Toxicology最新文献

{"title":"New insights into heavy metal cadmium-induced liver injury: Prominent role of programmed cell death mechanisms","authors":"Ruipeng Wang ,&nbsp;Jun Yan ,&nbsp;Honglong Zhang ,&nbsp;Xingwang Zhu ,&nbsp;Danna Xie ,&nbsp;Tingting Wang ,&nbsp;Xun Li","doi":"10.1016/j.tox.2025.154169","DOIUrl":"10.1016/j.tox.2025.154169","url":null,"abstract":"<div><div>The heavy metal cadmium (Cd) is an important environmental factor that induces liver injury and contributes to liver disease. Ongoing research aims to refine our understanding of the pathogenesis of cadmium-induced liver injury and the interactions between the various mechanisms. Oxidative stress, described as a pathophysiological basis of liver injury, is a process in which reactive oxygen species are generated, causing the destruction of hepatocyte structure and cellular dysfunction. Additionally, the activation of oxidative stress downstream signals regulates several forms of cell death, such as apoptosis, necroptosis, autophagy, ferroptosis, and pyroptosis, which significantly contributes to liver damage. Furthermore, the interplay between different types of programmed cell death highlights the complexity of liver injury mechanisms. This review summarizes the role of programmed cell death in Cd-induced liver injury and explores the relationships between different programmed cell death pathways, which is expected to provide new insights into the mechanisms of Cd-induced liver injury.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"517 ","pages":"Article 154169"},"PeriodicalIF":4.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033243","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":"Per- and polyfluoroalkyl substances as potentiators of hepatotoxicity in an exposome framework: Current challenges of environmental toxicology","authors":"Minna A Choi,&nbsp;Sophie Rose,&nbsp;Sophie Langouët","doi":"10.1016/j.tox.2025.154167","DOIUrl":"10.1016/j.tox.2025.154167","url":null,"abstract":"<div><div>Chronic liver diseases, including metabolic dysfunction-associated steatosic liver disease (MASLD) and hepatocellular carcinoma (HCC), are on the rise, potentially due to daily exposure to complex mixtures of chemical compounds forming part of the exposome. Understanding the mechanisms involved in hepatotoxicity of these mixtures is essential to identify common molecular targets that may highlight potential interactions at the molecular level. We illustrated this issue with two families of environmental contaminants, per- and polyfluoroalkyl substances (PFAS) and heterocyclic aromatic amines (HAAs), both of which could be involved in the progression of chronic liver diseases, and whose toxicity may be potentiated by interactions at the level of xenobiotic metabolism. In the study of exposome effects on chronic liver disease, New Approach Methodologies (NAMs) including omics analyses and data from various <em>in vitro</em>, <em>in vivo</em> and <em>in silico</em> approaches, are crucial for improving predictivity of toxicological studies in humans while reducing animal experimentation. Additionally, the development of complex <em>in vitro</em> human liver cell models, such as organoids, is essential to avoid interspecies differences that minimize the risk for humans. All together, these approaches will contribute to construct Adverse Outcome Pathways (AOPs) and could be applied not only to PFAS mixtures but also to other chemical families, providing valuable insights into mixture hepatotoxicity prediction in the study of the exposome. A better understanding of toxicological mechanisms will clarify the role of environmental contaminant mixtures in the development of MASLD and HCC, supporting risk assessment for better treatment, monitoring and prevention strategies.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154167"},"PeriodicalIF":4.8,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143903888","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 vitro to in vivo extrapolation modeling to facilitate the integration of transcriptomics data into genotoxicity assessment","authors":"Anouck Thienpont ,&nbsp;Eunnara Cho ,&nbsp;Andrew Williams ,&nbsp;Matthew J. Meier ,&nbsp;Carole L. Yauk ,&nbsp;Marc A. Beal ,&nbsp;Freddy Van Goethem ,&nbsp;Vera Rogiers ,&nbsp;Tamara Vanhaecke ,&nbsp;Birgit Mertens","doi":"10.1016/j.tox.2025.154165","DOIUrl":"10.1016/j.tox.2025.154165","url":null,"abstract":"<div><div><em>In vitro</em> transcriptomics holds promise for high-throughput, human-relevant data but is not yet integrated into regulatory decision-making due to the lack of standardized approaches. For genotoxicity assessment, transcriptomic biomarkers such as GENOMARK and TGx-DDI facilitate qualitative and quantitative analysis of complex <em>in vitro</em> transcriptomic datasets. However, advancing their use in quantitative testing requires standardized methods for deriving transcriptomic Points of Departure (tPoDs) and linking them to <em>in vivo</em> responses. Herein, we investigated different approaches to calculate tPoDs and applied <em>in vitro</em> to <em>in vivo</em> extrapolation to obtain administered equivalent doses (AEDs). Human HepaRG cells were exposed for 72 h to 10 known <em>in vivo</em> genotoxicants (glycidol, methyl methanesulfonate, nitrosodimethylamine, 4-nitroquinoline-N-oxide, aflatoxin B1, colchicine, cyclophosphamide, mitomycin C, ethyl methanesulfonate, and N-Nitroso-N-ethylurea) from the highest concentration that induces up to 50 % cytotoxicity through a range of lower concentrations. Gene expression data was generated using a customized version of the TempO-Seq® human S1500 + gene panel. The GENOMARK and TGx-DDI biomarkers produced genotoxic calls for all of these reference genotoxicants. Next, we performed benchmark concentration (BMC) modeling to generate both genotoxicity-specific biomarker (tPoD_biomarkers) and generic tPoDs (tPoD _S1500+). High-throughput toxicokinetic models estimated the human AEDs for these tPoDs, which were compared with (a) previously reported genotoxicity-specific AEDs from other New Approach Methodologies, and (b) <em>in vivo</em> PoDs from animal studies. We found that the generic AEDs were more conservative than genotoxicity-specific biomarker AEDs. For six of the nine genotoxicants, transcriptomic AEDs were lower than the <em>in vivo</em> PoDs; refined kinetic models may improve predictions. Overall, <em>in vitro</em> transcriptomic data in HepaRG cells provide protective estimates of <em>in vivo</em> genotoxic concentrations, consistent with other <em>in vitro</em> genotoxicity testing systems.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154165"},"PeriodicalIF":4.8,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143887291","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":"Cadmium induces the secretion of SASP factors regulated by MAPK and NF-κB signaling pathways in HEK293 cells: A possible mechanism of acute kidney damage induced by cadmium","authors":"Ziqi Ren ,&nbsp;Yuanchen Zheng ,&nbsp;Jianli Liu ,&nbsp;Zhicun Liu ,&nbsp;Jiahe Chen ,&nbsp;Haotian Liu ,&nbsp;Ruiquan Qi ,&nbsp;Huiping Ma","doi":"10.1016/j.tox.2025.154166","DOIUrl":"10.1016/j.tox.2025.154166","url":null,"abstract":"<div><div>Cadmium (Cd) is a highly toxic environmental pollutant, which can accumulate in the kidney, induce cell damage and trigger inflammatory responses. However, the specific regulation mechanism of nephrotoxicity induced by Cd remains unclear. This study was conducted to investigate the toxic effects of Cd on human embryonic kidney 293 (HEK293) cells and explore its potential mechanisms. Cell viability was assessed with MTT assay. Reactive oxygen species (ROS) levels and mitochondrial membrane potential (MMP) were evaluated through DCFH-DA staining and Rhodamine staining. Apoptosis was detected with Hoechst 33258 staining. The expression of the DNA damage biomarker 8-hydroxy-2’-deoxyguanosine (8-OHdG) was detected with the 8-OHdG ELISA kit. Senescence-associated secretory phenotype (SASP) factors and signaling pathways were analyzed by Western blot. The results showed that Cd exposure could induce oxidative stress and cellular inflammation. It could also impair MMP, contribute to cell apoptosis and activate MAPK and NF-κB signaling pathways. Finally, exposure to Cd triggered DNA damage and SASP production. However, NF-κB inhibitor BAY11–7082 and antioxidant NAC could inhibit these effects by suppressing NF-κB and MAPK signaling pathways. The present study revealed the specific mechanisms of Cd toxicity in HEK293 cells and provided useful information for elucidating the nephrotoxicity of Cd.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154166"},"PeriodicalIF":4.8,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143881877","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":"Emerging roles of histone modifications in environmental toxicants-induced neurotoxicity","authors":"Ishita Mehta ,&nbsp;Manika Verma ,&nbsp;Mohammed Nazish Quasmi,&nbsp;Dinesh Kumar,&nbsp;Ashok Jangra","doi":"10.1016/j.tox.2025.154164","DOIUrl":"10.1016/j.tox.2025.154164","url":null,"abstract":"<div><div>Epigenetics describes itself as heritable modifications in gene function that eventually alter gene and protein expression levels without any alterations in the genome sequence. Epigenetic alterations are closely association with several neurological diseases and neurodevelopmental disorders. In recent years, growing shreds of evidences suggested the crucial role of epigenetic modifications especially histone modifications in environmental toxicants-induced neurotoxicity. This review will give an overview of the state of knowledge on histone alterations and the ways in which environmental pollutants bisphenol-A, heavy metals, pesticides, and phthalates affects post-translational modifications to alter gene transcription and cause neurological abnormalities. We provide a brief summary of the results of recent research on the effects of environmental toxins on each of the prior identified processes of histone modifications, including the neurological consequences and changes in histones. There is also discussion of the limitations of current research findings. Furthermore, this review aims to provide viewers a comprehensive knowledge regarding the role of histone modifications in various environmental toxicants-induced neurological diseases and offers insights for future research.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154164"},"PeriodicalIF":4.8,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143874555","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":"Lead systemic toxicity: A persistent problem for health","authors":"Adriana Gonzalez-Villalva ,&nbsp;Rojas-Lemus Marcela ,&nbsp;López-Valdez Nelly ,&nbsp;Bizarro-Nevares Patricia ,&nbsp;Morales-Ricardes Guadalupe ,&nbsp;Casarrubias-Tabarez Brenda ,&nbsp;Cervantes-Valencia Maria Eugenia ,&nbsp;Ustarroz-Cano Martha ,&nbsp;García-Peláez Isabel ,&nbsp;T.I. Fortoul","doi":"10.1016/j.tox.2025.154163","DOIUrl":"10.1016/j.tox.2025.154163","url":null,"abstract":"<div><div>Lead (Pb) has been used by humans since prehistoric times to make tools due to its malleability and durability. The Roman Empire, the Industrial Revolution, and the introduction of Pb in gasoline during the 1920s contributed to increased environmental concentrations. Pb toxicity led to its removal from gasoline after several decades. However, Pb continues to be emitted from various anthropogenic sources, including but not limited to batteries, mining, foundries, smelting, e-waste recycling, and painting. Pb remains an environmental concern, as no established safe concentration for human health has been identified. Children are more susceptible to the absorption and poisoning of Pb. Occupational exposure to Pb poses a significant risk to workers and individuals living near lead industries. The primary routes of exposure are inhalation and ingestion, and bioaccumulation and biomagnification through the food chain are major sources of human exposure. This review aims to provide an overview of Pb and its systemic toxicity of Pb, including its effects on the lungs, blood, liver, kidneys, and nervous, cardiovascular, and reproductive systems. Since Pb is classified as a probable carcinogen for humans, the article also addresses genotoxicity and cancer risk. Furthermore, it reviews the most researched mechanisms of toxicity, including calcium mimicry, oxidative stress, and inflammation, along with other less-studied mechanisms. Nevertheless, the authors emphasize the importance of exploring less examined cells, tissues, and mechanisms to deepen the understanding of Pb toxicity at various concentrations, particularly in cases of chronic low-level Pb exposure, to develop better prevention and treatment strategies for lead poisoning.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154163"},"PeriodicalIF":4.8,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143887292","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":"Increased TSLP and oxidative stress reflect airway epithelium injury upon cigarette smoke exposure. Is there a role for carbocysteine?","authors":"Paola Pinto ,&nbsp;Daniele Donzì ,&nbsp;Serena Di Vincenzo ,&nbsp;Maria Ferraro ,&nbsp;Valentina Lazzara ,&nbsp;Maria Giuseppina Bruno ,&nbsp;Nadia Moukri ,&nbsp;Bernardo Patella ,&nbsp;Rosalinda Inguanta ,&nbsp;Elisabetta Pace","doi":"10.1016/j.tox.2025.154160","DOIUrl":"10.1016/j.tox.2025.154160","url":null,"abstract":"<div><div>Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory degenerative disease. Disease exacerbations accelerate lung function deterioration. Airway epithelium has a central role in COPD pathophysiology. Airway epithelium releases alarmins including the thymic stromal lymphopoietin (TSLP) in response to exogenous stressors. Notch-1 in the nucleus acts as inhibitor of TSLP gene expression. Here, we investigated, in human bronchial epithelial cells, the effects of cigarette smoke extract (CSE) in TSLP production exploring the relationship with oxidative stress events and with Notch-1 signaling. In CSE exposed 16HBE, the effects of carbocysteine were assessed on: intracellular and extracellular oxidative stress; nuclear Notch-1 expression; TSLP gene expression. The TSLP levels in sera from non-smokers, smokers and exacerbated COPD patients (before and after therapy with carbocysteine) were also explored. CSE induced TSLP gene expression and oxidative stress and reduced nuclear expression of Notch-1 in 16HBE. The use of an electrochemical sensor allowed a reliable tool to assess oxidative stress. TSLP concentrations were higher in sera from smokers and exacerbated COPD than in sera from non-smokers. Carbocysteine was able to counteract the effects of CSE in oxidative stress and in TSLP gene expression in 16HBE and to reduce TSLP in exacerbated COPD. In conclusion, increased oxidative stress induced by smoke exposure in airway epithelium leads to increased TSLP production and carbocysteine <em>in vitro</em> and <em>in vivo</em> mitigates the induced TSLP production. Oxidative stress detection by electrochemical sensors can open new avenues for evaluating epithelial damage and for identifying patients eligible to alarmin targeted biologics.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154160"},"PeriodicalIF":4.8,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143870285","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":"An adverse outcome pathway for DNA adduct formation leading to kidney failure","authors":"D.A. Barnes ,&nbsp;M.J. Janssen ,&nbsp;Huan Yang ,&nbsp;F.A. Redegeld ,&nbsp;R. Masereeuw","doi":"10.1016/j.tox.2025.154162","DOIUrl":"10.1016/j.tox.2025.154162","url":null,"abstract":"<div><div>An Adverse Outcome Pathway (AOP) is a conceptual framework in toxicology and risk assessment that outlines the series of events from a chemical's molecular interaction to the resulting adverse health effect. This framework offers a structured approach to organizing biological knowledge, making it especially useful for understanding the mechanisms through which chemicals cause harm. Following a comprehensive analysis of the literature, an AOP was elucidated for key events linking DNA adduct formation, caused by compounds such as platinum anticancer drugs, to tubular necrosis, resulting in kidney failure. Currently, cisplatin, carboplatin and oxaliplatin are the three most utilised Pt-based drugs used globally for the treatment of cancer. The hydrolysis of platinum anticancer agents post-cellular uptake yields electrophilic intermediates that covalently bind to nucleophilic sites on DNA to form adducts that represent the molecular initiating event. When DNA repair mechanisms become unbalanced, the nephrotoxic response following the formation of DNA adducts leads to DNA damage and mitochondrial dysfunction. These events promote the generation and release of reaction oxygen species (ROS) to induce oxidative stress, causing cell death and inflammation. Upon detachment from the basement membrane, these compromised cells are subsequently deposited in the tubular lumen. Tubular obstruction and inflammatory responses to proximal tubule insult can lead to secondary toxicity and tubular necrosis, further exacerbating kidney injury and precipitating a progressive decline of renal function, finally resulting in kidney failure.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154162"},"PeriodicalIF":4.8,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143870283","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":"Embryonic exposure to GenX causes reproductive toxicity by disrupting the formation of the blood-testis barrier in mouse offspring","authors":"Zhencheng Fan ,&nbsp;Runyang Hong ,&nbsp;Shuhao Li ,&nbsp;Liang Kong ,&nbsp;Qiyue Zhou ,&nbsp;Tan Ma ,&nbsp;Hao Chen ,&nbsp;Chun Pan","doi":"10.1016/j.tox.2025.154161","DOIUrl":"10.1016/j.tox.2025.154161","url":null,"abstract":"<div><div>As a replacement for perfluorooctanoic acid, hexafluoropropylene oxide dimer acid, commercially referred to as “GenX”, has attracted significant attention. However, a comprehensive understanding of the reproductive systems of male offspring exposed to GenX is lacking. This study aimed to investigate how embryonic exposure to GenX affects the reproductive development of male offspring and the underlying mechanisms. We administered GenX daily via gavage (2 mg/kg body weight/day) to the mice from day 12.5 of pregnancy until delivery. Our results suggested that embryonic exposure to GenX led to delayed onset of puberty in male offspring, with destruction of the testicular structure, disruption of the blood-testis barrier, decreased serum testosterone levels, decreased sperm count, impaired sperm motility, and increased rates of sperm abnormalities. We investigated the mechanism of blood-testis barrier breakdown <em>in vitro</em> by treating Sertoli cells (TM4) with GenX. GenX exposure caused the accumulation of senescent TM4 cells, decreased their glutathione (GSH) levels, and increased their oxidized glutathione levels. GenX inhibited glutaminase activity in TM4 cells, leading to decreased GSH synthesis, increased intracellular oxidative stress, and subsequent TM4 cell senescence, ultimately compromising the blood-testis barrier. Our findings indicated that embryonic exposure to GenX may cause Sertoli cell senescence by altering glutamine metabolism, disrupting the blood-testis barrier, and resulting in abnormal reproductive development in male offspring.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154161"},"PeriodicalIF":4.8,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143864734","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":"Mitigation of PFAS toxicity through sorbent treatment in Sprague-Dawley rats during prenatal and postnatal exposure","authors":"Meichen Wang ,&nbsp;Johnson O. Oladele ,&nbsp;Kelly J. Rivenbark ,&nbsp;Timothy D. Phillips","doi":"10.1016/j.tox.2025.154156","DOIUrl":"10.1016/j.tox.2025.154156","url":null,"abstract":"<div><div>PFAS (per- and polyfluoroalkyl substances) are prevalent and persistent environmental pollutants with significant toxicity, especially during critical windows of exposure such as pregnancy and lactation. This study investigated the prenatal and postnatal effects of PFAS exposure on the serum and liver of Sprague-Dawley rats, and the mitigating efficacy of orally administered sorbents. Animal groups included vehicle control, PFAS (0.95 mg/kg-bw/day), and PFAS co-treated with calcium montmorillonite (CM), CM-carnitine, CM-choline, activated carbon (AC), or acid processed montmorillonite (APM). Oral administration of PFAS resulted in accumulation in serum and liver by postnatal day (PND) 21, especially for PFOS. PFAS exposure also reduced body weight gain by 24 % in females and 35 % in males via reduced food and water conversion rates, impaired liver histopathological structure, caused hepatocellular hypertrophy, disrupted serum biochemistry, and reduced vitamins A and B2 in both sexes. Additionally, PFAS exposure increased oxidative stress and liver damage as evidenced by reduced antioxidants (GSH, SOD, GST), induced ALT, AST and pro-inflammatory cytokines (TGF-β and TNF-α), and suppressed CRP. Importantly, CM-carnitine and CM-choline were the most effective mitigating sorbents, significantly reducing PFAS bioavailability in the liver and serum and restoring biochemical parameters such as cholesterol, total protein, and glucose in serum. All sorbent treatments alleviated oxidative stress, normalized inflammatory markers, and improved nutrient levels in both serum and liver. Furthermore, the study revealed sex-specific responses, with females showing greater susceptibility to PFAS-induced metabolic changes and a more prominent response to sorbent mitigation. This study highlights the toxic effect of PFAS exposure in serum and liver during vulnerable windows of exposure such as pregnancy and lactation, and establishes the proof of concept for the oral administration of sorbents, particularly CM-carnitine, CM-choline, and a mixture of sorbents, as preventive mitigation strategies.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154156"},"PeriodicalIF":4.8,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143887183","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}