Toxicological Sciences最新文献

{"title":"Benzene metabolites increase vascular permeability by activating heat shock proteins and Rho GTPases.","authors":"Igor N Zelko, Ahtesham Hussain, Marina V Malovichko, Nalinie S Wickramasinghe, Sanjay Srivastava","doi":"10.1093/toxsci/kfaf055","DOIUrl":"10.1093/toxsci/kfaf055","url":null,"abstract":"<p><p>Benzene is a ubiquitous environmental pollutant, abundant in both the outdoor and indoor air. Chronic exposure is associated with increased risk for cardiovascular disease; however, the underlying mechanisms remain unknown. We examined the effect of bioactive benzene metabolites on endothelial integrity. In vitro, highly reactive benzene metabolites, specifically trans, trans-muconaldehyde (MA, 10 µM), decreased the impedance of murine cardiac microvascular endothelial cells (MCMVEC) in a time- and dose-dependent manner and increased the endothelial permeability to 70 kDa dextran. Intradermal injection of MA (400 pmol) increased the vascular leakage by 54% (P < 0.0001) in adult male C57BL/6J mice. This was accompanied by increased levels of endothelial microparticles in the circulation. RNA sequencing of MA-treated MCMVEC and human aortic endothelial cells revealed the robust induction of heat shock proteins (HSPs), particularly members of the HSP70 and HSP90 families. Reactome pathway enrichment analyses suggested that MA dysregulates pathways associated with G protein-coupled receptor and heat shock factor-1-dependent transactivation. Pharmacological inhibition of HSP70s and HSP90s prevented an MA-induced increase in MCMVEC monolayer permeability. Similarly, pharmacological inhibition of Rho-associated coiled-coil-containing protein kinase (ROCK) attenuated MA-induced endothelial permeability in MCMVEC, accompanied by a dose-dependent activation of Rac1 GTPase. To assess the contribution of HSPs to MA-induced endothelial function impairment, we generated a transgenic mouse overexpressing HSPA1B (a member of the HSP70 family; HSPA1B-TGEC). MA exposure increased the vascular leakage by 15% (P < 0.05) in HSPA1B-TGEC mice as compared with the littermate controls. Collectively, our data suggest that MA increases vascular permeability by activating HSP and GTPase signaling pathways.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"111-122"},"PeriodicalIF":3.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12198675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144014899","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":"Developmental perfluorooctanesulfonic acid exposure impairs exocrine pancreas function in zebrafish (Danio rerio).","authors":"Madeline C Tompach, Charlotte K Gridley, Marjorie Marin, Patrick F Murphy, Junghak Lee, John M Clark, Alicia R Timme-Laragy","doi":"10.1093/toxsci/kfaf041","DOIUrl":"10.1093/toxsci/kfaf041","url":null,"abstract":"<p><p>Developmental perfluorooctanesulfonic acid (PFOS) exposure in zebrafish reduces digestive gene expression and pancreas length, indicating exocrine insufficiency. This project focuses on the production and function of digestive proteases with PFOS exposure. We test the hypothesis that developmental PFOS exposure impairs exocrine pancreas function in the absence of severe morphological changes. Three larval timepoints were assessed, where the nutrient source varies (yolk feed at 4-d postfertilization [dpf], yolk depleted at 6 dpf, and exogenously fed at 9 dpf) to understand how nutrients were being used throughout exocrine pancreas development. Tg(ptf1a: GFP) zebrafish were exposed to 0 (0.01% DMSO), 1, 2, and 4 μM PFOS from 0 to 4 dpf. At 4 dpf, pancreas length was decreased with 1 μM and yolk sac area was reduced with 2 and 4 μM PFOS. By 6 dpf, pancreata of zebrafish exposed to 1 μM PFOS had recovered, and pancreas size was decreased with 4 μM PFOS. Protease activity was reduced with PFOS exposure, accompanied by decreases in digestive protease gene expression and trypsin protein. At 9 dpf, there was no measurable change in pancreas size or protease activity with 1 and 2 μM PFOS, indicating morphological and functional recovery even though PFOS was detected in the larvae. This study demonstrates that PFOS exposure can affect the function of the exocrine pancreas in the absence of a detectable change in organ size. We also highlight the mishandling of yolk nutrients, leading to undernutrition at later larval stages and show catch-up growth in morphology and function.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"46-57"},"PeriodicalIF":3.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12198669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744035","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":"Exposure to phthalates enhances estrogen and beta-catenin signaling pathways, leading to endometrial hyperplasia in mice.","authors":"Ritwik Shukla, Athilakshmi Kannan, Mary J Laws, Amy Wagoner Johnson, Jodi A Flaws, Milan K Bagchi, Indrani C Bagchi","doi":"10.1093/toxsci/kfaf062","DOIUrl":"10.1093/toxsci/kfaf062","url":null,"abstract":"<p><p>Phthalates, synthetic chemicals widely utilized as plasticizers and stabilizers in various consumer products, present a significant concern due to their persistent presence in daily human life. Although past research predominantly focused on individual phthalates, real-life human exposure typically encompasses complex mixtures of these compounds. The cumulative effects of prolonged exposure to phthalate mixtures on uterine health remain poorly understood. To address this knowledge gap, we conducted studies utilizing adult female mice exposed chronically to a mixture of phthalates for 12 mo through ad libitum chow consumption. Our studies revealed that continuous exposure to this phthalate mixture led to uterine hyperplasia with a significant increase in gland-to-stroma ratio. Endometrial hyperplasia is commonly caused by heightened estrogenic action and inflammatory response in the uterus, leading to increased proliferation of endometrial epithelial cells. Indeed, we observed a marked upregulation of several known estrogen-regulated genes, proinflammatory chemokines, elevated homing of macrophages, and increased KI67 staining in the endometrial epithelial cells upon phthalate exposure. Several signaling pathways, including the MAPK/ERK and Wnt/β-Catenin pathways, promote cell proliferation, leading to the hyperproliferative state of the endometrial cells. Our studies revealed no alteration of the MAPK/ERK pathway but a marked enhancement of the Wnt/β-Catenin signaling pathway in phthalate-exposed uteri. Collectively, this study underscores the significance of understanding the exposure to environmental factors in the pathogenesis of endometrial disorders.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"58-67"},"PeriodicalIF":3.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12198673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035684","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":"Inhalation of concentrated ambient PM2.5 promotes inactivation of telomerase reverse transcriptase, telomere shortening, and senescence of multiple cell types in mice.","authors":"Daniel Gomes, Jingjing Zhao, Marina V Malovichko, Petra Haberzettl, Daniel J Conklin, Timothy E O'Toole","doi":"10.1093/toxsci/kfaf045","DOIUrl":"10.1093/toxsci/kfaf045","url":null,"abstract":"<p><p>Although some prior studies have identified an association between exposure to fine air-borne particulate matter (PM2.5) and indices of aging, the extent of these associations and their underlying mechanisms are uncertain. In this study, we exposed male C57BL/6J mice to filtered air and concentrated ambient PM2.5 (CAP) and assessed 2 common hallmarks of aging, telomere shortening and a senescent phenotype. Of the cell types examined, peripheral blood mononuclear cells (PBMNCs), endothelial progenitor cells (EPCs), and bone marrow-derived c-kit+ cells, all 3 demonstrated shortened telomeres when isolated from CAP-exposed mice as compared with cells derived from filtered air controls. We found that telomere attrition in PBMNCs and EPCs was mitigated in those CAP-exposed mice receiving water supplemented with the antioxidant, carnosine, and was reversible in PBMNCs, but not EPCs, when CAP-exposed mice were allowed to recover in normal air conditions. Telomere attrition in these cell types appeared to result from the attenuated catalytic activity of telomerase reverse transcriptase (Tert). PBMNCs and EPCs obtained from CAP-exposed mice also displayed increased β-galactosidase activity and expression of genes characteristic of the senescence-activated secretory phenotype. Of PBMNC subtypes, the increase of β-galactosidase activity was greatest in CD8+ T-cells. Our results suggest that the pro-aging effects of PM2.5 impact multiple cell types, including bone marrow stem cells, and that telomere attrition resulted from attenuated Tert activity. The aging and senescence of multiple cell types, including bone marrow stem cells, may underlie the diverse pathological outcomes of PM2.5 exposure.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"147-157"},"PeriodicalIF":3.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12198680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143765095","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":"Prenatal exposure to environmentally relevant low-dosage dibutyl phthalate reduces placental efficiency in CD-1 mice.","authors":"Tasha Pontifex, Xinran Yang, Ayna Tracy, Zelieann Craig, Chi Zhou","doi":"10.1093/toxsci/kfaf050","DOIUrl":"10.1093/toxsci/kfaf050","url":null,"abstract":"<p><p>Dibutyl phthalate (DBP), a phthalate congener, is widely utilized in consumer products and medication coatings. Women of reproductive age have a significant burden of DBP exposure. Prenatal DBP exposure is associated with adverse pregnancy/fetal outcomes in the offspring. However, the role of fetal sex and the general mechanisms underlying DBP exposure-associated adverse pregnancy outcomes are unclear. We hypothesize that prenatal DBP exposure at an environmentally relevant low dosage adversely affects fetal-placental development and function during pregnancy in a fetal sex-specific manner. Adult female CD-1 mice (8 to 10 wk) were orally treated with vehicle (control) or with environmentally relevant low DBP dosages at 0.1 μg/kg/d (DBP0.1) daily from 30 days before pregnancy through gestational day (GD) 18.5. Dam adiposity was measured noninvasively using the echo-magnetic resonance imaging system. Lipid disposition in fetal labyrinth and maternal decidual area of placentas was examined using Oil Red O staining. DBP0.1 exposure did not significantly affect the body weight and adiposity of nonpregnant adult female mice nor the maternal weight gain pattern and adiposity during pregnancy in adult female mice. DBP0.1 exposure does not affect fetal weight but significantly increases the placental weight at GD18.5 (indicative of decreased placental efficiency) in a fetal sex-specific manner. We further observed that DBP0.1 significantly decreased lipid disposition in fetal labyrinth of female, but not male placentas, whereas it did not affect lipid disposition in maternal decidual. In conclusion, prenatal exposure to environmentally relevant low-dosage DBP adversely impacts the fetal-placental efficiency and lipid disposition in a fetal sex-specific manner.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"86-95"},"PeriodicalIF":3.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12198677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144045326","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":"Cadmium exposure following early-life respiratory syncytial virus infection promotes lung fibrosis through autophagy inhibition.","authors":"Zachery R Jarrell, Choon-Myung Lee, Ho Young Lee, Ki-Hye Kim, Gahyun Lim, Michael Orr, Sang-Moo Kang, Yan Chen, Dean P Jones, Young-Mi Go","doi":"10.1093/toxsci/kfaf054","DOIUrl":"10.1093/toxsci/kfaf054","url":null,"abstract":"<p><p>Early-life respiratory syncytial virus (RSV) infection (eRSV) is a major cause of severe respiratory illness in children and increases the risk of asthma and lung dysfunction later in life. Cadmium (Cd), a toxic environmental metal, exacerbates these risks when combined with eRSV. Our previous research demonstrated that eRSV reprograms lung metabolism and amplifies Cd toxicity, driving inflammation, and metabolic disruption through protein palmitoylation. Recent studies showed that inhibiting mTORC1 with rapamycin (Rapa) mitigates Cd-induced metabolic disruption and profibrotic signaling in lung fibroblasts. In this study, we employed a mouse model to investigate the role of mTORC1 in mediating the effects of chronic low-dose Cd exposure (3.3 mg CdCl2/L in drinking water for 16 wk) following eRSV (eRSV+Cd). The impact of mTORC1 inhibition was assessed using Rapa (14 ppm), with downstream autophagy markers analyzed as indicators of mTORC1 activity. Mice in the eRSV+Cd group showed significantly elevated levels of cytokines, chemokines, inflammatory cells, and collagen deposition, indicating stimulation of inflammation and fibrosis. Rapa treatment markedly reduced these pathological markers. Metabolomic profiling and single-cell RNA sequencing revealed disruptions in autophagy-associated metabolites and genes in the eRSV+Cd group, which were reversed by Rapa. Taken together, this study highlights the critical role of the mTORC1 activation-autophagy inhibition pathway in mediating the exacerbated inflammatory response and lung fibrosis induced by Cd exposure following eRSV. These results underscore the potential of targeting the mTORC1-autophagy pathway with Rapa as a therapeutic strategy to mitigate lung damage in individuals affected by these environmental and infectious insults.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"123-133"},"PeriodicalIF":3.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12198674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027701","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":"Profiling the cytotoxic effects of naled and other pesticides in primary human placental cytotrophoblasts.","authors":"Lin Li, Hao Chen, Unurzul Jigmeddagva, Ngantu Le, Mirhan Kapidzic, Stephanie Gee, Alizah Ali, Justine Levan, Romane Person, Jessica Chen, Amanda M Gutierrez, Chinomnso N Okorie, Mengjing Wang, Tracey J Woodruff, Susan J Fisher, Stephanie L Gaw, Joshua F Robinson","doi":"10.1093/toxsci/kfaf038","DOIUrl":"10.1093/toxsci/kfaf038","url":null,"abstract":"<p><p>Placental cytotrophoblasts (CTBs) play critical roles in placentation, including implantation, barrier function, uterine invasion, and maternal endovascular remodeling. Impairment of CTB function is linked with common pregnancy complications. In this context, environmental chemicals can contribute to CTB dysfunction. Evidence suggests that prenatal exposures to pesticides affect the placenta and contribute to pregnancy complications and adverse developmental outcomes. Despite being restricted in the European Union, dimethyl 1,2-dibromo-2,2 dichloroethyl phosphate (naled), a common organophosphate pesticide, is widely used in vector control and agriculture in the United States and abroad. In this study, we investigated the placentotoxic activity of naled in second-trimester primary human CTBs. We assessed the cytotoxicity of naled and 67 pesticides using the neutral red lysosomal cellular uptake assay and the lactate dehydrogenase release assay. Naled was one of the most toxic compounds (∼15th percentile), impairing viability and inducing cell death at levels similar to federally restricted pesticides (methoxychlor and triclosan) and at lower concentrations than other commonly used compounds in the organophosphate class (e.g. chlorpyrifos, dichlorvos, and malathion). Naled significantly altered expression of 297 genes (unadjusted P < 0.01, absolute fold change >1.5 with 10 or 30 µM), including molecules important in regulating the environmental stress response and developmental processes. Using a benchmark modeling approach, we identified specific genes and related pathways that may serve as early indicators of naled-response in CTBs at physiologically relevant exposure levels. Thus, our data suggest that naled may alter critical human CTB functions in vivo.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"96-110"},"PeriodicalIF":3.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12198676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161167","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":"Bayesian benchmark dose modeling analysis and derivation of points of departure for female reproductive toxicity following exposure to di(2-ethylhexyl) phthalate (DEHP) - effects on reproductive hormones, folliculogenesis and estrous cyclicity.","authors":"Antero Vieira Silva, Ilari Tarvainen, Mattias Öberg, Mary Laws, Patrick Hannon, Jodi Flaws, Pauliina Damdimopoulou","doi":"10.1093/toxsci/kfaf052","DOIUrl":"10.1093/toxsci/kfaf052","url":null,"abstract":"<p><p>Endocrine-disrupting chemicals such as di(2-ethylhexyl) phthalate (DEHP) pose significant risks to human reproductive health. However, regulatory frameworks often lack sufficient data on sensitive female-specific reproductive endpoints. This study investigates the sensitivity of hypothalamic-pituitary-ovarian (HPO) axis endpoints to DEHP exposure in adult female mice, applying Bayesian Benchmark dose (BBMD) modeling for dose-response assessment and derivation of points-of-departure (PODs) for risk assessment. Data from four studies where sexually mature female mice were exposed to DEHP (0.02 to 240 mg/kg bw/d) for 10 or 30 d via oral administration, or 30 d via diet, was modeled. Endpoints included ovarian follicle counts, serum hormones, estrous cyclicity, body, and organ weights. Results revealed dose-dependent changes and greater sensitivity of progesterone, ovarian follicle counts, and uterine weight, compared with estrous cyclicity, body weight, and other organ weights. For 10- and 30-d oral administration studies, the lowest nonzero BBMDLs were observed for serum progesterone levels (9.1 mg/kg bw/d) and primary follicle counts (19.5 mg/kg bw/d), respectively. These PODs were notably lower than most No-Adverse-Effect-Levels in the European Chemicals Agency's (ECHA's) \"Registered substances factsheet\" and \"ECHA CHEM\" databases. The majority of the studies derived PODs based on male (reproductive) endpoints. Finally, a derived no-effect level of 0.064 mg DEHP/kg bw/d was estimated, based on the overall lowest BBMDL, serum progesterone levels of the 10-d oral study. In conclusion, our study indicates that current guidelines may not fully capture reproductive risks for females, underscoring the need to refine regulatory endpoints to better protect female reproductive health in the context of DEHP exposure.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"30-45"},"PeriodicalIF":3.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12198667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024668","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":"Correction to: Repeated exposure to eucalyptus wood smoke alters pulmonary gene and metabolic profiles in male Long-Evans rats.","authors":"","doi":"10.1093/toxsci/kfaf080","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf080","url":null,"abstract":"","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144508424","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":"Kupffer cell expression of macrophage receptor with collagenous structure modulates macrophage gene induction and limits acute liver injury.","authors":"Lauren G Poole, Zimu Wei, Anthony Schulte, Holly M Cline, Matthew P Bernard, John P Buchweitz, Mitchell R McGill, James P Luyendyk","doi":"10.1093/toxsci/kfaf037","DOIUrl":"10.1093/toxsci/kfaf037","url":null,"abstract":"<p><p>Macrophages displaying a pro-repair and anti-inflammatory polarization have been implicated in resolution of acute liver injury. Macrophage receptor with collagenous structure (MARCO) expression marks tolerogenic hepatic macrophages and is expressed by pro-resolution macrophages in the injured liver. We tested the hypothesis that MARCO promotes repair of the acetaminophen (APAP)-injured liver. Robust and sustained induction of MARCO mRNA and protein expression was evident in livers of mice challenged with a hepatotoxic dose of APAP (i.e. 300 mg/kg), whereas hepatic MARCO induction failed in mice with APAP-induced liver failure (i.e. 600 mg/kg). Serum proteomics identified a significant increase in serum MARCO levels in surviving acute liver failure (ALF) patients, but not in ALF patients who died. MARCO expression was high in F480+ liver macrophages, and MARCO deficiency reduced macrophage expression of pro-resolution markers such as Gpnmb and Mertk during the repair phase (i.e. 48 h). The results suggested a delay in necrosis resolution along with a trend toward increased mortality in APAP-challenged MARCO-/- mice. Notably, a robust increase in peak hepatic injury (i.e. 6- to 24-h post-APAP challenge) was evident in MARCO-/- mice, which could not be ascribed to differences in NAPQI/APAP-adduct generation nor changes in hepatic neutrophil/macrophage numbers. Interestingly, a reduction in hepatic CD11c+ cells, shown previously to limit APAP-induced liver injury, was evident 24 h after APAP challenge in MARCO-/- mice. The results indicate that MARCO deficiency worsens APAP-induced acute liver injury in mice and provide experimental and initial translational evidence linking MARCO induction to positive outcomes in acute liver injury.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"417-427"},"PeriodicalIF":3.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12118956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674618","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}