Chemical Research in Toxicology最新文献

{"title":"Chlorogenic Acid Alleviates Early-Life GenX Exposure-Induced Neurotoxicity via Decreasing Lipopolysaccharide-Induced Pyroptosis by the Systemic Translocation and Suppressing the PI3K/AKT/NF-κB Pathway","authors":"Ming-Quan Lai,&nbsp;Mei-Ting Zhong,&nbsp;Jin-Jin Zhang,&nbsp;Ya-Qi Chen,&nbsp;Xiao-Fan Guo,&nbsp;Qi Wang* and Xiao-Li Xie*,&nbsp;","doi":"10.1021/acs.chemrestox.5c00172","DOIUrl":"10.1021/acs.chemrestox.5c00172","url":null,"abstract":"<p >Ammonium perfluoro (2-methyl-3-oxahexanoate) (GenX), a substitute for perfluorooctanoic acid, disrupts early-life intestinal homeostasis and impacts neurodevelopment. However, the mechanisms are unclear, and interventions are limited. In this study, pregnant mice were exposed to GenX (2 mg/kg/day) and chlorogenic acid (CGA, 30 mg/kg/day) from gestation day 0 to postnatal day 21. GenX exposure resulted in a significant reduction in birth length, body weight, and colon length in the pups as well as an infiltration of inflammatory cells, glandular atrophy, and a decrease in the number of goblet cells within the colon. Moreover, the expression of ZO-1, occludin, and claudin-5 decreased in the colon, indicating that exposure to GenX may have compromised intestinal barrier function. The GenX group exhibited increased levels of lipopolysaccharide (LPS) in both the serum and cortex, along with increased expression of NLRP3, GSDMD, GSDMD-N, IL-1β, IL-18, and Caspase-1 p10 in the colon and cortex, indicating pyroptosis activation. The elevated protein expression levels of inflammatory factors, including TNF-α, IFN-γ, COX-2, iNOS, p-PI3K, p-AKT, and p-NF-κB in the cortex, indicated the activation of the PI3K/AKT/NF-κB signaling pathway, contributing to the developmental neurotoxicity. CGA treatment improved intestinal barrier function and reduced LPS leakage and inflammation in the cortex, possibly by decreasing LPS translocation and pyroptosis. Taken together, CGA treatment effectively alleviated perinatal GenX exposure-induced intestinal homeostasis disruption and developmental neurotoxicity due to the LPS translocation and activation of pyroptosis.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 9","pages":"1524–1534"},"PeriodicalIF":3.8,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144843802","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":"Inhibitory Effects of Alkaloids on BCRP Implicated in Reversing Multidrug Resistance: A Case Example of Enhancing Temozolomide Cytotoxicity","authors":"Xiaoyan Duan,&nbsp;Jinjin Wu,&nbsp;Jiahuan Hu,&nbsp;Wanting Bai and Jinping Hu*,&nbsp;","doi":"10.1021/acs.chemrestox.5c00225","DOIUrl":"10.1021/acs.chemrestox.5c00225","url":null,"abstract":"<p >Breast cancer resistance protein (BCRP), an important ATP-binding cassette transporter, is mainly responsible for drug efflux from cells, especially in high-expressing tumor cells, and is closely associated with multidrug resistance (MDR). Numerous studies have demonstrated that the inhibition of BCRP can reverse MDR, so inhibiting BCRP is considered to be a promising strategy for cancer treatment. Alkaloids are the primary bioactive ingredients in various traditional Chinese medicines (TCMs), some of which have been reported to reverse MDR by inhibiting BCRP. Our objective was to identify potential inhibitors of BCRP from 130 alkaloids, evaluate the reversion of MDR in TMZ-resistant U251T and T98G cells, and clarify the structure–activity relationships of alkaloids in BCRP inhibition. Among them, eight alkaloids, including sempervirine, reserpine, coptisine chloride, geissoschizine methyl ether, vincristine sulfate, tetrahydroberberine, cyclovirobuxine, and berberrubine, exhibited significant inhibition (&gt;50%) of BCRP in BCRP-MDCK cells, with IC₅₀ ranging from 16.95–94.13 μM. Co-treatment with the inhibitor increased Temozolomide (TMZ) cytotoxicity in TMZ-resistant U251T and T98G cells, with IC₅₀ values declining by 2.1–97.3%. For sempervirine, coptisine chloride, and reserpine, the inhibition appeared to be even greater than the positive inhibitor KO143. Molecular docking analyses elucidated that the inhibitory effect of alkaloids on BCRP was related to π–π stacked, π–alkyl, and π–Sulfur interactions. The pharmacophore model illustrated that aromatic rings and hydrophobic groups may play a critical role in the potency of alkaloid inhibition on BCRP. Taken together, our findings provide valuable information for optimizing alkaloid structure and developing BCRP inhibitors with improved potency and specificity to reverse clinical MDR.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 9","pages":"1595–1610"},"PeriodicalIF":3.8,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144820140","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":"Triclocarban Disrupts Hepatic Lipid Homeostasis and Promotes Endoplasmic Reticulum Stress in Mice: A Multiomics Investigation","authors":"Qian Song,&nbsp;Rong Zhang,&nbsp;Xinyu Liu,&nbsp;Xiaoyan Ji,&nbsp;Ao Han,&nbsp;Fangrong He,&nbsp;Ruyun Ding and Hongna Zhang*,&nbsp;","doi":"10.1021/acs.chemrestox.5c00191","DOIUrl":"10.1021/acs.chemrestox.5c00191","url":null,"abstract":"<p >Triclocarban (TCC) is an antiseptic ingredient incorporated into many skin-contact hygiene products, raising public health concerns for its frequent detection in the general population. As the central metabolic organ, the liver plays a key role in lipid synthesis and metabolism; however, the in vivo effects of TCC on hepatic lipid homeostasis remain largely unclear. Herein, a percutaneous TCC exposure model was established based on human-relevant concentrations. An integrated multiomics approach, including hepatic transcriptomics and lipidomics, was applied to explore TCC effects on the liver. We discovered that continuous dermal absorption of TCC significantly disturbed hepatic lipid profiles, as manifested by the decrease in energy storage lipid triacylglycerol (TG) and its synthetic precursor diacylglycerol (DG). Integrated analysis of transcriptomics and targeted validation revealed that TG reduction could result from the decline in lipogenesis, acceleration of fatty acid β-oxidation, and elevated secretion of very-low-density lipoproteins (VLDLs). Cell membrane homeostasis was also disrupted through altering hepatocellular phosphatidylcholine (PC) and phosphatidylethanolamine (PE) levels, which may be related to the activation of endoplasmic reticulum (ER) stress, resulting in the promotion of hepatocyte apoptosis. Together, this work provides novel insights into the causal relationship between TCC exposure and the hepatic metabolic homeostasis.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 9","pages":"1564–1575"},"PeriodicalIF":3.8,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833465","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":"Region-Specific Metabolic Alterations in the Tryptophan Pathway in Cisplatin-Induced Acute Kidney Injury","authors":"Yue Feng,&nbsp;Ying Zhang,&nbsp;Jinxin Li,&nbsp;Junzhe Yu,&nbsp;Yuan Tian,&nbsp;Zunjian Zhang,&nbsp;Fengguo Xu* and Pei Zhang*,&nbsp;","doi":"10.1021/acs.chemrestox.5c00113","DOIUrl":"10.1021/acs.chemrestox.5c00113","url":null,"abstract":"<p >Cisplatin (DDP) is widely utilized in the clinical treatment of malignant tumors, but its effectiveness is significantly compromised by the adverse effects of acute kidney injury (AKI). Renal tubular cells are primarily responsible for DDP-induced AKI (DDP-AKI); however, the responses of heterogeneous renal tubular cells to DDP exposure have not been thoroughly explored. In this study, we employed a targeted metabolomics approach to investigate the metabolic responses of renal tubular cells in DDP-AKI rats. Tubular cells were isolated from the renal cortex and outer medulla, and a chemical derivatization-based liquid chromatography–tandem mass spectrometry (LC–MS/MS) metabolomics method was applied. Our findings revealed distinct metabolic profiles in tubular cells from the renal cortex and outer medulla, with outer medullary cells exhibiting greater sensitivity to DDP exposure. Further analyses identified the tryptophan pathway as a critical factor contributing to these regional differences. Additional functional investigations showed that intermediate metabolites of the tryptophan pathway alleviated DDP cytotoxicity in both cortical and outer medullary tubular cells primarily through modulation of the Bcl2/Bax and Caspase-3 pathway. This study enhances our understanding of the metabolic characteristics of tubular cells across heterogeneous renal regions in DDP-AKI and facilitates further exploration of the underlying mechanisms of DDP-induced nephrotoxicity.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 9","pages":"1472–1484"},"PeriodicalIF":3.8,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144820141","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":"Which Modern AI Methods Provide Accurate Predictions of Toxicological End Points? Analysis of Tox24 Challenge Results","authors":"Stephanie A. Eytcheson,&nbsp; and ,&nbsp;Igor V. Tetko*,&nbsp;","doi":"10.1021/acs.chemrestox.5c00273","DOIUrl":"10.1021/acs.chemrestox.5c00273","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 9","pages":"1443–1451"},"PeriodicalIF":3.8,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144802979","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":"Advancing Human and Environmental Safety Science Using In Silico Methods","authors":"Alessandra Roncaglioni,&nbsp;Simona Kovarich,&nbsp;Kamel Mansouri and Igor V. Tetko*,&nbsp;","doi":"10.1021/acs.chemrestox.5c00293","DOIUrl":"10.1021/acs.chemrestox.5c00293","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 8","pages":"1281–1282"},"PeriodicalIF":3.8,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144802978","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":"Evaluating the Toxicity of Electronic Cigarette Aerosols for Firsthand and Secondhand Exposure Under Different Device Operating Conditions","authors":"Kashala Fabrice Kapiamba,&nbsp;Hsin-Yin Chuang,&nbsp;Weixing Hao,&nbsp;Ta-Chun Lin,&nbsp;Lung-Chi Chen,&nbsp;Yue-Wern Huang and Yang Wang*,&nbsp;","doi":"10.1021/acs.chemrestox.5c00064","DOIUrl":"10.1021/acs.chemrestox.5c00064","url":null,"abstract":"<p >The rapid proliferation of electronic cigarettes (ECs) has raised significant concerns about their potential health effects on both users and bystanders. This study systematically investigates the impact of EC aerosol exposure on human alveolar epithelial cells (A549), considering variations in device parameters, nicotine concentration, and exposure type. Using a gravity-based air–liquid interface exposure system, we assessed cytotoxicity and epithelial barrier integrity by measuring cell viability and transepithelial electrical resistance (TEER). Our results indicate that EC aerosol exposure significantly reduces cell viability and disrupts monolayer integrity in a dose- and device-dependent manner. Notably, VUSE (pod-type) exposure led to a 16% decrease in viability and a 41% reduction in TEER, while VOOPOO (mod-type) exposure caused a 25% viability loss and a 61% reduction in TEER. Power settings played a critical role: at 60 W, cell viability dropped by 48% at 12 mg/mL nicotine concentration compared to 29% at 0 mg/mL. Moreover, under the same number of puffs (30 puffs), firsthand exposure resulted in a 73% viability decrease, whereas secondhand exposure showed a 47% reduction, indicating substantial bystander risks associated with EC usage. These findings underscore the importance of device specifications and exposure conditions in determining EC aerosol toxicity. The observed epithelial barrier disruption suggests increased vulnerability to respiratory diseases. Given the comparable toxicity of firsthand and secondhand aerosols, regulatory measures should extend beyond direct users to include bystander protection. This study highlights the urgent need for comprehensive toxicity assessments to inform public health policies on EC use.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 8","pages":"1344–1356"},"PeriodicalIF":3.8,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792946","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":"Mechanistic Interpretation of Toxicology Metabolomics Data","authors":"Aniko Kende*,&nbsp;David E. Cowie and Richard A. Currie,&nbsp;","doi":"10.1021/acs.chemrestox.5c00203","DOIUrl":"10.1021/acs.chemrestox.5c00203","url":null,"abstract":"<p >The toxicological interpretation of metabolomics data remains challenging, mainly due to the lack of relational knowledge of metabolic pathway perturbations and adverse outcomes. Here we propose an approach focused on the associative events defined by the adverse outcome pathway (AOP) concept to derive adverse effect predictions from toxicology metabolomics data sets by combining knowledge-driven hypothesis generation and data-driven hypothesis testing. By assessing the associative key events in an AOP, a list of plausible metabolite perturbations can be created, aiding the interpretation of the list of observed metabolite perturbations or differentially abundant metabolites (DAMs). We describe the critical steps of the interpretation and certainty assessment of the effect prediction using protoporphyrinogen oxidase (PPO) inhibition as an example. The approach could serve as a stepping stone toward creating a database of validated, toxicologically meaningful associative event signatures that can be deployed both in (early stage) research of chemical product development and in regulatory chemical safety assessment for hazard identification.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 8","pages":"1284–1290"},"PeriodicalIF":3.8,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144787805","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":"Formaldehyde Exposure Induces Systemic Epigenetic Alterations in Histone Methylation and Acetylation","authors":"Jiahao Feng,&nbsp;Chih-Wei Liu,&nbsp;Jingya Peng,&nbsp;Yun-Chung Hsiao,&nbsp;Danqi Chen,&nbsp;Chunyuan Jin* and Kun Lu*,&nbsp;","doi":"10.1021/acs.chemrestox.5c00150","DOIUrl":"10.1021/acs.chemrestox.5c00150","url":null,"abstract":"<p >Formaldehyde (FA) is a pervasive environmental organic pollutant and a Group 1 human carcinogen. While FA has been implicated in various cancers, its genotoxic effects, including DNA damage and DNA–protein cross-linking, have proven insufficient to fully explain its role in carcinogenesis, suggesting the involvement of epigenetic mechanisms. Histone post-translational modifications (PTMs) on H3 and H4, which are critical for regulating gene expression, may contribute to FA-induced pathogenesis, as lysine and arginine residues serve as targets for FA–protein adduct formation. This study aimed to elucidate the epigenetic consequences of FA on histone methylation and acetylation patterns through a comprehensive peptide analysis. Human bronchial epithelial cells (BEAS-2B) were exposed to low-dose (0.1 mM) and high-dose (0.5 mM) FA for 1 h, and their histone extracts were analyzed using high-resolution liquid chromatography–tandem mass spectrometry-based proteomics followed by PTM-combined peptide analysis and single PTM site/type comparisons. We identified 40 peptides on histone H3 and 16 on histone H4 bearing epigenetic marks. Our findings revealed that FA exposure induced systemic alterations in H3 and H4 methylation and acetylation, including hypomethylation of H3K4 and H3K79; changes in H3K9, H3K14, H3K18, H3K23, H3K27, H3K36, H3K37, and H3R40; as well as modifications in H4K5, H4K8, H4K12, and H4K16. These FA-induced histone modifications exhibited strong parallels with epigenetic alterations observed in cancers, leukemia, and Alzheimer’s disease. This study provides novel evidence of FA-induced epigenetic toxicity, offering new insights into the potential mechanisms underlying FA-driven pathogenesis.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 8","pages":"1367–1381"},"PeriodicalIF":3.8,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144751832","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":"Peptide Sequence and Cross-Link Structure Influence Translesion Synthesis Polymerase Bypass of 5-Formylcytosine-Mediated DNA-Peptide Cross-Links.","authors":"Qi Zhang, Iwen Fu, Suse Broyde, Natalia Y Tretyakova","doi":"10.1021/acs.chemrestox.5c00215","DOIUrl":"10.1021/acs.chemrestox.5c00215","url":null,"abstract":"<p><p>DNA-peptide cross-links (DpCs) are generated via the proteolytic cleavage of DNA-protein cross-links (DPCs), ubiquitous DNA lesions that block DNA replication and transcription. Translesion synthesis (TLS) DNA polymerases can facilitate replication bypass of DpC adducts in either an error-free or error-prone manner. We have previously demonstrated that local DNA sequence context significantly influences hPol <i>η</i>-mediated replication bypass of 5-formylcytosine (5fC)-mediated DpC lesions. However, the effects of peptide sequence on the efficiency and fidelity of the TLS bypass of 5fC-mediated DpC lesions remained unknown. In the present study, model DpCs containing three different peptides (NH₂-GGGKGLG<b>K*</b>GGA-COOH, NH₂-RP<b>K*</b>PQQFFGLM-COOH, and NH₂-RPKPQQF<b>K*</b>GLM-COOH, <b>K*</b> = oxy-lysine) were subjected to primer extension experiments in the presence of TLS polymerases. We found that <i>in vitro</i> replication of DpC-containing templates by hPol <i>η</i> was more efficient than that catalyzed by hPol <i>l</i> or hPol κ. HPLC-ESI-MS and HPLC-ESI-MS/MS analyses of hPol <i>η</i> primer extension products indicated that the replication bypass of DpC containing NH₂-RP<b>K</b>*PQQFFGLM-COOH was more error-prone than replication of the other two DpCs, leading to targeted C → T transitions, small deletions, and untargeted mutations downstream from the lesion. Steady-state kinetics investigation of hPol <i>η</i>-catalyzed nucleotide incorporation opposite the DpC lesions containing three different peptides revealed that, in all cases, error-free replication was far more efficient than incorporation of incorrect nucleotides. For mutagenic bypass, the catalytic efficiency of hPol <i>η</i>-mediated dAMP misincorporation opposite DpC with peptide NH₂-RP<b>K*</b>PQQFFGLM-COOH was higher than adenine misincorporation across from the other two DpCs and unmodified dC. These steady-state kinetic findings were further explained by molecular modeling and molecular dynamics simulations, revealing that the three different DpC lesions impose varying perturbations to the geometry of the C-G and C-A pairs at the hPol <i>η</i> active site. Collectively, our results reveal that the peptide sequence and conjugation chemistry of DpC lesions can influence the fidelity of lesion bypass by TLS polymerases.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144725975","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}