Toxicological Sciences最新文献

{"title":"Withdrawn as duplicate: Cobalt Mediates Stage-Specific Toxicity of Metal Mixtures in Cardiovascular-Kidney-Metabolic Syndrome.","authors":"Wei Zhang, GuangYu Jiang, Ziyan Liu, LianRui Duan, JiaYi Liang, Ziyan Wang, Huiwen Kang, Danyang Huang, Ai Gao","doi":"10.1093/toxsci/kfaf172","DOIUrl":"10.1093/toxsci/kfaf172","url":null,"abstract":"","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13293249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145763883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Do metals in tampons pose a health risk? A toxicological risk assessment study.","authors":"Ying Jin, Michael Eppihimer, Md Shah Alam, Anne T Powell, Edward Margerrison, Arghavan Victoria Nawaby","doi":"10.1093/toxsci/kfag065","DOIUrl":"10.1093/toxsci/kfag065","url":null,"abstract":"<p><p>Recently concern has been raised over metal content in tampons and the possibility of toxicological risk to women. As a result, researchers at the United States Food and Drug Administration (FDA) investigated metals present in tampons and estimated the maximum exposure and toxicological risk associated with tampon use. The levels of metals contained in, and released from 11 tampon products, which are legally marketed in the United States, were analyzed by inductively coupled plasma mass spectrometry (ICP-MS). Levels of metals released were determined under exaggerated test conditions (50°C for 24 h in acidified water) considering the recommended use of tampons. The potential for metals to be released from the tampons was used to conduct a toxicological risk assessment (TRA) based on ISO 10993 and FDA guidance. In this investigation, 19 metals were detected including ICH Class I metals-arsenic (As), cadmium (Cd), and lead (Pb) were found at trace levels. Based on the in-depth TRA, all detected metals had margins of safety (MoS) indicating that there is negligible toxicological concern from the presence of metals in tampon materials. This study expands on prior investigations of metal content in tampons.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148138996","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":"MEHP exposure damages the basement membrane by suppressing the expression of its constituent proteins in peritubular myoid cells of the rat testis.","authors":"Narayan Acharya, John H Richburg","doi":"10.1093/toxsci/kfag070","DOIUrl":"10.1093/toxsci/kfag070","url":null,"abstract":"<p><p>The basement membrane (BM) is a crucial support structure of the seminiferous epithelium, mainly made up of collagens, fibronectin, laminins, and proteoglycans. Along with the collagen fiber network, the peritubular myoid cell (PTMC) forms the tunica propria, which acts as a protective barrier for the blood-testis barrier (BTB). Here, we examined how PTMCs respond to mono-2-ethylhexyl phthalate (MEHP) exposure by altering the transcriptomic and proteomic profiles of extracellular matrix proteins, which are essential structural components of the BM. Bulk RNA was used for transcriptomics, and protein lysates were prepared for proteomics from primary PTMC isolates. Interstitial fluid (IF) was utilized to assess the baseline microenvironment of the testis, and the in vivo relevance of the protein changes was confirmed through immunofluorescence of testis cross-sections. Gene Set Enrichment Analysis (GSEA) revealed a suppression of genes in the basement membrane-linked pathway after MEHP exposure. These findings are further supported by proteomics analysis of PTMC lysates. Notably, downregulation of key basement membrane components-such as collagen IV, fibronectin, laminin, and others-was observed alongside the classical complement activation pathway in the testis microenvironment, specifically in the interstitial fluid. The data indicate that MEHP exposure downregulated the expression of BM component proteins in PTMC, underscoring the interconnections among BM degradation, BTB disruption, spermatogenesis, and disorganization of seminiferous tubule architecture during MEHP-induced testicular injury.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13309254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148278994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"UVB light activates an S phase-dependent DNA damage response in human keratinocytes independent of oxidative stress.","authors":"Yunqi An, Yi-Hua Jan, Jeffrey D Laskin","doi":"10.1093/toxsci/kfag069","DOIUrl":"10.1093/toxsci/kfag069","url":null,"abstract":"<p><p>Ultraviolet B (UVB; 280 to 320 nm) radiation damages DNA in epidermal cells and contributes to the development of skin cancer. In response, keratinocytes activate a DNA damage response (DDR) that regulates DNA repair through signaling pathways involving the protein kinases ATR (ataxia telangiectasia and Rad3-related), ATM (ataxia telangiectasia mutated), and DNA-PKcs (DNA-dependent protein kinase catalytic subunit). Activation of these kinases promotes recruitment of DNA repair proteins, including phosphorylated H2AX and p53, to sites of DNA damage. Treatment of primary human neonatal foreskin epidermal keratinocytes and HaCaT keratinocytes with UVB (2.5 to 50 mJ/cm2) resulted in dose- and time-dependent activation of DDR proteins. In HaCaT cells, DDR signaling was most pronounced in S phase compared with cells in G0/G1 or G2/M, as determined by flow cytometry and cell cycle synchronization. Confocal microscopy revealed the accumulation of phosphorylated DNA-PKcs and phosphorylated H2AX in discrete subnuclear foci in S-phase cells, consistent with recruitment to sites of DNA double-strand breaks. UVB also induced oxidative stress in HaCaT cells, as reflected by increased intracellular reactive oxygen species (ROS). Depletion of intracellular glutathione using buthionine sulfoximine significantly enhanced UVB-induced ROS production but had little or no effect on activation of DDR signaling. These findings demonstrate that UVB induces cell cycle-dependent DNA damage in human keratinocytes that is independent of oxidative stress. Understanding mechanisms of UVB activation of the DDR in keratinocytes will be important for elucidating molecular pathways contributing to skin carcinogenesis.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148219817","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":"Iodoacetic acid causes developmental toxicity in zebrafish.","authors":"Samuel Hatlestad, Brooke E Wagoner, Hyunho Kim, Jason S Xia, Chris Shim, Yuexi Wang, Alice Lua, Jing Yang, Jodi A Flaws, Wenyan Mei","doi":"10.1093/toxsci/kfag062","DOIUrl":"10.1093/toxsci/kfag062","url":null,"abstract":"<p><p>Water disinfection can generate disinfection byproducts (DBPs) such as iodoacetic acid (IAA) by reacting with organic matter in water supplies. In vitro studies have shown that IAA is a cytotoxic and genotoxic DBP. In vivo studies using animal models further indicate that IAA has toxic effects on reproductive function and the endocrine system. Yet, its developmental toxicity remains unknown. In this study, we show that exposure to IAA at concentrations ranging from 1 to 100 µM induces dose-dependent embryonic mortality, with the greatest sensitivity observed during the first 24 hours of development. Sublethal concentrations cause delayed or failed hatching and disrupt the development of multiple vital organs. Notably, IAA exposure impairs swim bladder inflation, reduces otolith size, and decreases heart rate. Moreover, IAA reduces intestinal mucus production by suppressing genes essential for mucin production. Given the crucial role of intestinal mucus in defending against pathogens and maintaining host and gut microbiota homeostasis, the deleterious effect of IAA on mucus production highlights its potential pathogenic role in driving disorders linked to epithelial barrier dysfunction and microbiome dysfunction. Together, these findings demonstrate that IAA induces pronounced developmental toxicity affecting multiple organ systems in zebrafish. This study provides the first in vivo evidence that IAA disrupts embryonic development and intestinal function.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148057037","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":"Artificial intelligence-augmented mixture toxicology: reframing unresolved risk at Camp Lejeune.","authors":"Peter Pressman, A Wallace Hayes","doi":"10.1093/toxsci/kfag066","DOIUrl":"10.1093/toxsci/kfag066","url":null,"abstract":"<p><p>Persistent uncertainty regarding health risks associated with contaminated drinking water at Camp Lejeune reflects a broader limitation in toxicology: the difficulty of evaluating complex chemical mixtures in genetically heterogeneous populations. Historical assessments have relied on single-chemical paradigms, assumptions of dose additivity, and population-average susceptibility. These approaches are not well aligned with exposures involving multiple volatile organic compounds (VOCs) that share metabolic pathways and generate reactive intermediates. This Forum article advances the position that artificial intelligence (AI)-enabled computational toxicology can strengthen mixture risk assessment by integrating toxicokinetic, toxicodynamic, and toxicogenomic data into mechanistically coherent, testable models. Using the Camp Lejeune VOC mixture-trichloroethylene, tetrachloroethylene, benzene, and vinyl chloride-as a case study, we illustrate how AI-augmented approaches can identify plausible interaction mechanisms, quantify genotype-dependent variability in internal dose, and generate probabilistic estimates of risk. We argue that the principal unresolved issue at Camp Lejeune is whether chronic low-level exposure to interacting mixtures disproportionately affected susceptible subpopulations. AI-driven approaches provide a tractable framework to address this question and to clarify the interface between mechanistic toxicology and public health decision-making.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148144765","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":"Technical and biological factors driving inter-individual body burden of arsenic species in murine models of human arsenic exposure.","authors":"Lu Wang, Qian Wang, Trenton M Wolfe, Nicholas V Pinkham, Reece Erickson, Masafumi Yoshinaga, Timothy R McDermott, Seth T Walk","doi":"10.1093/toxsci/kfag055","DOIUrl":"10.1093/toxsci/kfag055","url":null,"abstract":"<p><p>Arsenic is one of the most important environmental toxicants, requiring advanced analytical techniques to resolve individual species. There is little consensus on arsenic speciation methodology for in vivo studies. The objectives of this study were to generate a robust framework for arsenic speciation in murine models of human exposure and evaluate factors influencing the levels of arsenobetaine, inorganic arsenite, dimethylarsinate, monomethylarsonate, and inorganic arsenate resolved by high-performance liquid chromatography (HPLC)-inductively coupled plasma mass spectrometry (ICPMS). Enzyme-assisted digestion by papain vs. pepsin and maceration by bead beating vs. mechanical homogenization were evaluated using chemical standard spiking experiments. Dose-controlled mouse exposures to inorganic arsenite were conducted, and species detected in urine and bladder tissue were compared. Species in stool, liver, and bladder were compared between groups of mice eating a standard vs. purified diet, fasted vs. unfasted mice, and conventional vs. germ-free mice. Finally, between-lab differences in HPLC-ICPMS instrumentation/quantification procedures were evaluated. These comparisons led to several important conclusions, including: Significant conversion of inorganic arsenate to arsenite by papain, significant inorganic arsenate background in bead-beating lysing matrix, significant arsenobetaine in mice eating standard but not purified chow, significant correlation between species detected in urine and bladder, significant correlation of results between laboratories that differed in absolute quantification, and large inter-individual variability between mice of the same treatment group. Finally, diet type and the presence of a microbiome had the largest effect on arsenic species levels. Our results provide a benchmark for evaluating arsenic species in murine models, including adequate sample sizes for powering studies to avoid erroneous conclusions.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13265383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147975784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Contemporary Review: Temporal Dynamics of Neuroinflammation in Response to Environmental Exposure.","authors":"Brenna Baird, Shahani Noor, Shuguang Leng, Andrew K Ottens, Matthew J Campen","doi":"10.1093/toxsci/kfag051","DOIUrl":"10.1093/toxsci/kfag051","url":null,"abstract":"<p><p>Neuroinflammation is the brain's immune response to injury or disease and can negatively impact neurological functions, ranging from mood, cognition, learning, and memory, as well as promote neurodegenerative disease and even psychiatric conditions. Different environmental factors may trigger a neuroinflammatory response; the mechanisms of this activation may influence the pattern of activation, the immune subsets involved, and the persistence of the response. The duration of neuroinflammation may significantly outlast exposures, creating a potential unique vulnerability for rare or intermittent exposures. The neuroinflammatory response can be classified into acute, subacute, and chronic phases, with subacute neuroinflammation representing a transient state between acute and chronic inflammation. This phase, lasting from days to weeks, is denoted by metabolic disruptions, cognitive impairments, and peripheral immune activation. Environmental exposures, such as air pollution, pesticides, and heavy metals, and social factors impact oxidative stress, glial activation, and blood-brain barrier disruption, leading to neuronal injury and cognitive decline. Notably, exposures like diesel fumes and wildfire smoke have been shown to induce neuroinflammation, subsequently impacting memory and learning, and exacerbating mental health conditions such as post-traumatic stress disorder, depression, and anxiety. Triggering of reactive astrogliosis via impacts on the blood-brain barrier function may be the most common non-specific manner that environmental toxicants drive neuroinflammation, but direct outcomes from compounds that readily access the brain are also possible.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13265380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zearalenone exposure and the mammalian gut microbiome: a systematic review of the literature.","authors":"Alyssa Juenke, Candace R Longoria, Anjali Patel, Anushka Subrahmanian, Martin J Blaser, Zorimar Rivera-Núñez, Emily S Barrett","doi":"10.1093/toxsci/kfag064","DOIUrl":"10.1093/toxsci/kfag064","url":null,"abstract":"<p><p>Mycotoxins are fungal-derived metabolites found in the global food supply, particularly in cereal grains and processed foods. Zearalenone (ZEN), one of the more common mycotoxins, widely contaminates human food supplies at concentrations above established maximum contamination levels. However, the effects of ZEN exposure on human health have only begun to be explored, with most studies on this topic focusing on its endocrine-disrupting effects in the reproductive system. ZEN is readily absorbed following oral administration, making the gastrointestinal (GI) tract and its microbiota primary targets for toxicity. The gut microbiome plays a critical role in nutrient processing and immune function and can be heavily influenced by dietary and chemical exposures. Given widespread human dietary exposure to ZEN, we conducted a comprehensive literature review of ZEN and its metabolites in relation to the mammalian gut microbiome. We identified 19 studies, all conducted in animal models, and each reported alterations in gut microbiome composition in ZEN-treated groups compared with control animals. Several papers reported modified metabolism in ZEN-treated groups, particularly related to short-chain fatty acids. In light of this small but compelling literature and the expected increase in mycotoxin contamination due to the industrialization of the food supply and warmer weather conditions, we identified several priority areas for future study. These include better understanding the mechanisms by which ZEN and its metabolites affect the microbiome and ultimate translation to human health.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148057056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Airborne contaminant exposure and bone development: a systematic review and meta-analysis.","authors":"Madeline K M Vera-Colón, Ruth M Meletz, Celina N Phillipson, Nicole R L Sparks","doi":"10.1093/toxsci/kfag067","DOIUrl":"10.1093/toxsci/kfag067","url":null,"abstract":"<p><p>Air pollution, including particulate matter (PM10, PM2.5) and airborne metals (Cd, Hg, As, Pb) are a systemic health hazard, but osteotoxic effects remain underrecognized. We systematically synthesized human, animal, and in vitro evidence on airborne contaminants and outcomes to skeletal health. Following Office of Health Assessment and Translation (OHAT) guidance, we searched PubMed and Google Scholar (2014-2024; final search November 24, 2024) for English-language studies relating PM or airborne metals to skeletal outcomes, excluding studies limited to adult occupational exposures, age-related bone disease, or non-peer-reviewed reports. Studies were screened and data extracted in Covidence. Risk of bias was assessed using tools from the Quality Assessment and Risk of Bias Tool Repository, and certainty of evidence was graded with GRADE. We used a random-effects meta-analyses model to estimate relative risks (RRs) interpreted as directional consistency hazards for bone loss, impaired osteoblast differentiation, enhanced osteoclast activity, bone marrow adiposity, epigenetic changes, and altered bone microarchitecture. Fifty-three studies met the inclusion criteria. Across outcomes, meta-analyses showed higher hazard risk in exposed versus control groups, with RRs ranging from 7 to 10; for example, bone loss (RR 7.12, 95% CI 4.20-12.06) and altered bone microarchitecture (RR 10.28, 95% CI 4.67-22.61). Epidemiologic and experimental evidence may implicate oxidative stress, inflammation, and epigenetic dysregulation as key mechanisms. Overall certainty was low to moderate due to residual confounding, exposure misclassification, and heterogeneity. Growing evidence indicates that airborne PM and metals adversely affect bone health, particularly during critical developmental windows, underscoring the need to integrate skeletal endpoints into health assessment and policy.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13283646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148151402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}