Toxicology[JOURNAL]
Sun
200 papers
Toxic effects and mechanism of silver nanoparticles with different particle sizes and surface coatings in lung epithelial cells.
Jiang Z, Chen Y, Guo X … +2 more , Li K, Chen L
Toxicology · 2026 Mar · PMID 41506394 · Publisher ↗
With nanotechnology's advancement and popularity, nanosafety assessment has attracted public attention, nanosafety assessment has attracted public attention. Silver nanoparticles (AgNPs) have been extensively applied in...
With nanotechnology's advancement and popularity, nanosafety assessment has attracted public attention, nanosafety assessment has attracted public attention. Silver nanoparticles (AgNPs) have been extensively applied in people's work and life, but there is still limited knowledge of their potential toxicity to humans. Although many studies have shown that AgNPs causes physiological changes in the lung, the effects and molecular mechanisms of AgNPs on the lung are not fully understood at low-dose exposures and assessed with different physicochemical properties. To comprehensively compare the potential effects and molecular mechanisms of AgNPs with different particle sizes and surface modifications on A549 cells, three PVP-coated AgNPs with particle sizes of 20, 40, and 75 nm and Lipoic Acid (LA), mPEG, and BPEI-coated AgNPs with a particle size of 40 nm, which are referred to as PVP, PVP, PVP, LA, mPEG and BPEI were selected in this study. The methods used in this study included characterization of AgNP using transmission electron microscopy (TEM) and zeta potential, the study of cytotoxicity, oxidative stress, and subsequent damage to cell membrane integrity, apoptosis, and RNA-seq. Our findings indicated that AgNPs with different particle sizes and modifications had different toxicological effects, and the smaller size of AgNPs exerts the stronger cytotoxicity. In addition, transcriptome sequencing and qRT-PCR analyses confirmed that the mechanisms of action of these AgNPs varied, but PVP, PVP, PVP, LA, and BPEI AgNPs could all affect A549 cells via IL-17 signaling pathway. Our research findings demonstrate the deleterious effects of different nanosilvers on lung epithelial cells and reveal related possible pathways of influence.
Development and analysis of the adverse outcome pathway network for neurotoxicity.
Hui X, Li X, Liu S … +2 more , Ying GG, Chen CE
Toxicology · 2026 Mar · PMID 41500358 · Publisher ↗
Adverse Outcome Pathways (AOPs) and their networks offer a structured framework for understanding toxicological mechanisms and supporting non-animal testing strategies. This study developed a neurotoxicity-focused AOP ne...
Adverse Outcome Pathways (AOPs) and their networks offer a structured framework for understanding toxicological mechanisms and supporting non-animal testing strategies. This study developed a neurotoxicity-focused AOP network (NT-AOPn) based on AOP-Wiki data and analyzed its topological properties using graph theory. We identified key events with high connectivity and centrality-such as oxidative stress and decreased thyroxine-and determined the two most prevalent adverse outcomes: Impairment of Learning and Memory (ILM) and Decreased Cognitive Function (CFD). Further analysis of their subnetworks revealed system-level perturbations spanning metabolic, neurological, and reproductive systems, and uncovered two novel AOP pathways linking molecular initiating events to adverse outcomes. Additionally, chemical stressors including heavy metals and pesticides were associated with these pathways. Our findings enhance the mechanistic understanding of neurotoxicity and provide a foundation for in vitro assays and computational modeling in risk assessment.
NOX4/Keap1/Nrf2/ROS signaling drives ferroptosis in trimethyltin chloride-induced cardiac developmental malformations.
Chen J, Hu H, Fu J … +7 more , He Y, Zhou H, Lei J, Huang M, Wang J, Liu A, Liu Z
Toxicology · 2026 Mar · PMID 41485541 · Publisher ↗
Trimethyltin chloride (TMT), a pervasive environmental organic tin pollutant, has been implicated in cardiac injury, though its underlying mechanisms remain unclear. TMT exposure triggers excessive reactive oxygen specie...
Trimethyltin chloride (TMT), a pervasive environmental organic tin pollutant, has been implicated in cardiac injury, though its underlying mechanisms remain unclear. TMT exposure triggers excessive reactive oxygen species (ROS) generation, a key inducer of ferroptosis-a regulated form of cell death driven by iron-dependent lipid peroxidation. NADPH oxidase 4 (NOX4), highly expressed during cardiac development, plays a critical role in myocardial ROS production, while the Keap1/Nrf2 pathway regulates cellular ROS homeostasis. We hypothesized that TMT induces cardiac developmental defects by activating NOX4/Keap1/ROS-mediated ferroptosis. TMT exposure induced cardiac malformations, pericardial edema, and reduced heart rate in zebrafish embryos. Further studies revealed that TMT upregulated nox4 expression in embryonic hearts. Notably, pharmacological inhibition or genetic knockdown of nox4 markedly attenuated TMT-induced cardiac defects. Moreover, nox4 suppression antagonized TMT-triggered dysregulation of the Keap1/Nrf2 axis, ROS overaccumulation, mitochondrial damage, and ferroptosis-related abnormalities-including Fe²⁺ accumulation, elevated lipid peroxidation, and downregulated glutathione peroxidase 4 (GPX4) expression. Crucially, inhibition or knockdown of keap1 similarly mitigated TMT-induced ROS bursts, mitochondrial injury, and ferroptosis progression. Intervention with ferroptosis-specific inhibitors (Liproxstatin-1 and Myricetin) confirmed that ferroptosis directly contributes to TMT-induced cardiac developmental defects. This study demonstrates that TMT induces cardiac malformations by activating ferroptosis via the nox4/Keap1/Nrf2/ROS signaling axis. These findings reveal a novel mechanism underlying TMT cardiotoxicity, provide theoretical insights for assessing TMT exposure as a risk factor for congenital heart disease, and identify potential molecular targets for therapeutic intervention.
Bisphenol AP promotes pulmonary fibrosis by regulating macrophage function in a bleomycin-induced mouse model.
Chen Z, Lin Z, Ni M … +11 more , Li B, Zhang Q, Cao Z, Li W, Tang Y, Yao D, Cheng C, Hu Y, Liu X, Zhao J, Liu Z
Toxicology · 2026 Mar · PMID 41485540 · Publisher ↗
Bisphenols are extensively used in industrial and consumer products and may pose potential risks to human health. Previous studies have shown that bisphenol A (BPA) induces chronic inflammation and lung toxicity. Bisphen...
Bisphenols are extensively used in industrial and consumer products and may pose potential risks to human health. Previous studies have shown that bisphenol A (BPA) induces chronic inflammation and lung toxicity. Bisphenol AP (BPAP), a structural analogue of BPA, has also been associated with adverse health outcomes, including metabolic disorders and mood disturbances. However, its role in pulmonary diseases remains poorly characterized. In this study, a bleomycin (BLM)-induced pulmonary fibrosis (PF) model in C57BL/6 mice was employed to investigate the effects of BPAP on pulmonary pathology. Although BPAP exposure alone did not induce PF-related pathological changes, pretreatment with BPAP (0.4 mg/kg/day) initiated 14 days before BLM administration significantly aggravated BLM-induced histopathological alterations, inflammation, and collagen deposition. This exacerbation of fibrosis was accompanied by a marked upregulation of the M2 macrophage marker arginase-1. Further in vitro assays showed that 24-hour BPAP exposure inhibited macrophage proliferation, increased oxidative stress, and enhanced both phagocytic and chemotactic activities in the RAW 264.7 mouse macrophage cell line. Mechanistic analyses revealed that BPAP modulated several key molecules involved in cell cycle regulation, phagocytosis, and chemotaxis, specifically Ttk, Fcgr1, and Ccl5. These findings indicate that BPAP exacerbates BLM-induced PF by dysregulating macrophage function. This study provides new insights into the pulmonary toxicity of BPAP and underscores the potential health risks associated with its exposure.
In vivo high-throughput toxicity screening of brominated flame retardants using a Caenorhabditis elegans transcription factor RNAi platform.
Ahn S, Dufourcq Sekatcheff E, Choi J
Toxicology · 2026 Mar · PMID 41483840 · Publisher ↗
Brominated flame retardants (BFRs) such as tetrabromobisphenol A (TBBPA), hexabromocyclododecane (HBCDD), and decabromodiphenyl ethane (DBDPE) are extensively used in a variety of consumer products, including electronics...
Brominated flame retardants (BFRs) such as tetrabromobisphenol A (TBBPA), hexabromocyclododecane (HBCDD), and decabromodiphenyl ethane (DBDPE) are extensively used in a variety of consumer products, including electronics, textiles, and furniture. However, their environmental persistence and potential for neurodevelopmental toxicity have raised increasing concern. Legacy compounds such as TBBPA and HBCDD are undergoing regulation or being phased out, while alternatives like DBDPE remain poorly characterized, leaving uncertainties regarding their suitability as replacements. In order to rapidly fill knowledge gaps on these data poor substances and avoid regrettable substitutions, we established a high-throughput, mechanism-based in vivo toxicity screening platform. A RNAi approach on Caenorhabditis elegans Transcription Factors (TF) was used to assess biological pathways that were triggered by BFR exposure, leading to neurotoxicity (assessed via locomotion behavior). Using a 384-TF RNAi library, we identified 44 TFs modulating TBBPA-induced neurotoxicity. Pathway analyses (Reactome and CTD) highlighted retinoic acid receptor signaling as a key event, which mapped to four neurodevelopmental AOPs (AOP 520, 523, 532, and 533). Gene expression analysis of sex-1 and unc-55 confirmed retinoic acid signaling pathway activation. Application of the same framework to HBCDD and DBDPE revealed partially conserved behavioral and molecular responses, supporting the cross-chemical applicability of the TBBPA-derived AOP network. These findings demonstrate the utility of C. elegans-based TF RNAi screening as a fit-for-purpose New Approach Methodology (NAM) for mechanistic toxicology. By linking molecular initiating events to adverse outcomes, this strategy enables early hazard identification and read across strategy via AOP-informed, animal-free chemical risk assessment within next-generation risk assessment (NGRA) frameworks.
Bisphenol TMC exhibits greater estrogenic activity than Bisphenol A and three other structural analogues exemplified by higher estrogen receptor α-mediated gene expression and breast cancer cell proliferation.
Joos FL, van Diest RE, Smieško M … +4 more , Jäger MC, Kley M, Odermatt A, Bouitbir J
Toxicology · 2026 Mar · PMID 41482203 · Publisher ↗
Bisphenol A (BPA) and its structural analogues are widely used in plastics production, raising concern due to endocrine-disrupting properties. While many analogues share structural similarities with BPA, their endocrine-...
Bisphenol A (BPA) and its structural analogues are widely used in plastics production, raising concern due to endocrine-disrupting properties. While many analogues share structural similarities with BPA, their endocrine-disrupting effects remain insufficiently characterized. Cyclo-di-bisphenol A diglycidyl ether (cyclo-di-BADGE), tetrabromobisphenol S (TBBPS), bisphenol SIP (BPSIP), and bisphenol TMC (BPTMC) are particularly understudied. We assessed the estrogenic activity of these four BPA analogues compared to BPA. Transactivation assays in HEK-293 cells expressing estrogen receptor alpha (ERα) revealed that BPTMC was a more potent ERα agonist than BPA, with an EC of 87 ± 20 nM versus 400 ± 100 nM for BPA, while the other tested analogues showed no significant agonistic activity. In silico analysis attributed this higher affinity to greater hydrophobicity and a bulkier bridging group between its phenolic rings. None of the compounds inhibited 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) activity. However, BPTMC selectively inhibited 17β-HSD2 (IC = 4.8 ± 0.6 µM) but not BPA. Importantly, 24 h exposure of ERα-positive MCF-7 breast cancer cells to 1 µM BPTMC upregulated the expression of the ERα target genes GREB1, TFF1, and PGR, comparable to 10 nM E2, which was abolished by 100 nM of the ERα antagonist fulvestrant. Moreover, BPTMC stimulated MCF-7 cell proliferation at nanomolar concentrations over 72 h, and cell count analyses confirmed this effect. BPA also increased cell numbers, and both effects were reversed by fulvestrant. Collectively, we identified BPTMC as a potent ERα agonist capable of eliciting transcriptional and mitogenic responses at low concentrations, raising concerns about its endocrine-disrupting and breast cancer-promoting effects.
Mechanistic insights into TDCPP-induced DNA damage in GT1-7 cells.
Lei B, Li J, Yang Y … +6 more , Lu X, Liu T, Li N, Li Y, Li X, Feng C
Toxicology · 2026 Mar · PMID 41482202 · Publisher ↗
As a typical organophosphate ester compound, tris(1,3-dichloro-2-propyl) phosphate (TDCPP) exhibits both estrogenic activity and genotoxicity. However, the involvement of estrogen signaling pathways in TDCPP-induced geno...
As a typical organophosphate ester compound, tris(1,3-dichloro-2-propyl) phosphate (TDCPP) exhibits both estrogenic activity and genotoxicity. However, the involvement of estrogen signaling pathways in TDCPP-induced genotoxicity remains unclear. This study evaluated the effects of TDCPP (0.001-200 μM) on DNA damage and repair-related endpoints in GT1-7 mouse hypothalamic cells, and examined the roles of estrogen nuclear receptors (ERα/β) and G protein-coupled estrogen membrane receptor 1 (GPER1), as well as their downstream ERK1/2 and AKT signaling pathways, in TDCPP-induced DNA damage. Our results showed that TDCPP exposure elevated intracellular levels of reactive oxygen species (ROS) and malondialdehyde (MDA), induced DNA damage and G2/M cell cycle arrest, and increased mitochondrial damage and micronucleus formation. In addition, TDCPP significantly increased the protein expression of ATM and γ-H2AX, key markers of DNA double-strand breaks (DSBs), and upregulated the mRNA expression of most DSB repair-related genes, while downregulated mRNA expression of most DNA single-strand break (SSB) repair-related genes. TDCPP also upregulated both protein and gene expression of GPER1 and enhanced ERK1/2 phosphorylation. Pretreatment with the GPER1 inhibitor G15 or the ERK1/2 inhibitor U0126 significantly suppressed TDCPP-induced upregulation of ATM and γ-H2AX protein expression, reversed changes in mRNA levels of DSB/SSB repair-related genes, and reduced TDCPP-induced DNA damage in GT1-7 cells. These findings indicate that TDCPP activates the GPER1-ERK1/2 signaling pathway, which plays a critical role in mediating its DNA-damaging effects. CAPSULE: TDCPP induced DNA damage in GT1-7 cells by activating GPER1-ERK1/2 signaling pathway.
Maternal exposure to polypropylene nanoplastics disrupts sex- and region-specific lipid metabolism in the brains of C57BL/6N mouse offspring.
Lee J, Park S, Lee DY … +1 more , Cho SH
Toxicology · 2026 Mar · PMID 41482201 · Publisher ↗
Polypropylene nanoplastics (PPNPs), produced through the degradation of widely used plastic products, are increasingly recognized as emerging environmental contaminants with potential neurodevelopmental toxicity. However...
Polypropylene nanoplastics (PPNPs), produced through the degradation of widely used plastic products, are increasingly recognized as emerging environmental contaminants with potential neurodevelopmental toxicity. However, the long-term biochemical consequences of prenatal PPNP exposure on brain development remain poorly understood. In this study, we performed a region- and sex-specific targeted lipidomic analysis to examine how maternal oral exposure to PPNPs during pregnancy and lactation alters brain lipid composition in offspring at postnatal day 21. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we profiled lipid classes in the hippocampus (HP), cortex (CTX), cerebellum (CB), and dorsal raphe nucleus (DR) of both male and female mice. Our findings revealed distinct, region-specific lipid remodeling patterns in response to PPNP exposure. Females exhibited consistent reductions in neuroprotective lipids, including lysophosphatidylethanolamines (LPEs) and plasmalogens, most prominently in the hippocampus. Males, in contrast, displayed elevated triglyceride levels and region-specific alterations in phospholipid composition, such as reduced phosphatidylcholines in the hippocampus and dorsal raphe. These results indicate that maternal nanoplastic exposure, even without postnatal contact, can cause persistent, sex-specific disturbances in brain lipid metabolism. To our knowledge, this study provides the first targeted lipidomic characterization of offspring brains following maternal PPNP exposure and highlights the importance of brain region-specific lipid analysis for identifying localized disruptions in neurodevelopment caused by environmental pollutants.
Cx43 phosphorylation at Ser368 facilitates PASMC dedifferentiation in nicotine-induced pulmonary arterial remodeling.
Xu Y, Hou X, Guo S … +8 more , Zhou J, Jiang X, Zheng Z, Zhao L, Ren X, Yang L, Shi Y, Qin X
Toxicology · 2026 Mar · PMID 41478400 · Publisher ↗
BACKGROUND: Pulmonary arterial hypertension is a severe disease characterized by pulmonary vascular remodeling, which is closely associated with the phenotypic switching of pulmonary artery smooth muscle cells (PASMCs)....
BACKGROUND: Pulmonary arterial hypertension is a severe disease characterized by pulmonary vascular remodeling, which is closely associated with the phenotypic switching of pulmonary artery smooth muscle cells (PASMCs). Connexin 43 (Cx43) phosphorylation is a key regulator of intercellular communication. However, the specific mechanism underlying nicotine-induced dedifferentiation of PASMCs remains unclear. PURPOSE: This study aimed to investigate the molecular mechanism by which Cx43 phosphorylation promotes nicotine-induced phenotypic switching of PASMCs, thereby driving pulmonary vascular remodeling. METHODS: Using Tagln-Cre; Cx43 and Tagln-Cre; Cx43 deletion mice exposed to nicotine, a series of in vivo and in vitro experiments were conducted to investigate the mechanism by which nicotine promotes pulmonary arterial remodeling via protein kinase C-mediated phosphorylation of Cx43 and subsequent dedifferentiation of PASMCs. The involvement of this kinase pathway was further validated with its specific inhibitor, chelerythrine chloride. RESULTS: Nicotine increased PASMC dedifferentiation by promoting Cx43 phosphorylation at Ser368 (Cx43-pS368). In Tagln-Cre; Cx43 mice, these pathological changes were reduced. In vitro, chelerythrine chloride was utilized to inhibit nicotine-induced Cx43-pS368. This suppression of Cx43-pS368 effectively attenuated nicotine-induced PASMC dedifferentiation, thereby ameliorating pulmonary arterial remodeling. CONCLUSION: Nicotine can induce PASMC phenotypic transformation by modulating Cx43-pS368, thereby promoting pulmonary artery remodeling. Targeting this pathway could provide a therapeutic strategy for nicotine-related pulmonary vascular diseases.
Nickel refining fumes activate glutamine metabolism via the HIF-1α/Notch pathway to drive epithelial-mesenchymal transition in Beas-2B cells.
Sun QQ, Yu HN, Wu RZ … +7 more , Zhang B, Yao WX, Liu WY, Han J, Ju LY, Pan YL, Wu YH
Toxicology · 2026 Mar · PMID 41478399 · Publisher ↗
Occupational exposure to nickel refining fumes (NiRF) represents a critical risk factor for respiratory diseases; however, the molecular mechanisms governing NiRF-induced epithelial-mesenchymal transition (EMT) in bronch...
Occupational exposure to nickel refining fumes (NiRF) represents a critical risk factor for respiratory diseases; however, the molecular mechanisms governing NiRF-induced epithelial-mesenchymal transition (EMT) in bronchial epithelial cells remain incompletely elucidated. In vitro experiments using the human bronchial epithelial cell line Beas-2B as a model demonstrated that NiRF exposure robustly activated the hypoxia-inducible factor-1α (HIF-1α)/Notch signaling pathway, while concomitantly triggering glutamine metabolic reprogramming. This reprogramming phenotype was characterized by the upregulated expression of the glutamine transporter SLC1A5 and enhanced expression of glutaminase 1 (GLS1). Functional validation assays revealed that small interfering RNA (siRNA)-mediated silencing of HIF-1α (siHIF-1α) or Notch1 (siNotch1) significantly downregulated GLS1 expression, and reversed NiRF-induced glutamine metabolic activation. Furthermore, pharmacological inhibition of glutamine metabolism via treatment with a GLS1 inhibitor effectively abrogated the EMT process in Beas-2B cells, as evidenced by the upregulated expression of the epithelial marker E-cadherin and the downregulated expression of the mesenchymal markers N-cadherin and vimentin. In vivo experiments further confirmed that NiRF promoted EMT in lung tissue cells in a dose-dependent manner, accompanied by activation of the HIF-1α/Notch signaling pathway and enhanced glutamine metabolism (as reflected by the upregulated expression of both SLC1A5 and GLS1). Collectively, these findings verify that glutamine metabolic activation, mediated by the HIF-1α/Notch pathway, constitutes the core mechanism underlying NiRF-driven EMT in Beas-2B cells. This study provides novel theoretical insights and potential therapeutic targets for elucidating the pathogenesis of occupational NiRF-associated respiratory injury and developing targeted intervention strategies.
Macrophage-epithelial cells crosstalk and the role of CCL2-CCR2 axis in single-walled carbon nanotubes-induced lung inflammation and fibrosis.
Shen Y, Shi Z, Zou J … +7 more , Zhou Y, Yang Q, Zhao W, Gan Y, Hu X, Shen T, Zhang X
Toxicology · 2026 Mar · PMID 41461321 · Publisher ↗
Environmental and occupational exposure to carbon nanotube (CNT) raises concerns over their safety and adverse health impacts, especially lung inflammation and fibrosis. Immune cells and epithelial cells within alveoli i...
Environmental and occupational exposure to carbon nanotube (CNT) raises concerns over their safety and adverse health impacts, especially lung inflammation and fibrosis. Immune cells and epithelial cells within alveoli interact with each other to maintain lung homeostasis. To date, the contribution of lung macrophage-epithelial cells crosstalk to single-walled CNT (SWCNT)-caused lung injury and underlying mechanisms have not been systematically investigated. Here, we established a mice model of lung exposure to SWCNT and found that SWCNT induced M1-typed lung macrophages polarization during inflammation stage and abnormal epithelium regeneration during fibrosis stage, characterized by impaired alveolar epithelial type Ⅱ (AT2) cells to alveolar epithelial type Ⅰ (AT1) cells transition. Mechanistically, conditioned medium experiments combined with chemokines CCL2 siRNA intervene revealed that damaged lung epithelial cells-derived CCL2 by SWCNT activated CCR2 in macrophages, subsequently polarizing to M1 state. In vivo experiments further demonstrated CCL2-CCR2 axis regulated SWCNT-polarized M1 lung macrophages and pro-inflammatory cytokines secretion, which are involved in the impairment of AT2-AT1 cells transition. Importantly, inhibition of CCL2-CCR2 axis effectively restored SWCNT-induced lung inflammation and fibrosis. In conclusion, our findings elucidate the crosstalk of lung macrophages and epithelial cells, which further regulates the progression of SWCNT-induced lung injury, and target CCL2-CCR2 axis is expected to be potential therapeutic strategy for the prevention and treatment of lung injury induced by nanoparticles.
PPAR subtypes determine distinct modes of action of phthalate esters (PAEs) and per- and polyfluoroalkyl substances (PFAS) in disrupting human macrophage alternative activation.
Zhuang Z, You L, Kong J … +7 more , Tian Y, Li Y, Zhi Y, Zhang B, Wan Y, Jia X, Yang H
Toxicology · 2026 Mar · PMID 41456666 · Publisher ↗
Phthalate esters (PAEs) and per- and polyfluoroalkyl substances (PFAS) are ubiquitous pollutants tied to metabolic and immune disorders. The peroxisome proliferator-activated receptor (PPAR) pathway has been indicated to...
Phthalate esters (PAEs) and per- and polyfluoroalkyl substances (PFAS) are ubiquitous pollutants tied to metabolic and immune disorders. The peroxisome proliferator-activated receptor (PPAR) pathway has been indicated to mediate their toxic effects, but the specific functions of PPAR subtypes and their mediating roles remain unclear. In this study, we generated PPARα-, δ-, and γ-specific knockout THP-1 cell lines by using CRISPR/Cas9 system and then differentiated them into interleukin-4 (IL-4) and interleukin-13 (IL-13)-polarized macrophages (alternative activation). During the induction process, the cells were exposed to 0, 6.25, 12.5, 25, 50, 100 μM of five PAE metabolites: Mono-(2-ethylhexyl) phthalate (MEHP), Monocyclohexyl phthalate (MCHP), Monoisonyl phthalate (MINP), Monoisobutyl phthalate (MIBP), and Monobenzyl phthalate (MBzP); and five PFAS: Perfluoroundecanoic acid (PFUnDA), Perfluorodecanoic acid (PFDA), Perfluorooctanoic acid (PFOA), Potassium perfluorooctanesulfonate (PFOS-K), and Potassium 9-chlorohexadecafluoro-3-oxanonane-1-sulfonate (F53B) for 48 h. The results showed that PPARδ deletion abolished CD209 expression, confirming its essential role, whereas PPARα deletion reduced and PPARγ deletion enhanced CD209, indicating PPARα promotes and PPARγ restrains alternative activation. Compounds displayed subtype-selective actions: MEHP activated PPARα/γ; MBzP/MCHP inhibited PPARδ yet activated PPARγ; MINP activated PPARγ only. Among PFAS, PFOS-K activated PPARδ/γ; F53B inhibited PPARα; PFOA activated PPARγ; PFDA inhibited PPARα/δ. Transcriptomics revealed compound-specific enrichments-cholesterol (MEHP), fatty-acid (MCHP), glycolysis (PFOS-K), TCA cycle (PFOA)-despite common PPAR pathway engagement. In conclusion, PAEs and PFAS disrupt macrophage plasticity through distinct PPAR-subtype signatures, providing molecular landmarks for future hazard assessment of environmental pollutants.
Transcriptomic analysis of BPA alternative chemicals in primary human mammary epithelial cells.
Matteo G, Rowan-Carroll A, Bradford LM … +5 more , Meier MJ, Williams A, Christopher Corton J, Yauk CL, Atlas E
Toxicology · 2026 Mar · PMID 41429237 · Publisher ↗
Some everyday consumer products contain endocrine disruptors like bisphenol A (BPA) and its replacements. To date, most in vitro chemical screening to evaluate these compounds has been accomplished using immortalized cel...
Some everyday consumer products contain endocrine disruptors like bisphenol A (BPA) and its replacements. To date, most in vitro chemical screening to evaluate these compounds has been accomplished using immortalized cell lines, which differ significantly from human tissues. Our goal was to test BPA and select alternatives previously screened in breast cancer cells for toxicological potency and mechanism of action in human mammary epithelial cells (HMECs). HMECs from three human donors were exposed to BPA and four alternative chemicals (in concentration response format from 0.001 to 50 µM) for 48 h and global transcriptomic changes were quantified. Transcriptomic biomarker analysis was employed to explore chemically induced estrogen receptor alpha (ERα) activation and alterations in stress response pathways. Benchmark concentration (BMC) analysis was applied to gene expression data to derive transcriptomic points of departure (tPODs) to compare chemicals for potency. Pathway and upstream regulator analysis was applied among the genes fitting BMCs. All chemicals had tPODs within a single order of magnitude. Bisphenol AF (BPAF) was the most potent, followed by tetramethyl bisphenol F (TMBPF), bisphenol C (BPC), 4,4'-bisphenol S (BPS), and BPA. None of the chemicals activated the ERα biomarker. Some stress response biomarkers were activated at high exposure concentrations. Genes fitting BMCs clustered chemicals into two groups, with one group (BPAF and TMBPF) primarily inhibiting expression patterns and the other (BPC, BPS, and BPA) mostly activating. These data suggest that the BPA alternatives tested have similar toxicological potencies in HMECs and oppositely enrich various gene sets.
A scalable human liver-on-a-chip platform for predictive safety assessment.
Kulkarni G, Chen L, Sang J … +23 more , Seo JH, Grall R, Wang Y, Gilbride P, Yuan YC, Albaum-Getzen M, McCormack J, Ma J, Fanelli A, Meng L, Xu B, Huang X, Marshall T, Singh H, Qian X, Xie Z, Bai H, Si L, Ding C, Ouedraogo G, Kuang R, Xie X, Bai H
Toxicology · 2026 Mar · PMID 41422937 · Publisher ↗
Non-animal methods, including advanced in-vitro approaches such as liver-on-a-chip models, hold promise for hepatotoxicity testing but remain limited in pharmaceutical and regulatory adoption due to high costs, poor scal...
Non-animal methods, including advanced in-vitro approaches such as liver-on-a-chip models, hold promise for hepatotoxicity testing but remain limited in pharmaceutical and regulatory adoption due to high costs, poor scalability, low reproducibility, and insufficient validation. To address these challenges, we introduce a drug-induced liver injury (DILI) model based on the commercially available and highly adaptable OC-Plex microfluidic platform. Primary human hepatocytes (PHHs) maintained long-term viability and metabolic competence, confirmed by albumin and urea production as well as cytochrome P450 gene expression. The system reliably detected acetaminophen (APAP) - induced hepatotoxicity across six mechanistic readouts-albumin, viability, cytokeratin-18 (CK18), urea, CYP3A4 activity, and mitochondrial function. As an initial proof-of-concept, we tested 17 compounds, including both drugs and cosmetic ingredients. Among 13 compounds with known toxicity liabilities in humans, our model shows a high predictive performance (85.7 % sensitivity, 100 % specificity, and 92.3 % accuracy). Together, these findings demonstrate the feasibility of a cost-effective, scalable, and human-relevant liver-on-a-chip system for predictive hepatotoxicity testing. With future development and validation, this model holds great potential to replace animal testing in chemical safety assessment.
PM2.5 exposure exacerbates airway pyroptosis related inflammatory response in asthmatic mice by activating NLRP3 inflammasome.
Du H, Liu Z, Ge L … +4 more , Lei Y, Wang Y, Lan J, Zhao D
Toxicology · 2026 Mar · PMID 41421518 · Publisher ↗
BACKGROUND: Fine particulate matter (PM2.5)-induced airway epithelial damage plays a pivotal role in driving the development of airway inflammation. Although pyroptosis is recognized for its highly proinflammatory nature...
BACKGROUND: Fine particulate matter (PM2.5)-induced airway epithelial damage plays a pivotal role in driving the development of airway inflammation. Although pyroptosis is recognized for its highly proinflammatory nature, its precise role in PM2.5-associated airway inflammation, particularly in asthmatic condition, remains to be fully elucidated. METHODS: In ovalbumin (OVA)-sensitized asthmatic mice, we assessed pulmonary histopathology, inflammatory cell counts and Th2 cytokine levels (IL-4, IL-5, and IL-13) in bronchoalveolar lavage fluid (BALF), airway hyperresponsiveness (AHR), and airway epithelial pyroptosis. To investigate the effects of PM2.5 on airway epithelial cells, BEAS-2B cells were exposed to PM2.5. Cell viability was evaluated using the CCK-8 assay, while pyroptosis-related protein levels and inflammatory cytokine release were analyzed by Western blot and ELISA, respectively. Additionally, transmission electron microscopy (TEM) was employed to examine PM2.5-induced ultrastructural changes in BEAS-2B cells. To further elucidate the underlying mechanism, we administered the NLRP3 inhibitor MCC950 and the Caspase-1 inhibitor Ac-YVAD-cmk to verify the involvement of NLRP3 inflammasome activation and pyroptosis in PM2.5-exposed asthmatic mice. RESULTS: PM2.5 exposure significantly aggravated airway inflammation in asthmatic mice, as demonstrated by elevated histopathological inflammatory scores in lung tissues and increased pro-inflammatory cytokine levels in BALF. Furthermore, PM2.5 upregulated the abundance of pyroptosis-related markers, namely NLRP3, Caspase-1, GSDMD, and IL-1β, in the lung tissues of asthmatic mice. In BEAS-2B cells, PM2.5 exposure led to a dose-dependent reduction in cell viability and promoted the activation of NLRP3 inflammasome, subsequently leading to Caspase-1-mediated GSDMD cleavage and IL-1β secretion. TEM further confirmed pyroptosis, revealing characteristic morphological alterations such as cytoplasmic vacuolation, mitochondrial swelling, and plasma membrane pore formation in BEAS-2B cells exposed to PM2.5. Critically, inhibition of NLRP3 (MCC950) or Caspase-1 (Ac-YVAD-cmk) markedly attenuated PM2.5-induced pyroptosis and ameliorated airway inflammation in asthmatic mice, underscoring the pivotal role of the NLRP3/Caspase-1/GSDMD axis in this pathogenic process. CONCLUSION: Our findings demonstrate that PM2.5 exposure induces airway epithelial pyroptosis through NLRP3 inflammasome activation, thereby exacerbating airway inflammation in asthmatic mice.
Evaluating the absence of allometric scaling for hepatic microsomal Phase I and Phase II xenobiotic biotransformation among mammals.
Ockhuijsen L, Ragas AMJ, Hendriks AJ
Toxicology · 2026 Mar · PMID 41421517 · Publisher ↗
Elucidating consistent patterns for xenobiotic biotransformation among mammals is challenging because of intrinsic species differences. At the organism level, pharmacokinetic rate constants are believed to scale allometr...
Elucidating consistent patterns for xenobiotic biotransformation among mammals is challenging because of intrinsic species differences. At the organism level, pharmacokinetic rate constants are believed to scale allometrically to body weight with a power of ¾, akin to metabolic rate constants, but the mechanism for biotransformation scaling is unclear. Predicting xenobiotic biotransformation through a quantitative in vitro to in vivo extrapolation (QIVIVE) approach combining allometric scaling relationships related to liver physiology and in vitro xenobiotic biotransformation could be promising. This study explores the previously unexplored potential of allometric scaling for hepatic microsomal Michaelis-Menten parameters. Hepatic microsomal Michaelis-Menten parameters, viz., affinity (K), maximum velocity (V), and in vitro clearance (CL), were examined for the xenobiotic biotransformation enzymes Cytochrome P450 (CYP) and UDP-glucuronosyl transferase (UGT). To ensure validity, data for ≥ 4 mammals per substrate biotransformation pathway were collected through a literature search and available databases. Ordinary linear regressions per pathway for each parameter showed that only a few individual regressions scaled statistically significantly to body weight. Averaging all scaling exponents of significant regressions revealed that hepatic microsomal Michaelis-Menten parameters are independent of body weight. Although not statistically significant, the average scaling exponent for each Michaelis-Menten parameter was close to 0. Therefore, differences in enzyme abundance or liver physiology between species are likely contributors to the observed ¾ exponent for allometric scaling relationships of in vivo xenobiotic clearance. Characterisation of underlying mechanisms at an enzyme-substrate level might ultimately improve understanding and estimation of xenobiotic clearance for mammals in QIVIVE approaches.
Neurotoxic potential of synthetic cannabinoids' pyrolysis products.
Pita F, Dinis-Oliveira RJ, Silva JP … +2 more , de Pinho PG, Carvalho F
Toxicology · 2026 Mar · PMID 41421516 · Publisher ↗
Synthetic cannabinoids (SCs) represent a prominent class of new psychoactive substances (NPS), primarily consumed via inhalation methods such as smoking or vaping. Although the direct neurotoxic effects of SCs are well e...
Synthetic cannabinoids (SCs) represent a prominent class of new psychoactive substances (NPS), primarily consumed via inhalation methods such as smoking or vaping. Although the direct neurotoxic effects of SCs are well established, the pyrolysis process that occurs during smoking induces structural alterations that generate novel, frequently unidentified toxicants with potentially severe neurobiological consequences. This review addresses the neurotoxicity associated with parent SC compounds and their pyrolysis products, with particular emphasis on mechanisms, including oxidative stress, mitochondrial dysfunction, excitotoxicity, and neuroinflammation. A PRISMA-guided systematic review identified only nine studies specifically investigating the neurotoxic effects of SC pyrolysis products, revealing a significant gap in the literature and underscoring the urgent need for targeted research in this domain. The review further highlights that additional constituents, such as plant materials incorporated into SC formulations, can contribute to the generation of harmful byproducts and complicate forensic interpretation. The structural heterogeneity of SCs, in conjunction with variables such as polydrug use and chronic exposure, further exacerbates their toxicological profile. Future research should prioritise the identification and characterisation of pyrolysis-derived toxicants, the advancement of analytical methodologies for their detection, and the implementation of evidence-based public health strategies aimed at risk mitigation.
Mixture toxicity revisited: A translational review of experimental evidence from animal models to human health risk assessment.
Domingo JL
Toxicology · 2026 Feb · PMID 41401900 · Publisher ↗
This review examines research investigating how simultaneous exposure to multiple chemicals affects biological systems, highlighting deficiencies in conventional single-substance risk evaluation frameworks. Living organi...
This review examines research investigating how simultaneous exposure to multiple chemicals affects biological systems, highlighting deficiencies in conventional single-substance risk evaluation frameworks. Living organisms in their natural habitats face continuous exposure to diverse chemical combinations, which frequently result in interactive effects, including synergism and antagonism, that diverge from the straightforward additive outcomes anticipated by traditional toxicological approaches. Research using animal and aquatic experimental models has shown that these exposures depend on numerous variables, such as the specific chemicals involved, their dose relationships, duration of contact, measured biological outcomes, and underlying mechanistic processes. This review examines fundamental methodological frameworks, particularly concentration addition (CA) and independent action (IA) models, used for predicting mixture toxicity, with most mixture effects falling within a two-fold range of additivity predictions though important deviations occur. Additional complicating factors include the timing of exposure and the specific biological traits of test species. The present review also addresses difficulties in applying findings from animal research to human populations, given differences in toxicokinetic processes and genetic makeup across species. To navigate these complexities, this review supports the adoption of mechanism-based frameworks incorporating high-throughput omics technologies, computational approaches, and standardized protocols for evaluating environmentally realistic mixtures. The review advocates for implementing tiered, cumulative risk-assessment methodologies that accurately represent real-world exposure conditions and emphasize protection of susceptible populations. This transformation is vital for advancing predictive toxicology and strengthening protections for public and environmental health. Ultimately, the review argues for moving beyond the obsolete single-substance paradigm toward comprehensive, evidence-driven approaches equipped to handle the multifaceted nature of chemical exposures. This review critically evaluates experimental animal studies in chemical mixture toxicology, emphasizing the complexities and prospects of applying animal findings to human health risk assessment. It identifies key gaps linking controlled experiments with epidemiological data and proposes research directions to advance risk evaluation and management of real-world chemical co-exposures.
Prenatal diesel exhaust exposure enhances neonatal hyperoxia-induced kidney injury via oxidative stress and lipid disruption.
Ho SY, Chang YS, Chou HC … +1 more , Chen CM
Toxicology · 2026 Feb · PMID 41397479 · Publisher ↗
Prenatal exposure to diesel exhaust particles (DEP) and postnatal oxygen therapy are both clinically relevant perinatal stressors, but their combined effects on kidney development are not well characterized. Using a rat...
Prenatal exposure to diesel exhaust particles (DEP) and postnatal oxygen therapy are both clinically relevant perinatal stressors, but their combined effects on kidney development are not well characterized. Using a rat model (Sprague Dawley, n = 10/group), pregnant dams received DEP via intranasal instillation (500 μg/day in PBS, gestational day 16-21; NIST SRM 2975), and offspring were maintained in either room air or 85 % oxygen chambers from birth through postnatal day 14. At postnatal day 14, kidneys were analyzed by histology, Western blot, ELISA, and LC-MS metabolomics. Offspring that received both prenatal DEP and postnatal oxygen showed more severe tubular injury across sexes, and higher kidney-to-body weight ratios that were driven primarily by significant increases in male offspring, whereas changes in females did not reach statistical significance. Kidney injury molecule-1 (KIM-1) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels were increased, and 8-OHdG showed a significant interaction between DEP and oxygen exposure. Interleukin-1 (IL-1), IL-6, and tumor necrosis factor-α (TNF-α) were elevated by both DEP and oxygen, indicating additive effects. Serum cystatin C, a marker of renal dysfunction, was also increased in all exposed groups and was highest in the dual-exposure group. Cystatin C levels showed strong positive correlations with renal levels of IL-1, IL-6, and TNF-α. Untargeted metabolomics revealed changes in glycerophospholipid metabolism that were specific to the group exposed to both DEP and oxygen. These results suggest that prenatal DEP exposure may increase renal sensitivity to postnatal oxidative stress, pointing to a time-sensitive window of vulnerability during early kidney development.
Food-borne polystyrene microplastic exposure exacerbates cognitive deficiency via enhanced neuronal synaptic damage and neuroinflammation in Alzheimer's disease.
Liu C, Zhao Y, Dao JJ … +8 more , Ma YK, Liu J, Qiao CM, Cui C, Shen YQ, Chen SX, Yu L, Zhao WJ
Toxicology · 2026 Feb · PMID 41391557 · Publisher ↗
The impact of polystyrene microplastics (PS-MPs) on the nervous system has been documented, yet the potential role of PS-MPs exposure in exacerbating neuronal damage and neuroinflammation in Alzheimer's disease (AD) rema...
The impact of polystyrene microplastics (PS-MPs) on the nervous system has been documented, yet the potential role of PS-MPs exposure in exacerbating neuronal damage and neuroinflammation in Alzheimer's disease (AD) remains unclear. Our research demonstrated that oral exposure to PS-MPs caused hippocampal mitochondrial damage in APP/PS1 mice, reduced expression of hippocampal mitochondrial and synapse-associated proteins, inhibited ErbB4 signaling pathway, and damaged hippocampal neurons. Additionally, PS-MPs exposure induced overactivation of astrocytes and microglia with NLRP3 pathway activation, increased β-amyloid (Aβ) deposition, and ultimately worsened cognitive dysfunction in APP/PS1 mice. Subsequent in vitro findings showed that PS-MPs exacerbated hippocampal neuronal damage under Aβ pathology, suppressed ErbB4 signaling pathway, and disrupted mitochondrial and synaptic function. The compromised hippocampal neurons enhanced microglial NLRP3 pathway activation. These results suggest that exposure to PS-MPs induces hippocampal neuronal damage, impairs mitochondrial and synaptic function, and exacerbates neuroinflammation and cognitive deficits, ultimately contributing to AD progression. Collectively, these findings enhance our understanding of the mechanisms by which MPs expedite the progression and influence management of AD.
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