BA) metabolism and related signal transduction and inflammatory pathways in healthy Sprague-Dawley (SD) rats after oral administration of a 13-fold clinical equivalent dose (450 mg/kg) for 5 days. It is noteworthy that GE administration altered the content and composition of BAs and disrupted BA metabolism. At the same time, the expressions of farnesoid X receptor (FXR) and its downstream proteins bile salt export pump (BSEP) and sodium taurocholate cotransporting polypeptide (NTCP) are significantly inhibited. In addition, the inhibition of FXR will increase the signal transduction of the protein kinase R-like endoplasmic reticulum kinase (PERK)-thioredoxin-interacting protein (TXNIP)-nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome axis, thereby triggering cysteine protease-1 (caspase-1), leading to the release of inflammatory factors and worsening liver injury. The addition of the FXR agonist obeticholic acid (OCA) effectively reversed the expressions of the above proteins and mRNA, and alleviated the liver injury caused by GE by restoring BAs homeostasis and regulating the inflammatory pathway. Conclusion: GE causes severe liver injury by affecting bile acid metabolism and inflammatory pathways, and the inhibition of FXR is a crucial factor.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111740"},"PeriodicalIF":2.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145221472","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 : 2025-10-01DOI: 10.1016/j.toxlet.2025.111739
Yehao Sun , Karen Lin , Felix Effah , Francisco Cartujano Barrera , Dongmei Li , Scott McIntosh , Matthew D. McGraw , Irfan Rahman
Background
E-cigarettes and other electronic nicotine delivery systems (ENDs) remain a significant public health risk. Although deployed as tobacco smoking cessation tools, e-cigarettes have gained greater popularity among non-smokers, specifically adolescents and young adults. Previous research has focused primarily on the toxicities associated with nicotine, flavorings, and other chemicals generated from e-cigarette liquid aerosolization; however, little attention has been given to the two primary and most abundant chemicals found in most e-cigarette liquids – propylene glycol (PG) and vegetable glycerin (VG).
Purpose
The purpose of this review is to assess the toxicity associated with PG/VG in e-cigarettes to inform future ENDS regulations.
Methods
Database searches were performed using PubMed for relevant literature published from 1/1/2014–9/1/2025. Cited articles about the prevalence, toxicities, and public perceptions of PG/VG.
Results
Toxicity associated with PG/VG inhalation is primarily due to thermal degradation byproducts (TDBs) generated by PG/VG-containing e-liquids. More specifically, high-power ENDS devices with sub-ohm power capabilities generate aerosols with larger mass and higher concentrations of TDBs. The most common TDBs identified in e-cigarette aerosols include formaldehyde, acetaldehyde, acrolein, acetone, acetoin/diacetyl, as well as benzene. These TDBs, along with other chemical adducts, contribute significantly to the e-cigarette aerosols’ potential to cause oxidative stress, airway inflammation, and increase risks for cancer. Mechanistically, the toxicity associated with e-cigarette aerosols is mediated through the activation of the NF-κB and MAPK pathways, as well as the dysfunction of ion channels responsible for mucus hydration. These effects of e-cigarette aerosol exposures, whether induced by TDBs or other chemicals, can be affected by factors involved in the aerosolization process, including the ratio of PG/VG, the device power, and the resistance of the coil.
Conclusions
E-cigarettes are often considered a harm-reduction alternative to combustible cigarettes due to PG and VG’s FDA designation as “Generally Recognized as Safe” (GRAS) for consumption. However, when heated and inhaled, mixtures of PG/VG in e-cigarette liquids have their toxicities independent of the other constituents of e-liquids. Future regulations that focus on the PG/VG ratios, set limits on thermal degradation byproducts, and establish exposure thresholds for e-cigarette aerosols will help reduce toxic exposures associated with PG/VG inhalation. As such, further research is needed on PG/VG alone to understand its long-term health effects better and to inform evidence-based public health policies.
{"title":"Toxicity of humectants propylene glycol and vegetable glycerin in electronic nicotine delivery systems","authors":"Yehao Sun , Karen Lin , Felix Effah , Francisco Cartujano Barrera , Dongmei Li , Scott McIntosh , Matthew D. McGraw , Irfan Rahman","doi":"10.1016/j.toxlet.2025.111739","DOIUrl":"10.1016/j.toxlet.2025.111739","url":null,"abstract":"<div><h3>Background</h3><div>E-cigarettes and other electronic nicotine delivery systems (ENDs) remain a significant public health risk. Although deployed as tobacco smoking cessation tools, e-cigarettes have gained greater popularity among non-smokers, specifically adolescents and young adults. Previous research has focused primarily on the toxicities associated with nicotine, flavorings, and other chemicals generated from e-cigarette liquid aerosolization; however, little attention has been given to the two primary and most abundant chemicals found in most e-cigarette liquids – propylene glycol (PG) and vegetable glycerin (VG).</div></div><div><h3>Purpose</h3><div>The purpose of this review is to assess the toxicity associated with PG/VG in e-cigarettes to inform future ENDS regulations.</div></div><div><h3>Methods</h3><div>Database searches were performed using PubMed for relevant literature published from 1/1/2014–9/1/2025. Cited articles about the prevalence, toxicities, and public perceptions of PG/VG.</div></div><div><h3>Results</h3><div>Toxicity associated with PG/VG inhalation is primarily due to thermal degradation byproducts (TDBs) generated by PG/VG-containing e-liquids. More specifically, high-power ENDS devices with sub-ohm power capabilities generate aerosols with larger mass and higher concentrations of TDBs. The most common TDBs identified in e-cigarette aerosols include formaldehyde, acetaldehyde, acrolein, acetone, acetoin/diacetyl, as well as benzene. These TDBs, along with other chemical adducts, contribute significantly to the e-cigarette aerosols’ potential to cause oxidative stress, airway inflammation, and increase risks for cancer. Mechanistically, the toxicity associated with e-cigarette aerosols is mediated through the activation of the NF-κB and MAPK pathways, as well as the dysfunction of ion channels responsible for mucus hydration. These effects of e-cigarette aerosol exposures, whether induced by TDBs or other chemicals, can be affected by factors involved in the aerosolization process, including the ratio of PG/VG, the device power, and the resistance of the coil.</div></div><div><h3>Conclusions</h3><div>E-cigarettes are often considered a harm-reduction alternative to combustible cigarettes due to PG and VG’s FDA designation as “Generally Recognized as Safe” (GRAS) for consumption. However, when heated and inhaled, mixtures of PG/VG in e-cigarette liquids have their toxicities independent of the other constituents of e-liquids. Future regulations that focus on the PG/VG ratios, set limits on thermal degradation byproducts, and establish exposure thresholds for e-cigarette aerosols will help reduce toxic exposures associated with PG/VG inhalation. As such, further research is needed on PG/VG alone to understand its long-term health effects better and to inform evidence-based public health policies.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111739"},"PeriodicalIF":2.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145226062","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 : 2025-09-30DOI: 10.1016/j.toxlet.2025.111738
Bo Wang , Hongyu Ma , Yuying Cheng , Dangdang Cheng , Feifei Wang
Background
Sensitivity testing for cosmetic formulations mainly involves human patch tests. Cell models, including KeratinoSensTM, ARE-Nrf2 luciferase LuSens and h-CLAT, can predict chemical sensitization according to the OECD 442E standard.
Objective
The aim of this study was to identify a potential approach for the assessment of the sensitization potential of cosmetics using skin models cocultured with THP-1 cells.
Methods
We identified the surface markers CD54 and CD86 in THP-1 cells using flow cytometry and enzyme-linked immunosorbent assays (ELISAs); detected the relative secretion of IL-18, MTT and 7AAD; and evaluated tissue and cell viability. Adverse reactions were analysed using the human patch test.
Results
The relative level of IL-18 secretion after exposure to cinnamyl aldehyde, 2,4-dinitrochlorobenzene, propyl gallate and coumarin was less than 0.79. The relative fluorescence intensity of CD54 was greater than 150, and that for CD86 was greater than 200. Using RFI CD54 ≥ 150, RFI CD86 ≥ 200 or RS IL-18 ≤ 0.79 as the potential sensitization standard, an 18-item cosmetic formulation caused sensitization. Moreover, a 23-item cosmetic formulation caused sensitization in the human patch test. The sensitivity to the products in the in vitro test reached 56.52 %, compared with 75 % for the cleaning products.
Conclusion
RFI CD54/CD86 and IL-18 may serve as a new approach to evaluate potential sensitization to cosmetics. In vitro SkinEthic and THP-1 cell coculture combined with the human patch test may better predict potential sensitization to cosmetics.
{"title":"Application of an in vitro reconstructed human skin coculture with THP-1 on cosmetics in skin sensitization","authors":"Bo Wang , Hongyu Ma , Yuying Cheng , Dangdang Cheng , Feifei Wang","doi":"10.1016/j.toxlet.2025.111738","DOIUrl":"10.1016/j.toxlet.2025.111738","url":null,"abstract":"<div><h3>Background</h3><div>Sensitivity testing for cosmetic formulations mainly involves human patch tests. Cell models, including KeratinoSens<sup>TM</sup>, ARE-Nrf2 luciferase LuSens and h-CLAT, can predict chemical sensitization according to the OECD 442E standard.</div></div><div><h3>Objective</h3><div>The aim of this study was to identify a potential approach for the assessment of the sensitization potential of cosmetics using skin models cocultured with THP-1 cells.</div></div><div><h3>Methods</h3><div>We identified the surface markers CD54 and CD86 in THP-1 cells using flow cytometry and enzyme-linked immunosorbent assays (ELISAs); detected the relative secretion of IL-18, MTT and 7AAD; and evaluated tissue and cell viability. Adverse reactions were analysed using the human patch test.</div></div><div><h3>Results</h3><div>The relative level of IL-18 secretion after exposure to cinnamyl aldehyde, 2,4-dinitrochlorobenzene, propyl gallate and coumarin was less than 0.79. The relative fluorescence intensity of CD54 was greater than 150, and that for CD86 was greater than 200. Using RFI CD54 ≥ 150, RFI CD86 ≥ 200 or RS IL-18 ≤ 0.79 as the potential sensitization standard, an 18-item cosmetic formulation caused sensitization. Moreover, a 23-item cosmetic formulation caused sensitization in the human patch test. The sensitivity to the products in the in vitro test reached 56.52 %, compared with 75 % for the cleaning products.</div></div><div><h3>Conclusion</h3><div>RFI CD54/CD86 and IL-18 may serve as a new approach to evaluate potential sensitization to cosmetics. In vitro SkinEthic and THP-1 cell coculture combined with the human patch test may better predict potential sensitization to cosmetics.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111738"},"PeriodicalIF":2.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213868","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 : 2025-09-29DOI: 10.1016/j.toxlet.2025.111730
Xianhao Wang , Xinyue Wang , Ruxu Yan , Tianqi Ma , Xiangyun Wang , Fengxue Shi , Zhongxu Zhao , Lingyue Kong , Jingen Zhou , Dong Li , Yangyang Yuan
Environmental pollutants are increasingly recognized as important modulators of immune function, yet the influence of volatile organic compound (VOC) exposure on immunoglobulin E (IgE) levels remains poorly characterized. Using data from the National Health and Nutrition Examination Survey (NHANES) 2005–2006, we systematically evaluated the association between VOC metabolites and total IgE levels through five statistical approaches combined with machine learning algorithms. Mediation analyses were conducted to examine the role of inflammatory markers in these associations. Finally, functional enrichment analyses were employed to identify potential pathways and key molecular targets. Our analyses consistently demonstrated significant positive associations between VOC exposure and elevated total IgE levels. 2-aminothiazoline-4-carboxylic acid (ATCA), N-Acetyl-S-(2-cyanoethyl)-L-cysteine (CYMA), and N-Acetyl-S- (3-hydroxypropyl)-L-cysteine (HPMA) emerged as robust risk factors. Mediation analysis revealed that eosinophil (EOS) counts accounted for 15.89–29.03 % of the observed associations between VOC metabolites and total IgE levels. TNF and IL-17 signaling pathways were significantly enriched. Integrated analyses confirmed VOC exposure as a significant environmental risk factor for elevated total IgE levels, primarily driven by ATCA, CYMA, and HPMA, with inflammatory responses as a plausible mechanism.
环境污染物被越来越多地认为是免疫功能的重要调节剂，但挥发性有机化合物（VOC）暴露对免疫球蛋白E （IgE）水平的影响尚不清楚。利用2005-2006年国家健康与营养检查调查（NHANES）的数据，我们通过五种统计方法结合机器学习算法，系统地评估了VOC代谢物与总IgE水平之间的关系。进行中介分析以检查炎症标志物在这些关联中的作用。最后，利用功能富集分析来确定潜在的途径和关键的分子靶点。我们的分析一致表明，VOC暴露与总IgE水平升高之间存在显著的正相关。2-氨基噻唑-4-羧酸（ATCA）、n -乙酰基- s -（2-氰乙基）- l-半胱氨酸（CYMA）和n -乙酰基- s -（3-羟丙基）- l-半胱氨酸（HPMA）被认为是强有力的危险因素。调解分析显示，在观察到的VOC代谢物与总IgE水平之间的相关性中，嗜酸性粒细胞（EOS）计数占15.89% ~ 29.03%。TNF、IL-17信号通路显著富集（Padjust < 0.05）。综合分析证实，VOC暴露是总IgE水平升高的重要环境风险因素，主要由ATCA、CYMA和HPMA驱动，炎症反应是一种可能的机制。
{"title":"Association between volatile organic compound exposure and elevated total immunoglobulin E: Risk factor screening in mixed exposure scenarios and potential biological mechanisms","authors":"Xianhao Wang , Xinyue Wang , Ruxu Yan , Tianqi Ma , Xiangyun Wang , Fengxue Shi , Zhongxu Zhao , Lingyue Kong , Jingen Zhou , Dong Li , Yangyang Yuan","doi":"10.1016/j.toxlet.2025.111730","DOIUrl":"10.1016/j.toxlet.2025.111730","url":null,"abstract":"<div><div>Environmental pollutants are increasingly recognized as important modulators of immune function, yet the influence of volatile organic compound (VOC) exposure on immunoglobulin E (IgE) levels remains poorly characterized. Using data from the National Health and Nutrition Examination Survey (NHANES) 2005–2006, we systematically evaluated the association between VOC metabolites and total IgE levels through five statistical approaches combined with machine learning algorithms. Mediation analyses were conducted to examine the role of inflammatory markers in these associations. Finally, functional enrichment analyses were employed to identify potential pathways and key molecular targets. Our analyses consistently demonstrated significant positive associations between VOC exposure and elevated total IgE levels. 2-aminothiazoline-4-carboxylic acid (ATCA), N-Acetyl-S-(2-cyanoethyl)-L-cysteine (CYMA), and N-Acetyl-S- (3-hydroxypropyl)-L-cysteine (HPMA) emerged as robust risk factors. Mediation analysis revealed that eosinophil (EOS) counts accounted for 15.89–29.03 % of the observed associations between VOC metabolites and total IgE levels. TNF and IL-17 signaling pathways were significantly enriched. Integrated analyses confirmed VOC exposure as a significant environmental risk factor for elevated total IgE levels, primarily driven by ATCA, CYMA, and HPMA, with inflammatory responses as a plausible mechanism.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111730"},"PeriodicalIF":2.9,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145207645","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 : 2025-09-29DOI: 10.1016/j.toxlet.2025.111732
Xiaoming Shen, Chuanqing Bao
Background
Bisphenol A (BPA) is a widespread endocrine-disrupting chemical found in consumer products. While BPA exposure has been associated with various health risks, its specific impact on colorectal cancer (CRC) progression and underlying mechanisms remain poorly understood.
Methods
In this five-year retrospective cohort study, we analyzed 63 CRC patients selected from an initial cohort of 574. Urinary BPA was quantified using HPLC-MS/MS, and patients were stratified into normal (n = 15), low (n = 30), and high (n = 18) BPA exposure groups. Flow cytometry and immunohistochemistry profiled immune cell populations in blood and tumor tissues. Multivariate regression analyses identified relationships between BPA exposure, metabolic parameters, and clinical outcomes.
Results
BPA levels showed significant inverse correlations with HDL/LDL ratio (p = 0.010) and positive correlations with BMI (p = 0.028). Patients with high BPA exposure demonstrated significantly higher rates of metastasis (61.1 % vs. 10 % in low exposure and 0 % in normal exposure groups, p < 0.001) and shorter overall survival (median 20 months vs. 51 months in low exposure group, p = 0.034). Flow cytometric analysis revealed dose-dependent reductions in circulating CD8 + T cells, CD4 + T cells, and NK cells with increasing BPA exposure. Immunohistochemical analysis showed pronounced decreases in tumor-infiltrating CD8 + T lymphocytes correlating with BPA exposure levels (p = 0.0027). High BPA exposure was also significantly associated with increased post-surgical infection rates (OR=1.9, 95 % CI: 1.1–3.1).
Conclusion
These preliminary findings suggest BPA exposure represents a potential risk factor for CRC progression, likely mediated through metabolic alterations and immunosuppression within the tumor microenvironment. Environmental exposures may significantly influence cancer outcomes through immune-metabolic pathways, though further validation in larger cohorts is warranted.
{"title":"Bisphenol A exposure associates with colorectal cancer metastasis and immunosuppression: A five-year cohort study","authors":"Xiaoming Shen, Chuanqing Bao","doi":"10.1016/j.toxlet.2025.111732","DOIUrl":"10.1016/j.toxlet.2025.111732","url":null,"abstract":"<div><h3>Background</h3><div>Bisphenol A (BPA) is a widespread endocrine-disrupting chemical found in consumer products. While BPA exposure has been associated with various health risks, its specific impact on colorectal cancer (CRC) progression and underlying mechanisms remain poorly understood.</div></div><div><h3>Methods</h3><div>In this five-year retrospective cohort study, we analyzed 63 CRC patients selected from an initial cohort of 574. Urinary BPA was quantified using HPLC-MS/MS, and patients were stratified into normal (n = 15), low (n = 30), and high (n = 18) BPA exposure groups. Flow cytometry and immunohistochemistry profiled immune cell populations in blood and tumor tissues. Multivariate regression analyses identified relationships between BPA exposure, metabolic parameters, and clinical outcomes.</div></div><div><h3>Results</h3><div>BPA levels showed significant inverse correlations with HDL/LDL ratio (p = 0.010) and positive correlations with BMI (p = 0.028). Patients with high BPA exposure demonstrated significantly higher rates of metastasis (61.1 % vs. 10 % in low exposure and 0 % in normal exposure groups, p < 0.001) and shorter overall survival (median 20 months vs. 51 months in low exposure group, p = 0.034). Flow cytometric analysis revealed dose-dependent reductions in circulating CD8 + T cells, CD4 + T cells, and NK cells with increasing BPA exposure. Immunohistochemical analysis showed pronounced decreases in tumor-infiltrating CD8 + T lymphocytes correlating with BPA exposure levels (p = 0.0027). High BPA exposure was also significantly associated with increased post-surgical infection rates (OR=1.9, 95 % CI: 1.1–3.1).</div></div><div><h3>Conclusion</h3><div>These preliminary findings suggest BPA exposure represents a potential risk factor for CRC progression, likely mediated through metabolic alterations and immunosuppression within the tumor microenvironment. Environmental exposures may significantly influence cancer outcomes through immune-metabolic pathways, though further validation in larger cohorts is warranted.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111732"},"PeriodicalIF":2.9,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145207662","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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