Toxicological Sciences最新文献

{"title":"Hepatic cellular stress response pathways exhibit species differences in basal and inducible activity.","authors":"Hannah Coghlan, Sophie Regan, Bhavik Chouhan, Dominic P Williams, Rowena Sison-Young, Andrew R Jones, Ian M Copple","doi":"10.1093/toxsci/kfag061","DOIUrl":"10.1093/toxsci/kfag061","url":null,"abstract":"<p><p>Cellular stress response pathways such as the nuclear factor erythroid 2-related factor 2 (NRF2) oxidative stress response, endoplasmic reticulum (ER) stress response, and macroautophagy afford protection against many forms of drug toxicity, including the liver toxicity associated with the formation of reactive drug metabolites. In many cases, clinical drug-induced liver injury is poorly predicted by preclinical toxicology studies. To maximize the translatability of preclinical toxicology studies and inform species selection, we have investigated the relative hepatic stress response capacities of humans and preclinical animal species commonly used in toxicology testing. In control liver tissue, the basal gene and protein expression of stress response pathway components was found to be greater in rodents than nonrodent preclinical species and humans. In addition, following in vitro exposure to pharmacological modulators of autophagy and the NRF2 and ER stress responses, rodent hepatocytes generally displayed a greater capacity, relative to those of nonrodent preclinical species and humans, for adaptation to cellular stress. In all, our results indicate that rodent preclinical species possess a greater basal and adaptive hepatic capacity for mitigation of chemical insult than nonrodent preclinical species and humans. This study represents the first to provide a comprehensive comparison of stress response pathway capacity of humans and the animal species most commonly used for preclinical drug safety assessment. Our findings can be used to inform the selection of species for safety testing of drugs with a liability for reactive metabolite-mediated liver toxicity, and to interpret the findings of such studies.</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/PMC13387358/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148057071","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 exposure to a PFAS mixture impairs the anamnestic response to influenza A virus infection in mice.","authors":"Christina M Post, Jackie J Agyemang, Katya A McDonald, Carrie A McDonough, B Paige Lawrence","doi":"10.1093/toxsci/kfag058","DOIUrl":"10.1093/toxsci/kfag058","url":null,"abstract":"<p><p>Developmental exposure to per- and polyfluoroalkyl substances (PFAS) has been linked to reduced antibody responses to childhood vaccines, but the underlying mechanisms remain unclear. Antibody production relies on interactions between various immune cell types, and it is unknown which are affected by PFAS exposure during development. To investigate this in a human-health-relevant system, an in vivo model was established to delineate effects of developmental exposure to a mixture of 4 PFAS commonly found in human serum: Perfluorooctanoic acid (PFOA), perfluorooctane sulfonate, perfluorohexane sulfonate, and perfluorononanoic acid. Pregnant mice consumed water containing these PFAS throughout gestation and lactation. PFAS were measured in both mothers and offspring, and an exposure that did not cause signs of overt toxicity was selected. The immune response to influenza A virus (IAV) infection was assessed in male and female offspring. Results showed that developmental PFAS exposure reduced IAV-specific antibody levels in both sexes. However, it diminished T follicular helper cells and germinal center B cells-critical for antibody production-in only female offspring. These findings highlight possible sex-specific immune effects and identify potential cellular mechanisms behind reduced antibody levels. Because these immune cells are essential for antibody production in humans, this study provides valuable insights into how PFAS exposure may impact 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/PMC13252598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148017521","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":"Cigarette smoke extract suppresses peptide transporter 2 function in alveolar epithelial cells via aryl hydrocarbon receptor signaling.","authors":"Masashi Kawami, Maya Nakanishi, Yuma Furuichi, Ryoko Yumoto, Yasuo Uchida, Mikihisa Takano","doi":"10.1093/toxsci/kfag056","DOIUrl":"10.1093/toxsci/kfag056","url":null,"abstract":"<p><p>Cigarette smoke is a major risk factor for chronic respiratory diseases, yet the molecular mechanisms underlying its effects on pulmonary defense remain incompletely understood. Although transporters such as P-glycoprotein and CFTR have been implicated in smoking-related dysfunction, little is known about the impact of cigarette smoke on peptide transporter 2 (PEPT2), which plays a dual role in xenobiotic disposition and host defense by mediating the uptake of di- and tripeptides, bacterial fragments, and peptide-like drugs. Here, we investigated the effects of cigarette smoke extract (CSE) on the functional expression of PEPT2 in alveolar epithelial cells. Using the human H441 cell line, we found that CSE reduced PEPT2 activity and mRNA expression in a concentration-dependent manner. Among signaling inhibitors, only PD98059 reversed the CSE-induced suppression, whereas U0126 had no effect. Consistently, the AhR ligand benzo[a]pyrene decreased PEPT2 expression and function, and this effect was abolished by AhR antagonists. Other AhR ligands, including leflunomide and omeprazole, produced similar inhibitory effects. These findings indicate that CSE suppresses PEPT2 in an AhR-dependent manner, whereas the underlying transcriptional mechanisms remain to be clarified. These findings suggest that PEPT2 is a previously unrecognized target of cigarette smoke-related transporter regulation and are consistent with the involvement of AhR signaling in its suppression. These findings provide insight into potential alterations in epithelial transport function and their possible implications for pulmonary defense and drug disposition in smokers.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147975771","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":"Omeprazole activation of CD4+ and CD8+ T-cells through off-target covalent modification of cellular proteins.","authors":"Sophie Grice, Sa'd Albashtawy, Georgia Wells, Luisa Hering, Kareena Adair, Joscelyn Sarsby, Philip Brownridge, Megan Ford, Rachel Lloyd, Lucy Hampson, Annette Wagner, Yonghu Sun, Hong Liu, Sean Hammond, Xiaoli Meng, Furen Zhang, Dean Naisbitt","doi":"10.1093/toxsci/kfag046","DOIUrl":"10.1093/toxsci/kfag046","url":null,"abstract":"<p><p>Targeted covalent inhibition of protein function is increasingly used as a therapeutic mode of action; however, there is a need to characterize off-target binding interactions and to understand whether this represents an immunological risk. Given that the proton-pump inhibitor omeprazole exerts its mechanism of action through covalent inhibition, it serves as an ideal model to investigate the relationship between off-target protein binding and T-cell activation. Binding of omeprazole, omeprazole metabolites, and alternative proton-pump inhibitors to antigen-presenting cells and GST-pi was characterized by mass spectrometry. Omeprazole-responsive clones were generated and assessed in terms of cytokine secretion, pathways of T-cell activation, and crossreactivity with omeprazole metabolites, alternative proton-pump inhibitors, and unrelated drugs. Omeprazole stimulated CD4+ and CD8+ T-cell clones to proliferate and secrete cytokines and cytolytic molecules. HLA-restricted T-cell activation was dependent on processing of omeprazole protein adducts by antigen-presenting cells. Omeprazole-modified CYS-containing peptides derived from 36 off-target proteins were detected within antigen-presenting cells. Omeprazole metabolites and alternative protein pump inhibitors that form protein adducts also activated omeprazole-responsive T-cells. In conclusion, T-cells were activated with omeprazole via a hapten mechanism and exhibited considerable promiscuity to metabolites and structurally related drugs of the same pharmacological class. Similar off-target binding interactions may be a relevant concern for the increasing number of covalent inhibitor drugs receiving regulatory approval.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13167194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147780890","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":"Integration of mechanistic and repeat dose toxicity data in the derivation of an oral reference dose for HFPO-DA.","authors":"Chad M Thompson, Melissa M Heintz, Sarah I Rogers, Melissa J Vincent, Laurie C Haws","doi":"10.1093/toxsci/kfag045","DOIUrl":"10.1093/toxsci/kfag045","url":null,"abstract":"<p><p>HFPO-DA (ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate) is a short-chain perfluoroether carboxylic acid used as a polymerization aid in the manufacture of some types of fluorinated polymers. Existing toxicity criteria for HFPO-DA include chronic and subchronic oral reference dose (RfD) values based on liver effects in mice. New mechanistic data demonstrate that these liver effects are incontrovertibly linked to rodent-specific peroxisome proliferator-activated receptor alpha (PPARα) signaling pathways that lack human relevance. Therefore, it was critical to reevaluate existing HFPO-DA RfD values. A literature review was conducted to identify human and animal studies that might serve as the basis of updated toxicity criteria. Relevant studies were considered along with a newly completed chronic bioassay in mice. No epidemiological studies were determined acceptable for use in toxicity value development. The only neoplasms in the chronic mouse bioassay were in the liver and were considered PPARα related. The most sensitive extrahepatic noncancer endpoints in rodents involved placental lesions in reproductive and developmental toxicity studies and reduced testicular cellularity in mice following chronic exposure. Both effects resulted in RfD values of 0.001 mg/kg-d. Also presented are probabilistic risk assessment methods that resulted in a similar probabilistic RfD. These results indicate the need to update existing toxicity criteria for HFPO-DA.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13176454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147676987","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":"In vitro and preclinical assessment of drug interactions between fluoroquinolones and a nonsteroidal antiinflammatory drug predicting risk of seizure.","authors":"Yuki Seki, Ikue Mihara, Taroumaru Okawa, Atsuko Ojima, Kazumasa Aoyama, Masaki Mikamoto, Yuka Morimitsu, Takeo Kamakura, Yasuaki Goto, Aoi Odawara, Yukiko Oshiro, Tomohiko Taniguchi, Motohiro Shiotani, Takashi Yoshinaga, Shoji Asakura, Yuto Ishibashi, Naoki Matsuda, Ikuro Suzuki, Norimasa Miyamoto","doi":"10.1093/toxsci/kfag039","DOIUrl":"10.1093/toxsci/kfag039","url":null,"abstract":"<p><p>Seizures are a common reason for drugs to fail during development, but they are difficult to predict preclinically. Enoxacin, a fluoroquinolone, rarely causes convulsions as a monotherapy, but convulsions have been seen after combination therapy with fenbufen, a nonsteroidal antiinflammatory drug. The interaction between the drugs is thought to result from inhibition of GABAA receptors, which are not their primary targets. Here, we show that, among 15 marketed fluoroquinolones and 1 active metabolite, 6, including enoxacin, inhibited γ-aminobutyric acid (GABA)-evoked depolarization in cells expressing human GABAA receptors when administered with felbinac, the active metabolite of fenbufen. Within these 6, except for a prodrug, possessed a piperazinyl group at the seventh position of the quinolone ring. We also administered enoxacin or norfloxacin plus felbinac to rats and determined the cerebrospinal fluid concentrations of each drug when convulsions occurred. As we previously reported, an increase in network burst frequency recorded from primary cultured rat cortical neurons on microelectrode arrays is a risk marker for seizures, so we tested whether this assay could predict seizures induced by drug interactions between fluoroquinolones and felbinac. When co-administered with felbinac, only those fluoroquinolones that inhibited GABA currents in patch-clamp tests increased network burst frequency. Principal component analysis using 17 microelectrode array parameters supported that the mechanism of action was due to GABA antagonism in rodent neurons. Thus, the microelectrode array assay predicted seizure risks from the combination of enoxacin and the active metabolite of fenbufen and identified other fluoroquinolones with seizure risk potential.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147514910","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":"Gestational and lactational exposure to phthalates and nanoplastics induces inflammation and oxidative imbalance in the prostate of adult rats.","authors":"Vanessa A Rocha, Marina Cavalheiro, Patrick V Souza, Natalia Magosso, Matheus N Fioretto, Mirella F Moreira, Victoria C Pinha, Ariana M Aquino, Debora H Quadreli, Glaura S A Fernandes, Luis A Justulin, Jodi A Flaws, Wellerson R Scarano","doi":"10.1093/toxsci/kfag057","DOIUrl":"10.1093/toxsci/kfag057","url":null,"abstract":"<p><p>The intrauterine microenvironment is highly susceptible to environmental disturbances, which may result in persistent effects on offspring health. Given that plastic-derived contaminants can cross the placental barrier and act as endocrine-disrupting chemicals, this study evaluated the effects of perinatal exposure to an environmentally relevant phthalate mixture (PM) and nanoplastics (NPs) on the prostate of adult rats. Pregnant Sprague-Dawley rats were allocated into 6 experimental groups: Ctrl (vehicle), T1 (20 μg/kg/d PM), T2 (200 mg/kg/d PM), T3 (NPs: 1.0 mg/kg/d), T4 (20 μg PM + NPs), and T5 (200 mg PM + NPs). Treatments were administered orally from gestational day 10 to postnatal day (PND) 21. Male offspring were euthanized on PND120, and ventral prostate samples were collected. Histological evaluation revealed increased inflammatory foci and stromal expansion in all exposed groups (T1-T5), along with reduced luminal compartment in T1, T3, and T4 compared with controls. All treated groups showed increased total and degranulated mast cells and enhanced androgen receptor immunoreactivity. Tumor necrosis factor (Tnf) expression was increased in all exposure groups, whereas Rela gene expression was elevated in the T4 and T5 groups. Oxidative stress analysis demonstrated increased lipid peroxidation and glutathione S-transferase (GST) activity in all treated animals. Catalase (CAT) activity was reduced in T1, T3, and T5, whereas superoxide dismutase (SOD) activity increased in T3, T4, and T5. Elevated levels of reduced, oxidized, and total glutathione (GSH, GSSG, tGSH) were observed in T5. Overall, perinatal exposure to PM and NPs induced persistent inflammation and altered redox status in the prostate, increasing susceptibility to pathological disorders.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147975792","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":"Late gestational exposure to flutamide alters stromal composition and immune landscape in the rat mammary gland during pre-puberty, peri-puberty, and adulthood.","authors":"David Tovar Parra, Alec McDermott, Jysiane Cardot, Melany Nicole Juarez, Fabien Joao, Rhizlane El Omri-Charai, Line Berthiaume, Bhawna Dhawan, Arash Aghigh, Yann Breton, François Légaré, Géraldine Delbès, Martin Pelletier, Étienne Audet-Walsh, Isabelle Plante","doi":"10.1093/toxsci/kfag053","DOIUrl":"10.1093/toxsci/kfag053","url":null,"abstract":"<p><p>Perinatal development of the mammary gland is regulated by hormonal signals that influence cell proliferation, extracellular matrix remodeling, immune cell recruitment, and intracellular signaling. Although the role of estrogen in mammary gland development is well established, the impact of androgens remains less understood. To address this gap, we inhibited androgen signaling in utero using the anti-androgen flutamide (FLU) and investigated the effects on mammary gland development in rats. Using an integrative strategy combining histology, transcriptomics, lipidomics, cytokine profiling, and high-resolution imaging, mammary tissue were analyzed at pre-puberty (postnatal days [PND] 21), peri-puberty (PND46), and adulthood (PND90). FLU exposure induced subtle, yet significant, alterations in mammary morphology and molecular signatures. At PND21, the FLU-exposed group exhibited an increased number of adipocytes with reduced size. Transcriptomic analysis revealed differentially expressed genes at PND21 and enrichment in pathways related to androgen response and immune signaling, but minimal changes at later developmental stages. Lipidomic profiling showed transient disruption in long-chain fatty acid composition at early developmental stages. Cytokine profiling revealed a reduced adaptive immune response at PND46 and PND90, and second-harmonic generation imaging demonstrated changes in collagen fiber orientation and density across all developmental stages. These data indicate that prenatal androgen signaling is essential for proper stromal development and the establishment of early transcriptional networks in the mammary gland, with only minor long-term effects on glandular architecture in adult nulliparous females.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13220753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147975743","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":"High-concentration MEHP triggers mtDNA depletion in undifferentiated HepaRG and C2C12 cultures and disrupts mitochondrial homeostasis in both HepaRG culture states.","authors":"Md Mostafijur Rahman, Pabitra Khadka, Carolyn K J Young, Jing Wang, Elizabeth M McCormick, Marni J Falk, Matthew J Young","doi":"10.1093/toxsci/kfag049","DOIUrl":"10.1093/toxsci/kfag049","url":null,"abstract":"<p><p>Phthalates are often called \"everywhere chemicals\" because they are widely used in consumer products and are detectable in the environment and humans. One of the most studied phthalates, di-2-ethylhexyl phthalate (DEHP), is metabolized to mono-(2-ethylhexyl) phthalate (MEHP), which is known to disrupt metabolic processes through peroxisome proliferator-activated receptor (PPAR) signaling. However, accumulating evidence suggests that lipophilic phthalates also affect mitochondria, key regulators of oxidative metabolism, autophagy, and apoptosis. Based on previous observations that undifferentiated cells are more sensitive to a mitotoxic agent, we hypothesized that MEHP differentially affects mitochondrial function and mitochondrial DNA (mtDNA) maintenance across hepatic cell states. To test this, we used the human HepaRG hepatoma-derived cell line, which can be cultured in undifferentiated and differentiated states, and assessed viability and mitochondrial function following prolonged 6- and 12-d high-concentration MEHP treatments. Prolonged treatments reduced viability and altered bioenergetics in both states. Short treatments (1 to 3 d) reduced viability only in differentiated cultures and were associated with mtDNA depletion in undifferentiated cultures. In both states, MEHP increased the expression of the low-molecular-weight mitochondrial genome maintenance exonuclease (MGME1) isoform, altered the levels of autophagy-related factors, and induced apoptosis. In another mitochondrial-competent myoblast model (C2C12 cells), a high concentration of MEHP was associated with mtDNA depletion, whereas lower concentrations were associated with modest reductions in cell density without detectable mtDNA loss. These results demonstrate state-dependent mitochondrial responses to MEHP and indicate that a reduced endpoint cell density is a sensitive outcome occurring independently of, and at lower concentrations than, mtDNA depletion in undifferentiated cells.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13195206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147782029","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":"RNAseq analysis demonstrates polarization state-dependent responses to ambient particulate matter in a particle composition-specific manner.","authors":"Timothy R Smyth, Stephanie Brocke, Weidong Wu, Zhen An, Ilona Jaspers","doi":"10.1093/toxsci/kfag050","DOIUrl":"10.1093/toxsci/kfag050","url":null,"abstract":"<p><p>Macrophages are key innate immune cells which exist on a spectrum between pro-inflammatory (M1) and pro-resolutory (M2) states while retaining the ability to reprogram following exposure to new stimuli. Particulate matter (PM) exposure significantly alters macrophage function, leading to increasing respiratory infection morbidity and mortality. However, the influence of macrophage polarization on PM responses remains poorly understood. We hypothesized that human macrophages would demonstrate polarization state- and seasonality-specific responses to airborne PM collected from Xinxiang, China. CD14+CD16- monocytes were differentiated into macrophages and polarized using established methods with or without PM co-exposure followed by RNA sequencing (RNAseq). Macrophage expression profiles were primarily determined by inflammatory (M1) versus naive (M0) and alternative activation (M2), regardless of PM exposure. However, differential expression analysis using polarization state-specific reference groups uncovered distinct gene and pathway expression patterns. Directly polarized M0- > M1 macrophages exhibited the fewest unique differentially expressed genes (DEGs) but displayed similar pathway level activity to reprogrammed M2- > M1 cells. M2 macrophages showed the highest number of unique DEGs suggesting increased chemotactic pathway activity. Conversely, M0 cells exhibited greater expression of major inflammatory cytokines and chemokines. Although polarization state was the primary driver of gene and pathway responses, expression levels varied depending on PM collection dates and correlated strongly with individual PM components in M0 and M2 cells. These findings highlight the need to consider both particle seasonality and macrophage polarization state when studying PM's impact on macrophages as these factors may contribute to the negative health outcomes associated with PM exposure during respiratory infections.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13189859/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147821123","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}