Current Research in Toxicology最新文献

{"title":"AOP Report: Decreased ALDH1A (RALDH) activity leading to decreased fertility via disrupted meiotic initiation of fetal oogonia","authors":"Monica K. Draskau ,&nbsp;Cassy M. Spiller ,&nbsp;Eleftheria M. Panagiotou ,&nbsp;Johanna Zilliacus ,&nbsp;Anna Beronius ,&nbsp;Pauliina Damdimopoulou ,&nbsp;Josephine Bowles ,&nbsp;Terje Svingen","doi":"10.1016/j.crtox.2025.100257","DOIUrl":"10.1016/j.crtox.2025.100257","url":null,"abstract":"<div><div>This report describes a novel adverse outcome pathway (AOP) highlighting how the inhibition of aldehyde dehydrogenase 1A<!--> <!-->(ALDH1A) enzymatic activity can lead to female infertility in mammals through disrupted meiotic entry of fetal germ cells (AOP-Wiki 398). In mammals, all-trans retinoic acid (atRA) can induce germ cell meiosis; during fetal life in females, germ cells enter meiosis prophase I. Reduced levels or absence of atRA disrupts this process, impairing germ cell development and leading to a reduced ovarian reserve in postnatal ovaries. The synthesis of atRA from vitamin A precursors involves an intermediate catalytic conversion of retinal by ALDH1A. Evidence for this AOP, particularly the upstream events, is primarily derived from mouse studies (both genetic models and exposure studies, including explanted ovaries). Human evidence, especially for downstream events, corroborates that the ovarian reserve directly impacts fertility. In reproductive toxicity studies (both animal studies and human epidemiology), fertility is a critical endpoint for chemical safety assessments. Although infertility has multiple causes, this AOP specifically captures events of perturbed meiosis due to reduced atRA signaling during development, thus supporting the use of <em>in silico</em> and <em>in vitro</em> data on nuclear receptor activity of the retinoic acid and retinoid X receptors (RAR/RXR) and atRA synthesis/expression to predict potential <em>in vivo</em> effects.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"9 ","pages":"Article 100257"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145262703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pulmonary inflammation and immune responses induced by nanocellulose: Insights from in vivo and in vitro models","authors":"Katsuhide Fujita,&nbsp;Sawae Obara,&nbsp;Junko Maru,&nbsp;Yuka Kawai,&nbsp;Shigehisa Endoh,&nbsp;Akihiro Moriyama","doi":"10.1016/j.crtox.2025.100259","DOIUrl":"10.1016/j.crtox.2025.100259","url":null,"abstract":"<div><div>The increasing use of nanocellulose (NC), including cellulose nanofibrils (CNFs) and cellulose nanocrystals (CNCs), in industrial, biomedical, and consumer products has raised concerns regarding potential inhalation exposure, as these materials contain components within the respirable particle size range (&lt;10 µm). Despite expanding applications, data on NC-induced pulmonary and systemic immune effects remain limited. This study investigated the pulmonary and immunotoxic effects of CNF1 (TEMPO-oxidized), CNF2 (mechanically fibrillated), and CNC1 in rats following intratracheal instillation, using multi-walled carbon nanotubes (MWCNTs) as a benchmark. All materials were administered at 2.0 mg/kg body weight, with fiber diameters of 14.1–28.2 nm and lengths of 0.7–2.2 µm. At 28 d post-instillation, all NC were phagocytosed by alveolar macrophages. Bronchoalveolar lavage fluid (BALF) and histopathological analyses revealed that CNF2 induced limited inflammation with granuloma formation and minimal BALF changes, whereas CNF1 and CNC1 triggered similar changes in BALF inflammatory markers. Although CNC1 elicited the most notable histopathological changes among NCs, all NC-induced responses were less severe than those caused by MWCNTs. No significant alterations were observed in lymphocyte subsets in the spleen or thymus, indicating minimal systemic immunotoxicity. <em>In vitro</em> assays using NR8383 alveolar macrophages were performed to compare CNC1, sulfuric acid-hydrolyzed CNC2, and desulfurized CNC3. All CNCs were internalized and stimulated pro-inflammatory cytokine production, with responses influenced by surface chemistry despite similar size and morphology. CNC1 and CNC2 exhibited low cytotoxicity following 48h exposure at concentrations up to 100 μg/mL. In contrast, CNC3 induced mild to moderate cytotoxicity under the same conditions, upregulated genes linked to inflammatory responses, oxidative stress, apoptosis, and extracellular matrix degradation. These findings reveal that NCs generally exhibit lower pulmonary toxicity than MWCNTs; however, their biological effects are strongly modulated by fiber morphology, surface characteristics, and deposition behavior. To ensure safe use of NCs, comprehensive, material-specific toxicity assessments and standardized evaluation frameworks are essential. In particular, rigorous endotoxin testing and control should be incorporated into future studies to maintain validity and reproducibility of hazard evaluations. Additionally, long-term and repeated exposure models, mechanistic investigations, and case-by-case safety assessments are required, especially for NC variants with limited biodegradability and prolonged pulmonary retention.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"9 ","pages":"Article 100259"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145262701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A long-term mouse testis organ culture system to identify germ cell damage induced by chemotherapy","authors":"Satoshi Yokota ,&nbsp;Kiyoshi Hashimoto ,&nbsp;Takuya Sato ,&nbsp;Koichi Uemura ,&nbsp;Kazuhide Makiyama ,&nbsp;Takuya Nishimura ,&nbsp;Satoshi Kitajima ,&nbsp;Takehiko Ogawa","doi":"10.1016/j.crtox.2025.100228","DOIUrl":"10.1016/j.crtox.2025.100228","url":null,"abstract":"<div><div>We previously developed the acrosin-green fluorescent protein (GFP) transgenic neonatal mouse organ culture system for rapid and accurate assessment of testicular toxicity. This system effectively evaluates drug-induced toxicity in male germ cells before meiotic entry but cannot assess post-meiotic germ cell toxicity. For many chemicals, the specific stage of germ cell differentiation that is susceptible to toxicity remains unclear, highlighting the need for new methods. In this study, we incubated neonatal mouse testis organ cultures for 35 days to allow post-meiotic cells to develop. The tissue was then exposed to cisplatin to determine the cells that are targeted and to assess the reversibility of the toxicity. We monitored changes in tissue volume and GFP fluorescence, which tracks the progression of spermatogenesis, and confirmed findings by histological analysis. Cisplatin inhibited tissue growth and reduced GFP fluorescence in a concentration-dependent manner. Higher concentrations targeted not only spermatogonia, but also spermatocytes and spermatids. Recovery from toxicity was observed at clinically relevant doses. This study demonstrates that long-term mouse testis organ culture can be used to assess testicular toxicity, enabling the identification of specific germ cell stages targeted by chemicals such as cisplatin.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100228"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143610947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"L-3-n-butylphthalide alleviates intermittent alcohol exposure-induced hypothalamic cell apoptosis via inhibiting the IRE1α-ASK1-JNK pathway in adolescent rats","authors":"Shanyong Yi ,&nbsp;Lai Wei ,&nbsp;Bin Zhao ,&nbsp;Zhijun Yao ,&nbsp;Bin Yang","doi":"10.1016/j.crtox.2024.100211","DOIUrl":"10.1016/j.crtox.2024.100211","url":null,"abstract":"<div><div>Exposure to alcohol can induce different degrees of damage to various tissues and organs, and brain is the most vulnerable part affected by alcohol. However, there is no detailed report on whether intermittent alcohol exposure can result in pathological changes in the hypothalamus of adolescent rats and the detailed mechanism. This study investigated pathological changes in the hypothalamus, probed the levels of inflammatory factors, and detected the expression of proteins related to endoplasmic reticulum stress (ERS) to determine whether ERS is involved in the injury process of the hypothalamus and the protective mechanism of L-3-n-butylphthalide (L-NBP). The results showed that intermittent alcohol exposure induced hypothalamic nerve injury, including cell apoptosis, increased the levels of inflammatory factors, and upregulated the expression of glucose-regulated protein 78 (GRP78), p-Inositol Requiring Enzyme 1α (p-IRE1α), apoptosis signal-regulating kinase 1 (ASK1), and p-c-Jun N-terminal kinase (p-JNK)). Tauroursodeoxycholic acid (TUDCA), an ERS inhibitor, significantly reduced the pathological damage described above. The increases in the levels of inflammatory factors, pathological injury, and increased levels of proteins associated with the IRE1α-ASK1-JNK pathway were alleviated by L-NBP. The present study indicated that intermittent alcohol exposure could lead to hypothalamic cell apoptosis in adolescent rats and L-NBP could alleviate the above injury by inhibiting the IRE1α-ASK1-JNK pathway.</div><div>Abbreviations: Ang-2, Angiopoietin-2; ASK1, Apoptosis signal-regulating kinase 1; ER, Endoplasmic reticulum; ERS, Endoplasmic reticulum stress; ELISA, Enzyme-linked immunosorbent assay; GFAP, Glial fibrillary acidic protein; GRP78, Glucose-regulated protein 78; IBA1, Ionized calcium binding adapter molecule 1; i.p., Intraperitoneal; IRE1α, Inositol Requiring Enzyme 1α; JNK, c-Jun N-terminal kinase; L-NBP, L-3-n-butylphthalide; PND, Postnatal day; PVDF, Polyvinylidene difluoride; SDS-PAGE, Sodium dodecyl sulfate–polyacrylamide gel electrophoresis; TRAF2, TNF-receptor associated factor 2; TUDCA, Tauroursodeoxycholic acid; VEGF, Vascular endothelial growth factor.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100211"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11741027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Reproductive cytotoxic and genotoxic impact of polystyrene microplastic on Paracentrotus lividus spermatozoa” [Curr. Res. Toxicol. 22(6) (2024) 100173]","authors":"Filomena Mottola,&nbsp;Maria Carannante,&nbsp;Angela Barretta,&nbsp;Ilaria Palmieri,&nbsp;Lucia Rocco","doi":"10.1016/j.crtox.2024.100185","DOIUrl":"10.1016/j.crtox.2024.100185","url":null,"abstract":"","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100185"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Approach for systematically assessing study reliability and relevance in evaluations of monosodium glutamate safety","authors":"William D. Klaren ,&nbsp;Brianna N Rivera ,&nbsp;Amy M Sheppard ,&nbsp;Kara Franke ,&nbsp;Daniele S Wikoff","doi":"10.1016/j.crtox.2025.100256","DOIUrl":"10.1016/j.crtox.2025.100256","url":null,"abstract":"<div><div>Monosodium glutamate (MSG) is a well-studied food additive. In addition to numerous authoritative assessments of safety, a substantial volume of research is ongoing with MSG; this includes a growing volume of research assessing the ameliorating potential of various substances against purported MSG-induced toxicity. This work set out to develop an approach for evaluating the combined reliability and relevance of these types of investigations as part of ingredient safety assessments, and subsequently, to apply such to a case study of MSG publications involving co-exposures with other substances. The approach assesses the reliability of the studies utilizing SciRAP, and the relevance in context of study design, dose relevance, and biological validity, resulting in an overall categorization of the informativeness of an individual study, or study quality. In a case study application to 39 studies assessing MSG toxicity and ameliorative properties of a variety of substances, no publications were deemed of ‘high’ study quality for the purpose of assessing safety, due primarily to low relevance to human safety (e.g., use of an acute high dose during neonatal lifestages) and limited reliability in study conduct and reporting. The approach herein can facilitate objective assessments of the quality of MSG safety or toxicity studies and could also be tailored to other food additives or ingredients.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"9 ","pages":"Article 100256"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145104421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GenX induces offspring vascular endothelial ferroptosis by targeting GPX4 for ubiquitination-dependent degradation","authors":"Jing Li ,&nbsp;Yuhui Cui ,&nbsp;Chengyi Zheng ,&nbsp;Yiwei Zhang ,&nbsp;Shuxian Li ,&nbsp;Lingbing Li","doi":"10.1016/j.crtox.2025.100260","DOIUrl":"10.1016/j.crtox.2025.100260","url":null,"abstract":"<div><div>GenX, a widely used replacement for PFOA, has become ubiquitously distributed in aquatic ecosystems, soil, and biota, yet its developmental toxicity in offspring is poorly characterized. This study delineates the intergenerational vascular consequences of gestational GenX exposure. Pregnant mice exposed to GenX exhibited adverse pregnancy outcomes, notably fetal growth restriction and placental structural impairment. Pathological evaluation demonstrated labyrinthine zone disorganization and diminished Occludin expression in placentas, indicating disrupted barrier function that likely facilitates maternal-fetal GenX transfer. Critically, exposed offspring displayed systemic vascular maldevelopment, marked by aberrant angiogenesis and endothelial dysfunction. Mechanistic investigations revealed that GenX provoked ferroptosis in vascular endothelial cells, evidenced by depleted GSH, suppressed SOD activity, elevated MDA and Fe²⁺ levels, and mitochondrial ROS overproduction. Strikingly, GenX directly interacted with GPX4, a master ferroptosis suppressor, and accelerated its ubiquitination-mediated degradation. Functional rescue experiments confirmed that GPX4 overexpression abolished GenX-induced endothelial ferroptosis and restored vascular homeostasis. Our data establish GPX4 as the keystone target through which GenX disrupts offspring vascular development via ferroptosis. This work provides the crucial evidence connecting environmental GenX exposure to offspring’s endothelial dysregulation, uncovers a novel toxicological axis involving GPX4 destabilization, and underscores the importance of reassessing the developmental safety of GenX.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"9 ","pages":"Article 100260"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145216605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of the endocrine disrupting potential of Di-isodecyl phthalate","authors":"I.A. Lea ,&nbsp;D. Feifarek ,&nbsp;A. Mihalchik ,&nbsp;M. Heintz ,&nbsp;L. Haws ,&nbsp;H. Nyambego ,&nbsp;K. Goyak ,&nbsp;C. Palermo ,&nbsp;S.J. Borghoff","doi":"10.1016/j.crtox.2025.100221","DOIUrl":"10.1016/j.crtox.2025.100221","url":null,"abstract":"<div><div>Low molecular weight <em>ortho</em>-phthalates have been implicated in perturbing androgen pathways when administered during the masculinization programming window. Di-isodecyl phthalate (DIDP) is a high molecular weight phthalate and as a high production volume chemical, its ability to disrupt endocrine pathways is important to understand its potential hazard. Both DIDP (and its metabolites) were evaluated to determine the potential to perturb endocrine pathways through a weight of evidence (WoE) assessment in accordance with the European Chemicals Agency (ECHA)/European Food Safety Authority (EFSA) Endocrine Disruptor Guidance (2018). A literature review was performed of toxicological data for DIDP related to estrogen, androgen, thyroid, or steroidogenesis pathways. Literature searches returned 41 relevant articles from which data were extracted and assessed in conjunction with data from 105 high-throughput assays. Because some of the <em>in vitro</em> assays lack metabolic capabilities, an <em>in silico</em> assessment of estrogen (E), androgen (A), thyroid (T) or steroidogenesis (S) activity was conducted. Based on the available evidence for the T pathway, DIDP did not elicit adverse thyroid outcomes <em>in vivo</em>. When considering the T mechanistic data, there was evidence that DIDP induced the liver pregnane X receptor (PXR) and some indication that DIDP increased iodide uptake in the thyroid. As there were no studies evaluating thyroid hormone levels <em>in vivo</em>, a data gap was identified because per the ECHA/EFSA guidance, the lack of this information prevents drawing a conclusion on the T pathway. However, the E, A and S pathways were sufficiently assessed to conclude a limited or lack of E, A or S related apical outcomes in <em>in vivo</em> studies; there was also a lack of endocrine activity in <em>in vitro</em> or <em>in vivo</em> mechanistic studies. These results suggest that DIDP does not meet the ECHA/EFSA criteria for an endocrine disruptor, therefore DIDP is unlikely to disrupt the androgen pathway during development.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100221"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143429111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The skin allergy risk assessment-integrated chemical environment (SARA-ICE) defined approach to derive points of departure for skin sensitization","authors":"Emily N. Reinke ,&nbsp;Joe Reynolds ,&nbsp;Nicola Gilmour ,&nbsp;Georgia Reynolds ,&nbsp;Judy Strickland ,&nbsp;Dori Germolec ,&nbsp;David G. Allen ,&nbsp;Gavin Maxwell ,&nbsp;Nicole C. Kleinstreuer","doi":"10.1016/j.crtox.2024.100205","DOIUrl":"10.1016/j.crtox.2024.100205","url":null,"abstract":"<div><div>Mechanistically based non-animal methods for assessing skin sensitization hazard have been developed, but are not considered sufficient, individually, to conclusively define the skin sensitization potential or potency of a chemical. This resulted in the development of defined approaches (DAs), as documented in OECD TG 497, for combining information sources in a prescriptive manner to provide a determination of risk or potency. However, there are currently no DAs within OECD TG 497 that can derive a point of departure (POD) for risk assessment. The Skin Allergy Risk Assessment – Integrated Chemical Environment (SARA-ICE) DA for skin sensitization is a Bayesian statistical model that estimates a human-relevant metric of sensitizer potency, the ED₀₁, an estimate of the human predictive patch test dermal dose at which there is 1% chance of inducing sensitization, which can be used in a risk assessment paradigm. The model accounts for variability of input data and explicitly quantifies uncertainty. SARA-ICE derives the ED₀₁ from a variety of <em>in vitro</em> and <em>in vivo</em> test method data and is built upon historical human, murine, and <em>in vitro</em> test data for 434 chemicals. In addition to the ED₀₁ POD SARA-ICE DA also provides a Globally Harmonized System of Classification and Labelling of Chemicals (GHS) classification probability for GHS subcategories 1A, 1B and not classified (NC). Here we describe the SARA-ICE model and its evaluation, including performance versus benchmark PODs. In addition, via a case study with isothiazolinones (ITs), we demonstrate the utility of SARA-ICE for integrating different data inputs and compare the ED₀₁ for six ITs to existing historical data.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100205"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11719337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A high-fat diet exacerbates arsenic toxicity in various organs. A systematic review of toxicity and mechanism","authors":"Hoda Vahedi ,&nbsp;Fateme Pourmotahari ,&nbsp;Ali Akbar Oroojan ,&nbsp;Amin Rasekhian ,&nbsp;Soheila Alboghobeish","doi":"10.1016/j.crtox.2025.100250","DOIUrl":"10.1016/j.crtox.2025.100250","url":null,"abstract":"<div><h3>Background</h3><div>Arsenic contamination in drinking water remains a primary global health concern. Recent evidence indicates that dietary habits, especially high-fat diets, may exacerbate arsenic-induced toxicity. This systematic review examines the impact of high-fat diets on arsenic toxicity across various organs and investigates the mechanisms underlying this interaction.</div></div><div><h3>Methods</h3><div>A comprehensive literature search was conducted in PubMed, Scopus, Web of Science, and Embase databases. Studies involving animal models exposed to both arsenic and high-fat diets were included in this analysis. The methodological quality of the studies was assessed using the SYRCLE risk of bias tool.</div></div><div><h3>Results</h3><div>A total of 20 studies met the inclusion criteria. High-fat diets were found to increase arsenic bioavailability and intensify oxidative stress in several organs, including the brain, heart, testes, and kidneys. Combined exposure to arsenic and high-fat diets resulted in complex metabolic disturbances, including impaired fatty acid metabolism in adipose tissue and a unique diabetogenic effect characterized by glucose intolerance without the typical features of type 2 diabetes. Interestingly, this combination also caused reduced weight gain despite increased insulin resistance and β-cell dysfunction. Modulation of hepatic autophagy pathways emerged as a possible mechanism linking arsenic toxicity to metabolic dysregulation.</div></div><div><h3>Conclusions</h3><div>This review highlights that high-fat diets amplify arsenic toxicity through several mechanisms, including increased bioavailability, elevated oxidative damage, and altered metabolic signaling. The synergistic effects on glucose regulation and multi-organ toxicity underscore the importance of considering dietary habits in assessing arsenic-related health risks. Further research is warranted to clarify the molecular mechanisms involved and to design targeted strategies for mitigating arsenic toxicity, particularly in populations consuming high-fat diets.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"9 ","pages":"Article 100250"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144670596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}