Toxicology[JOURNAL]
Sun
200 papers
Evaluation of 2,2'-Dimorpholinodiethyl Ether (DMDEE) in Pathology, Perinatal, and Genotoxicity Studies.
Frawley R, Smith-Roe SL, Cunny H … +6 more , Cora MC, Stinson K, Xie G, Waidyanatha S, McIntyre B, Cimon K
Toxicology · 2026 Jul · PMID 42398847 · Publisher ↗
2,2'-Dimorpholinodiethyl ether (DMDEE) is a tertiary amine catalyst used in the production of polyurethane foams. Human exposure may occur occupationally through inhalation of DMDEE vapors. B6C3F1/N mice (5-6 weeks old)...
2,2'-Dimorpholinodiethyl ether (DMDEE) is a tertiary amine catalyst used in the production of polyurethane foams. Human exposure may occur occupationally through inhalation of DMDEE vapors. B6C3F1/N mice (5-6 weeks old) were exposed to 0-1000mg DMDEE/kg in water by oral gavage daily for 4 weeks. Time-mated Harlan Sprague Dawley (HSD) rats (12-14 weeks old) were exposed to 0-500mg DMDEE/kg in water from gestation day (GD) 6 through post-natal day (PND) 27 by oral gavage; their pups were directly dosed from PND12 through PND27. Blood was collected from mice (4-weeks), rat dams (GD18, PND4, PND28) and rat pups (PND 4, PND 28) for hematology, clinical chemistry, and micronucleus evaluation; mouse tissues were analyzed for histopathology. DMDEE (500-6000 μg/plate) was evaluated for mutagenicity using Salmonella typhimurium (TA98, TA100) or Escherichia coli WP2 uvrA pKM101. No DMDEE-related effects were observed on pregnancy or litter parameters in HSD rats. The mouse and rat micronucleus tests and the bacterial reverse mutation tests were negative. At 1000mg DMDEE/kg, behavioral observations of circling, repetitive head lifting, and abnormal gait were accompanied by cytoplasmic vacuolization in epithelial cells of the brain choroid plexus, and in the renal cortical tubules in male and female mice. Cytoplasmic vacuolization was also observed in the epithelial cells in the coagulating gland, prostate, and epididymis of male mice. These data indicate deficits in the cellular structure and function of neurological and renal tissues in male and female mice, as well as male reproductive tissues at higher doses and suggest caution in the industrial use of DMDEE.
Retraction notice to "Involvement of both intrinsic and extrinsic pathways in hepatoprotection of arjunolic acid against cadmium induced acute damage in vitro" [Toxicology 283 (2011) 129-139].
Pal S, Pal PB, Das J … +1 more , Sil PC
Toxicology · 2026 Jun · PMID 42379985 · Publisher ↗
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Crystalline silica particles exposure modulated miRNA expression profiles in human macrophage-like THP-1 cells.
Kummari E, Lindeman B, Nygaard UC … +5 more , Helle-Valle T, Ghosh M, Hoet PHM, Dirven H, Duale N
Toxicology · 2026 Jun · PMID 42379284 · Publisher ↗
Occupational and environmental exposure to crystalline silica particles is a major global health concern linked to silicosis, pulmonary fibrosis, autoimmune disease, and lung cancer. MicroRNAs (miRNAs) regulate gene expr...
Occupational and environmental exposure to crystalline silica particles is a major global health concern linked to silicosis, pulmonary fibrosis, autoimmune disease, and lung cancer. MicroRNAs (miRNAs) regulate gene expression post-transcriptionally and are emerging as potential effect biomarkers of exposure in human biomonitoring studies. To identify intracellular and extracellular miRNAs responses to silica-particle exposure in human THP-1 derived macrophages, differentiated THP-1 derived macrophages were exposed to 0-300µg/mL crystalline silica particles for 24hours. Cytotoxicity was assessed via LDH release assays. Expression profiles of 24 selected miRNAs were evaluated in intracellular and extracellular compartments, i.e., in cell-suspension and in their conditioned culturing media (secreted exosomes). Significant miRNAs were identified using fold change > ±1.5 and adjusted p < 0.05 (BH method), followed by functional enrichment and correlation analyses. Silica exposure induced dose-dependent cytotoxicity up to 200µg/ml. Nine intracellular miRNAs (miR-132-5p, miR-1-3p, miR-146a-5p, miR-146b-3p, miR-146b-5p, miR-148a-3p, miR-181a-3p, miR-181c-3p, miR-193a-3p) were significantly modulated; five of these (miR-132-5p, miR-1-3p, miR-146a-5p, miR-148a-3p, miR-193a-3p) were also changed in the secreted exosomes. These five miRNAs showed often non-linear dose-response expression patterns, with bell-shaped or U-shaped trends. Functional enrichment analysis linked these miRNAs to immune activation, inflammatory signalling, and fibrotic pathways, and diseases including silicosis, pulmonary fibrosis, and metabolic disorders. Correlation analyses revealed co-regulation within intracellular and extracellular compartments, with selective miRNA export suggested for miR-193a-3p. In this macrophage model, silica exposure modulates miRNA expression in a non-linear dose-dependent and compartment-specific manner, highlighting intracellular and extracellular miRNAs as potential mechanistic mediators and biomarkers of exposure.
Sex-specific cellular and molecular mechanisms of PFAS-induced reproductive toxicity.
Bhagwan AS, Gowtham A, Kumar D … +1 more , Kaundal RK
Toxicology · 2026 Jun · PMID 42379283 · Publisher ↗
Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants widely detected in water, food, consumer products, and household dust, resulting in ongoing human exposure and bioaccumulation. Accumul...
Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants widely detected in water, food, consumer products, and household dust, resulting in ongoing human exposure and bioaccumulation. Accumulating evidence increasingly implicates PFAS in reproductive dysfunction. Although PFAS-associated reproductive toxicity has been widely reviewed, critical knowledge gaps persist regarding the sex-specific cellular and molecular mechanisms mediating these effects and the reproductive toxicity of emerging replacement PFAS. Increasing epidemiological, in vivo, and in vitro evidence indicates that PFAS disrupt reproductive health through multiple mechanisms common to both sexes, including oxidative stress, mitochondrial dysfunction, endocrine perturbation, inflammation, epigenetic modifications, and dysregulation of cell survival pathways. However, emerging data reveal sex-specific differences in susceptibility and molecular responses. In males, PFAS specifically disrupt steroidogenesis, the blood-testis barrier (BTB), induce germ cell apoptosis, and impair spermatogenesis, leading to reduced sperm quality and fertility. In females, PFAS exposure perturbs ovarian homeostasis by impairing folliculogenesis, oocyte maturation, steroid hormone biosynthesis, and granulosa/cumulus cell function, thereby contributing to diminished ovarian reserve and reproductive dysfunction. Distinct alterations in hormone signaling, lipid metabolism, nuclear receptor activation, and epigenetic regulation mediate these sex-specific effects. Beyond gonadal toxicity, PFAS exposure during pregnancy disrupts placental development and endocrine signaling, contributing to placental dysfunction, adverse pregnancy outcomes, and developmental programming associated with metabolic, neurodevelopmental, and immune abnormalities in offspring. This review presents current epidemiological and mechanistic evidence to delineate shared and sex-specific pathways underlying reproductive toxicity induced by both legacy and emerging PFAS. The findings provide an updated perspective on PFAS-induced reproductive toxicity and have implications for future risk assessment and targeted interventions.
Neurotoxicity and mechanisms of deltamethrin and its metabolite 3-PBA in HT22 cells.
Liang Y, Shi T, Zhang R … +6 more , Mao G, Feng W, Li Q, Chen Y, Chen N, Wu X
Toxicology · 2026 Jun · PMID 42379282 · Publisher ↗
Deltamethrin (DLM) along with its main metabolite 3-phenoxybenzoic acid (3-PBA) are increasingly detected in environmental media. They both have the ability to accumulate on human by food chains with potential neurotoxic...
Deltamethrin (DLM) along with its main metabolite 3-phenoxybenzoic acid (3-PBA) are increasingly detected in environmental media. They both have the ability to accumulate on human by food chains with potential neurotoxicity. However, at present, there are relatively few studies on the neurotoxic effects of DLM and 3-PBA. This study investigated the neurotoxicity and mechanism in HT22 hippocampal neurons by DLM (5, 25, 50, 100, and 150 μM) and 3-PBA (100, 500, 1000, 1500, and 2000 μM). Cytotoxicity assays revealed that both DLM and 3-PBA dose-dependently inhibited HT22 cell viability. Notably, DLM exhibited higher potency than 3-PBA, as evidenced by its lower IC value. Enzyme-linked immunoassay showed that exposure to DLM and 3-PBA interfered with the secretion of neurotransmitters (Ach, DA, GABA) and disrupted the transmission of signaling molecules (NO). Biochemical analysis revealed that both compounds reduced intracellular antioxidants (SOD and GSH-Px), and surged ROS production. This oxidative imbalance led to mitochondrial dysfunction and subsequent apoptosis. Oxidative damage mechanism study showed that DLM and 3-PBA exposure reduced the expression levels of Nrf2, HO-1, and AKT proteins, as well as the transcription of Nrf2, HO-1, and Akt genes in the Nrf2/HO-1 antioxidant pathway, reducing the antioxidant capacity of HT22 cells. Apoptotic mechanism showed that DLM and 3-PBA reduced the expression levels of Bcl-2, Bcl-xL proteins and genes. They also increased the expression levels of JNK, BAX, Cyto c, Caspase-9 proteins, alongside the upregulation of JNK, BAX, Cyto c, and Caspase-9 genes in the endogenous apoptotic signaling pathway. Meanwhile, DLM and 3-PBA exposure also increased the expression levels of FasL, FADD, Caspase-8, Caspase-3 proteins, as well as FasL, FADD, Caspase-8, and Caspase-3 genes in the exogenous apoptotic signaling pathway, thereby inducing apoptosis. These findings highlight the potential neurotoxicity and molecular mechanisms of DLM and 3-PBA, emphasizing the need for further research to assess and mitigate the health risks associated with pesticide exposure.
Polystyrene nanoplastics impair epithelial barrier establishment and modulate extracellular vesicle release in human bronchial cells cultured at the air-liquid interface.
Milillo C, Bruno A, D'Ascanio F … +11 more , Gatta M, Battistelli M, Burattini S, Di Carlo P, Parrón-Ballesteros J, Niccolai E, Dovizio M, Lanuti P, Batanero E, Amedei A, Ballerini P
Toxicology · 2026 Jun · PMID 42349742 · Publisher ↗
The growing production of plastics has led to widespread environmental contamination by micro- and nanoplastics (MNPLs), raising increasing concern about their potential impact on human respiratory health. Among them, na...
The growing production of plastics has led to widespread environmental contamination by micro- and nanoplastics (MNPLs), raising increasing concern about their potential impact on human respiratory health. Among them, nanoplastics (NPs) can penetrate deeply into the lungs. However, their impact on human bronchial epithelial cells remains poorly characterized. Here, we assessed the effects of 40 nm polystyrene (PS)-NPs on human bronchial Calu-3 cells cultured at the air-liquid interface (ALI) during early epithelial establishment, a three-dimensional model representing a functionally immature or compromised airway epithelial barrier. Chronic exposure (120 h) to PS-NPs (12 and 120 µg/cm²) interfered with barrier establishment in a concentration- and time-dependent manner, as demonstrated by reduced transepithelial electrical resistance (TEER) and decreased expression of the junctional proteins E-cadherin and Zonula Occludens-1 (ZO-1). PS-NPs also promoted the release of multiple inflammatory mediators, with osteopontin (OPN), a recognized biomarker of air pollution exposure, together with IL-2 and IL-10, showing the most consistent increases across both epithelial compartments. Other cytokines displayed concentration- and compartment-dependent secretion patterns. This polarized secretion pattern suggests selective activation of epithelial signaling pathways and paracrine communication toward the submucosal milieu. Furthermore, PS-NPs were internalized by Calu-3 cells and packaged into extracellular vesicles (EVs), a process that may limit acute cellular damage while potentially enabling propagation of NP-induced signals. Overall, these findings indicate that PS-NP exposure perturbs epithelial barrier function and polarized intercellular communication under conditions mimicking a compromised airway epithelium, suggesting a mechanistic role for NPs as aggravating factors of pre-existing epithelial dysfunction.
Effects of HFPO-DA (GenX) exposure on placental glycolysis and metabolic microenvironment in pregnant rats.
Pang Y, Wang Z, Liu Y … +7 more , Feng C, Song Y, Cao S, Wang D, Zhang L, Lu P, Yu L
Toxicology · 2026 Jun · PMID 42336261 · Publisher ↗
Hexafluoropropylene oxide dimer acid (HFPO-DA; GenX) is an environmentally persistent per- and polyfluoroalkyl substance (PFAS) alternative whose placental toxicity remains poorly understood. Pregnant Sprague-Dawley rats...
Hexafluoropropylene oxide dimer acid (HFPO-DA; GenX) is an environmentally persistent per- and polyfluoroalkyl substance (PFAS) alternative whose placental toxicity remains poorly understood. Pregnant Sprague-Dawley rats (n = 20, 5 dams/group) received oral HFPO-DA at 0, 1, 10, or 100 mg/kg·day from gestational day (GD) 0-19. Placental tissues collected on GD20 were analysed by targeted metabolomics, lipidomics, histopathology, immunohistochemistry (IHC), and immunofluorescence (IF). After false discovery rate (FDR) correction, three energy metabolites were significantly altered (q < 0.05): oxaloacetate and glutamate were downregulated, while pyruvate was dose-dependently upregulated, consistent with restricted TCA cycle entry. Lipidomics identified 148 nominally significant lipid species, with elevated ceramides and long-chain fatty acids alongside reduced triglycerides, a pattern suggestive of impaired mitochondrial β-oxidation capacity. Histopathology revealed dose-dependent villous hyperplasia, trophoblast disorganization, and vascular lesions at the high dose. Protein analysis showed decreased SDHB, increased HIF-1α and PDK1, and a non-significant rise in PDHA1, collectively consistent with a shift toward Warburg-like metabolic reprogramming. These findings suggest that gestational HFPO-DA exposure may disrupt placental energy and lipid homeostasis at supra-environmental doses, identifying placental metabolism as a potentially sensitive target of next-generation PFAS.
Acute or repeated exposure of aerosolized flame retardants induces molecular and structural alterations in lung slices.
Furtuoso Rodrigues MMS, de Menezes RC, Furtado de Mendonça IC … +3 more , Meschiari CA, da Silva ACG, Valadares MC
Toxicology · 2026 Jun · PMID 42336260 · Publisher ↗
Organophosphate flame retardants (OPFRs) such as tributyl phosphate (TBP) are widely used industrial additives increasingly detected in the environment and human tissues, yet their inhalation toxicity remains poorly char...
Organophosphate flame retardants (OPFRs) such as tributyl phosphate (TBP) are widely used industrial additives increasingly detected in the environment and human tissues, yet their inhalation toxicity remains poorly characterized. In this study, we employed the ex vivo porcine precision-cut lung slice (pPCLS) model to investigate the cytotoxic, oxidative stress, and structural effects of aerosolized TBP under both acute and repeated exposure conditions. Using the Vitrocell®, pPCLS were exposed to TBP aerosols at deposited surface concentrations (µg/cm²) within ranges commonly applied in ALI-based inhalation toxicology models and selected to simulate cumulative low-dose exposure scenarios reported for organophosphate flame retardants in indoor environments. Acute exposure (24 h) caused a reduction in tissue viability, increased reactive oxygen species (ROS) production, and enhanced caspase-3 activation, indicating mitochondrial stress and apoptosis induction. There is a potential tendency for markers (K-RAS, p53, and MMP-15) to increase. Histological analyses revealed disruption of extracellular matrix architecture. Repeated low-dose exposure (5 × 24 h) led to progressive tissue disorganization and early signs of fibrogenic remodeling, evidenced by increased collagen deposition, p53 expression, reduced tissue viability, and sustained oxidative stress. These findings suggest that cumulative subcytotoxic exposure to aerosolized TBP can initiate pathways associated with chronic pulmonary injury. The pPCLS model demonstrated high reproducibility, preserved lung architecture, and responsiveness to chemical insult, reinforcing its translational relevance for respiratory toxicology. Overall, our results provide mechanistic insight into TBP-induced lung toxicity and highlight precision-cut lung slices as a useful model for evaluating inhalation hazards of industrial chemicals.
Perfluorooctanoic acid induces mitochondrial dysfunction-driven apoptosis and PINK1/Parkin-mediated mitophagy in testicular cells.
Yilmaz BO, Aydin Y
Toxicology · 2026 Jun · PMID 42336259 · Publisher ↗
Per- and polyfluoroalkyl substances (PFAS) have become an important focus of research in recent years due to their widespread use and environmental persistence. Perfluorooctanoic acid (PFOA) has attracted considerable at...
Per- and polyfluoroalkyl substances (PFAS) have become an important focus of research in recent years due to their widespread use and environmental persistence. Perfluorooctanoic acid (PFOA) has attracted considerable attention due to its effects on the reproductive system, yet its molecular mechanisms in testicular cells remain unclear. This study aimed to investigate the effects of PFOA on oxidative stress, mitochondrial function, and interconnected programmed cell death pathways. Mouse Sertoli (TM4) and spermatogonial (GC-1) cells were exposed to PFOA at concentrations of 200-800 µM for 24 h, and its effects on cell viability and cytotoxicity were evaluated. Oxidative stress levels were determined by measuring reactive oxygen species production, malondialdehyde levels, antioxidant enzyme activities, and mitochondrial membrane potential. In addition, the potential cell death pathways, including apoptosis, autophagy, mitophagy, and ferroptosis, were assessed by analyzing gene and protein expression using RT-qPCR and Western blot. PFOA exposure resulted in a concentration-dependent and significant increase in intracellular ROS levels, accompanied by a significant decrease in mitochondrial membrane potential in both cell lines. The antioxidant defense system and NRF2 signaling were markedly suppressed. PFOA exposure also significantly activated intrinsic apoptotic pathways, as supported by increased apoptotic gene expression and elevated caspase-3 protein levels. A clear increase in autophagy- and mitophagy-related markers was observed, suggesting that cells develop an adaptive response to mitochondrial damage. These findings provide important mechanistic insights into mitochondrial dysfunction and associated cell death processes in PFOA-exposed testicular cells.
Cytotoxicity of silica micro/nano particles with amine surface modifications to 6-3 murine microglial cell line.
Ono K, Koide K, Roy DC … +2 more , Fukamachi K, Suzui M
Toxicology · 2026 Jun · PMID 42320586 · Publisher ↗
Silica nanoparticles (SiNPs) are widely used in biomedical applications, yet their neurotoxicity and underlying mechanisms remain vaguely understood. Microglia, the resident immune cells of the brain, play a central role...
Silica nanoparticles (SiNPs) are widely used in biomedical applications, yet their neurotoxicity and underlying mechanisms remain vaguely understood. Microglia, the resident immune cells of the brain, play a central role in responding to exogenous particles, making them an important target for nanoparticle safety assessment. Here, we investigated the uptake and cytotoxicity of silica particles with distinct sizes and surface properties, including 3 μm-plain, 50 nm-plain, and 50 nm-NH₂, using 6-3 microglial cells derived from mouse neonates. All particle types were internalized, but only 50 nm-plain SiNPs induced severe cytotoxicity, killing approximately 80% of cells. Mechanistically, these nanoparticles entered microglia mainly through clathrin-mediated endocytosis, which triggered lysosomal swelling, lysosomal membrane permeabilization (LMP), and cathepsin-dependent cell death. In contrast, 3 μm-plain particles were incorporated via phagocytosis without overt toxicity, and 50 nm-NH₂ particles maintained viability comparable to untreated controls, with no detectable cytotoxicity. Notably, inhibition of clathrin-mediated endocytosis or cathepsin activity significantly attenuated cell death, underscoring lysosomal dysfunction as a pivotal event in SiNP-induced microglial toxicity. These findings identify lysosomal membrane destabilization as a key mechanism of SiNP-induced microglial cytotoxicity and suggest that amino surface modification may represent a useful strategy for designing safer neurocompatible SiNPs. Our results provide critical insights into nanoparticle-microglia interactions, with implications for the safe design of silica-based nanomaterials for targeted delivery of therapeutic drugs into the brain.
Adverse interactions of plastic nanoparticles with cultured primary microglial cells.
Adamiak K, Struzynska L
Toxicology · 2026 Jun · PMID 42288309 · Publisher ↗
Due to ever-increasing production, plastics have become ubiquitous in the environment, with polystyrene (PS) being one of the most commonly produced types of plastics. Under the influence of mechanical pressure or UV rad...
Due to ever-increasing production, plastics have become ubiquitous in the environment, with polystyrene (PS) being one of the most commonly produced types of plastics. Under the influence of mechanical pressure or UV radiation, plastic waste can decompose into smaller micro/nanoparticles (MPs/NPs), posing a threat to biological life, including humans. Recent findings indicate that MPs/NPs can penetrate biological barriers, including the blood-brain barrier (BBB) and affect cells of the central nervous system (CNS), including microglia, immune cells that play a key role in monitoring the neuronal microenvironment and responding to toxic compounds. The results of our study using primary microglial cells show that exposure to different concentrations (1, 25, 50 µg/mL) of polystyrene nanoparticles (PS-NPs; 25 nm) for different periods of time (24-48 h) results in a time- and concentration-dependent profile of NP internalization via an actin-dependent pathway. Once absorbed by cells, PS-NPs are directed to the endosomal-lysosomal system and induce cell activation, as evidenced by morphological changes (Sholl parameters) and increased levels of the Iba1 marker. The toxic effect of PS-NPs on primary microglia is expressed by reduced cell viability, overproduction of ROS and increased number of protein carbonyl groups induced by oxidative stress. These changes are accompanied by overexpression of pro-inflammatory chemokines, indicating activation of primary microglial cells towards a pro-inflammatory phenotype. The results suggest that PS-NPs may be a significant environmental risk factor leading to pro-inflammatory activation of microglia, which constitutes the first line of defense in the brain and is associated with the course of many neurological disorders.
Subclinical immunometabolic perturbations in the neonatal lung following maternal microplastic exposure in mice.
Ho SY, Chou HC, Chen CM
Toxicology · 2026 Jun · PMID 42269851 · Publisher ↗
Maternal exposure to microplastics has raised concerns regarding early-life health effects, yet the molecular alterations preceding structural lung injury remain poorly defined. We investigated whether perinatal polystyr...
Maternal exposure to microplastics has raised concerns regarding early-life health effects, yet the molecular alterations preceding structural lung injury remain poorly defined. We investigated whether perinatal polystyrene microplastic (PS-MP) exposure is associated with inflammatory and metabolic changes in neonatal mouse lungs. Pregnant C57BL/6 mice received PS-MPs (100 or 1000 μg/L) in drinking water from gestation day 14 to postnatal day (PD) 14, corresponding to an estimated intake of approximately 16-160 μg/kg/day, within an environmentally relevant sub-mg/kg/day exposure range. Lung tissues were analyzed at PD7 and PD14 using cytokine assays, NF-κB assessment, histopathology, and untargeted metabolomics. High-dose exposure (1000 μg/L) was associated with enrichment of arachidonic and linoleic acid metabolism, reductions in cyclic AMP (cAMP)- and purine-associated metabolites, and decreased glutathione-related and acylcarnitine-associated features. Targeted biochemical analyses confirmed reduced pulmonary cAMP levels, increased GSSG concentrations, and decreased GSH/GSSG ratios following exposure. These alterations were accompanied by increased IL-1, IL-6, and TNF-α at both PD7 and PD14. NF-κB expression showed exposure-associated increases, although the statistical robustness was influenced by litter-level variability. Despite these changes, lung architecture and lung-to-body weight ratios remained preserved, and only modest, dose-specific growth reduction was observed. Collectively, these findings suggest that perinatal microplastic exposure is associated with early immunometabolic perturbations characterized by inflammatory activation, altered lipid metabolism, reduced pulmonary cAMP levels, and disrupted glutathione redox homeostasis despite preserved lung histoarchitecture.
Exposure matters: The impact of exposure characteristics on In Vitro neurotoxicity of pesticides and implications for regulatory testing.
Meerman JJ, Sinnige TL, Klerx W … +5 more , Tuominen A, Legler J, Piersma AH, Heusinkveld HJ, Westerink RHS
Toxicology · 2026 Jun · PMID 42269850 · Publisher ↗
Current risk assessment does not capture neurodegenerative effects of pesticides. Since pesticide exposure is linked to Parkinson's Disease (PD), test methods for regulatory assessment are needed. Acute toxicity tests fa...
Current risk assessment does not capture neurodegenerative effects of pesticides. Since pesticide exposure is linked to Parkinson's Disease (PD), test methods for regulatory assessment are needed. Acute toxicity tests fail to reflect the diversity in real-life exposure. Therefore, our aim was to determine to what extent duration, time after, and frequency of exposure affect pesticide-induced effects related to neurodegeneration in vitro. To this end, differentiated SH-SY5Y human neuroblastoma cells were exposed to pesticides (dinoseb, endosulfan, mancozeb, rotenone; 0.1 μM - 100 μM). Cells were exposed for (a) 24 h, (b) 24 h followed by 18 h without exposure, (c) 24 h followed by 72 h without exposure, (d) four six-hour exposures with 18 h in exposure-free medium, (e) 96 h. Mitochondrial metabolic activity and cytotoxicity were determined by alamar blue and lactate dehydrogenase assays. Pesticide concentrations were determined by mass spectrometry methods. Our results show that increasing exposure duration increased the potency, but the degree differed per pesticide. Increasing time after exposure increased the potency, but only for mancozeb and rotenone. Increasing exposure frequency (while maintaining the total exposure time) caused a left-shift only for mancozeb. These left-shifts could not be explained by an increase in the amount of pesticide measured in the cells. These data indicate that variations in exposure scenarios impact potencies of pesticides in vitro. To ensure that in vitro strategies for risk assessment generate relevant data, these strategies should be informed by real-life exposure. To define a relevant range of exposure scenarios, more extensive evaluation is required.
Cadmium exposure activates ferroptosis through downregulated PPARγ expression in preeclampsia placenta.
Li X, Wu Y, Zhao Z … +9 more , Wang Y, Li M, Geng Y, Yin J, Lin W, Cheng H, Zhao B, Yang Y, Yu Z
Toxicology · 2026 Jun · PMID 42263808 · Publisher ↗
This study aimed to investigate mechanism of cadmium activated ferroptosis in preeclampsia placenta. Placenta were collected to detect expressions of PPARγ and ferroptosis markers. JEG3 cells were treated with CdCl₂ (20 ...
This study aimed to investigate mechanism of cadmium activated ferroptosis in preeclampsia placenta. Placenta were collected to detect expressions of PPARγ and ferroptosis markers. JEG3 cells were treated with CdCl₂ (20 μM) and PPARγ siRNA for 24 h to investigate whether cadmium exposure activated ferroptosis and role of PPARγ in ferroptosis. JEG3 cells were treated with RSL3 (0.5 μM), CdCl₂, PPARγ siRNA and ferrostatin-1 (1 μM) to demonstrate association between ferroptosis and preeclampsia. Ferroptosis was activated in preeclampsia, with increased peroxiredoxin-3 and decreased GPX4 expressions, increased MDA concentration, enhanced 4HNE signal and Fe accumulation. Protein expression and nuclear translocation of PPARγ were significantly down-regulated in preeclampsia placenta. Ferroptosis was activated, protein expression and nuclear translocation of PPARγ were significantly decreased in CdCl₂-treated cells. PPARγ siRNA transfection led to ferroptosis activation. Placental growth factor (PLGF) expression was significantly down-regulated in preeclampsia placenta, CdCl₂-treated, RSL3-treated and PPARγ siRNA-transfected cells. Glutathione concentration was decreased in preeclampsia placenta and CdCl₂-treated cells. CdCl₂ pretreatment exacerbated PPARγ siRNA transfection-induced increase in HO1 expression and decrease in PLGF expression. Rosiglitazone (1 μM) protected against CdCl₂ induced ferroptosis, ferrostatin-1 restored PLGF expression in CdCl₂ and PPARγ siRNA induced ferroptosis in cells. Our results indicate that cadmium exposure activates ferroptosis through downregulated PPARγ in preeclampsia placenta.
Lipid dysregulation in mouse ovarian antral follicles after oral exposure to a human relevant mixture of three phthalates.
Miller KL, Massey T, Metzler V … +6 more , Adams A, Liu X, Burns K, Porter LR, Snider J, Craig ZR
Toxicology · 2026 Jun · PMID 42252051 · Publisher ↗
Dibutyl phthalate, benzyl butyl phthalate, and di-2-ethylhexyl phthalates leach from consumer and medical products, leading to chronic daily exposure in women. Phthalates are associated with impaired ovarian function and...
Dibutyl phthalate, benzyl butyl phthalate, and di-2-ethylhexyl phthalates leach from consumer and medical products, leading to chronic daily exposure in women. Phthalates are associated with impaired ovarian function and metabolic syndrome in women. In mice, oral exposure to human relevant levels of a mixture of these phthalates disrupted the ovarian follicle proteome causing dysregulation of lipid metabolism proteins. This study aimed to establish the consequences of those alterations on the follicular lipid profile and identify relevant systemic impacts of phthalates. Adult CD-1 female mice were pipet fed vehicle (corn oil) or the phthalate mixture (32 µg/kg/day) for 10 days. Antral follicles were isolated and subjected to targeted lipid profiling, neutral lipid and triglyceride quantification, and expression analyses of key lipid homeostasis enzymes. Liver and serum samples were also tested for systemic effects. Lipid profiling revealed that phthalate-treated mice had significantly increased follicular free fatty acid (FFA), acylcarnitine, and lysophospholipid content with some changes also observed in liver and serum. Neutral lipid content was unaffected, but decreased follicle and increased hepatic triglyceride content were observed in phthalate-treated mice. Phthalate exposure increased follicular fatty acid synthase expression, decreased carnitine o-palmitoyltransferase 2 and altered some key triglyceride hydrolysis enzymes. These results strongly suggest that human relevant phthalate mixture exposure leads to lipid, gene and protein changes consistent with increased FFA synthesis, impaired beta oxidation, and decreased triglyceride abundance in antral follicles. These findings add key mechanistic information to the poorly understood associations between phthalate burden, antral follicle function, and metabolic dysfunction in women.
Cell Painting phenomics reveals size-dependent phenotypic responses to titanium dioxide nanoparticles in HepG2 cells.
Boustani A, Ounoughi A, Zetzsche J … +6 more , Karlsson P, Kotlyar O, Särndahl E, Engwall M, Scherbak N, Alijagic A
Toxicology · 2026 May · PMID 42218974 · Publisher ↗
Titanium dioxide nanoparticles (TiO₂NPs) are widely produced engineered nanomaterials with ongoing human exposure through consumer and occupational uses. Conventional in vitro assays often focus on cytotoxicity and may t...
Titanium dioxide nanoparticles (TiO₂NPs) are widely produced engineered nanomaterials with ongoing human exposure through consumer and occupational uses. Conventional in vitro assays often focus on cytotoxicity and may therefore overlook early or sublethal cellular perturbations. Here, we applied Cell Painting-based phenomics to resolve size-dependent sub-lethal phenotypic signatures of TiONP exposure in human HepG2 hepatocytes. Two TiONPs (<25 nm and <100 nm) were characterized by field emission scanning electron microscopy and evaluated following 24-hour exposure at five concentrations: 6.25, 12.5, 25, 50, and 100 µg/mL. Cell viability was assessed using the alamarBlue assay, and high-dimensional phenotypic profiles were generated using Cell Painting-based phenomics, including automated high-content imaging and CellProfiler-based feature extraction. TiONP exposure induced modest reductions in viability at the highest concentration, indicating limited acute cytotoxicity. In contrast, phenomic profiling revealed clear, concentration-dependent phenotypic perturbations for both size fractions, with markedly stronger and more consistent effects for the < 100 nm TiONPs. At 100 µg/mL, the < 100 nm TiONPs altered 50.9% of the measured phenotypic features, compared with 28.9% for the < 25 nm particles, with prominent contributions from endoplasmic reticulum-, actin/Golgi/plasma membrane-, mitochondria-, and RNA-associated features. Dimensionality reduction and correlation analyses confirmed reproducible, concentration-dependent phenotypic trajectories. Importantly, the TiONP-induced phenotypes were distinct from those induced by the reference chemical CA-074Me, which produced broad perturbations and served as a reference chemical to verify assay sensitivity and dynamic range. Overall, Cell Painting phenomics sensitively captures size-dependent, sublethal cellular phenotypes induced by TiONPs, supporting its value as a New Approach Methodology for nanosafety assessment beyond conventional viability endpoints.
Perfluoroalkyl and polyfluoroalkyl substances exposure and liver disease: A review.
Peng J, Gong R, Li R … +3 more , Li L, Yu H, Wen Q
Toxicology · 2026 Sep · PMID 42208886 · Publisher ↗
Per- and polyfluoroalkyl substances (PFASs) are widely used in numerous industrial processes and consumer products and are now ubiquitously distributed in the environment, thereby creating multiple routes of human exposu...
Per- and polyfluoroalkyl substances (PFASs) are widely used in numerous industrial processes and consumer products and are now ubiquitously distributed in the environment, thereby creating multiple routes of human exposure. Their physicochemical properties confer high persistence, bioaccumulation potential, and toxicity, which have raised increasing concern about their long-term impacts on human health. Because of its central role in xenobiotic uptake, metabolism, transport, and excretion, the liver is considered a major target organ of PFAS toxicity. Over the past few years, a growing body of epidemiological, in vivo, and in vitro evidence has linked PFAS exposure to a broad spectrum of hepatic abnormalities, including liver injury, cholestatic liver injury and bile acid dysregulation, metabolic dysfunction-associated steatotic liver disease (MASLD), and hepatocellular carcinoma (HCC). In addition to legacy long-chain PFASs, short-chain congeners and emerging alternatives such as GenX and 6:2 Cl-PFESA have also shown considerable hepatotoxic potential. This review summarizes current evidence on the contribution of PFAS exposure to liver disease, with particular attention to human relevance and the mechanisms underlying PFAS-induced hepatotoxicity, including oxidative stress, inflammatory activation, disruption of the gut-liver axis and enterohepatic circulation, lipid metabolic reprogramming, and impairment of bile acid homeostasis. Remaining knowledge gaps and future perspectives are also highlighted to support mechanistic understanding and improve PFAS-related liver risk assessment.
Macrophage-amplified toxicity of indium tin oxide nanoparticles to bronchial epithelial cells involving ROS-associated NF-κB signaling.
Zhang Y, Hong YQ, Liu Y … +4 more , Yuan Y, Lu ZX, Zhang X, Zhu TT
Toxicology · 2026 Sep · PMID 42203026 · Publisher ↗
Indium tin oxide nanoparticles (ITO NPs) are widely used in optoelectronic industries, and increasing occupational exposure has raised concern about their pulmonary toxicity. Although ITO exposure has been associated wit...
Indium tin oxide nanoparticles (ITO NPs) are widely used in optoelectronic industries, and increasing occupational exposure has raised concern about their pulmonary toxicity. Although ITO exposure has been associated with severe lung diseases, the mechanisms underlying epithelial injury remain unclear. Here, a simplified macrophage-epithelial cell model using RAW264.7 macrophages and BEAS-2B epithelial cells was established to investigate how macrophages modulate ITO NP-induced epithelial toxicity. Direct exposure to ITO NPs caused limited toxicity in BEAS-2B cells, whereas conditioned medium from ITO NP-exposed RAW264.7 cells was associated with reduced epithelial viability, increased LDH release, and EMT-like changes. Dissolved indium species alone did not fully account for the observed effects, whereas macrophage-derived oxidative stress and associated inflammatory responses appeared to contribute more substantially to the epithelial responses. Transcriptomic and biochemical analyses showed that ITO NPs induced oxidative stress and activated NF-κB signaling in macrophages. Inhibition of ROS or NF-κB attenuated macrophage-derived cytotoxicity and reduced EMT-like changes in epithelial cells. These findings support a role for macrophages as important regulators of ITO NP-induced epithelial injury and provide additional mechanistic insight into ITO-related pulmonary toxicity.
Early-life exposure to phthalates and nanoplastics alters gut microbiota and intestinal morphophysiology in rat dams and male offspring.
Magosso N, Fioretto MN, Fávaro I … +6 more , de Souza PV, Moreira MF, Rocha VA, Barbosa FC, Rodrigues J, Scarano WR
Toxicology · 2026 Sep · PMID 42203025 · Publisher ↗
Phthalates and nanoplastics, common contaminants in everyday products and a result of their degradation, respectively, are linked to environmental degradation and human exposure. Research suggests that these substances c...
Phthalates and nanoplastics, common contaminants in everyday products and a result of their degradation, respectively, are linked to environmental degradation and human exposure. Research suggests that these substances can affect the gut microbiota and morphology, especially during pregnancy and lactation. Changes in the maternal microbiota can have lasting immunological and inflammatory effects on the offspring. This study investigated the effects of gestational (design 1) and gestational and lactational (design 2) exposure to a mixture of phthalates (PM) and nanoplastics (NPs), isolated or in combination, on colon histology and gut microbiota composition of directly exposed mothers (1), and of the male pups of these mothers (2). Pregnant Sprague Dawley rats were randomly divided into 4 groups: CTR (control; vehicle), PM (20 μg/kg/day of phthalate mixture), NPs (1 mg/kg/day nanoplastics NPs-100nm), PM+NPs (20 μg/kg/day PM + 1 mg/kg/day NPs-100nm). Treatment was administered orally from gestational day 5 (GD5) to GD20 for maternal fecal collection (design 1), or from GD10 to postnatal day 22 (PND22) for fecal collection from male pups (design 2). At the end of the treatment period, pregnant rats (GD20) and post-weaning male rats (PND22), 5-6 rats from each group, were euthanized. Colon samples and feces were collected for morphological and microbiome composition analysis, respectively. PM exposure increased goblet cells and reduced class and order Erysipelothichia/Erysipelotrichales at GD20, and reduced class and order Clostridia/Clostridiales at PND22. In addition, PM+NPs exposure increased goblet cells and class and order Bacilli/Lactobacillales and Gammaproteobacteria/Enterobacteriales at GD20. These findings provide evidence that exposure to PM+NPs during gestation affects the maternal microbiota and goblet cells; while this exposure during gestation and lactation causes alterations in the gut microbiota of the offspring, without histological changes. This may also provide information about the mechanistic effects of co-exposure in humans.
The respiratory sensitizer methylene diphenyl diisocyanate (MDI) reprograms human cells of the alveolar tract.
Blömeke B, Lichter J, Weßendorf A … +7 more , Lobes N, Jax M, Aruna O, Rolle-Kampczyk U, Engelmann B, Bergen MV, Bock U
Toxicology · 2026 Sep · PMID 42203024 · Publisher ↗
This study applied a suite of human-relevant, non-animal cell models to investigate early events associated with respiratory sensitization induced by 4,4'-methylene diphenyl diisocyanate (MDI), a representative low-molec...
This study applied a suite of human-relevant, non-animal cell models to investigate early events associated with respiratory sensitization induced by 4,4'-methylene diphenyl diisocyanate (MDI), a representative low-molecular-weight respiratory sensitizer. Phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 macrophage-like cells (THP-1M) and primary human monocyte-derived macrophages were exposed to MDI (3-300 µM, 4 h), resulting in a restricted cytokine response characterized primarily by enhanced IL-1α and IL-1β production. In contrast, lipopolysaccharide (LPS, 1 ng/mL-10 µg/mL) induced a pronounced pro-inflammatory response consistent with classical M1-like activation. Flow cytometric analysis of THP-1M indicated a partial M2a-like immunomodulatory phenotype following MDI exposure, characterized by increased CD1a and reduced CD14 expression. This response was accompanied by changes in selected central carbon metabolites, whereas LPS induced changes more consistent with M1-like activation. In human alveolar epithelial type I-like cells (hAELVi), MDI induced changes in selected central carbon metabolites, indicating epithelial metabolic responsiveness. In epithelial-macrophage coculture (hAELVi/THP-1M), metabolic responses to MDI were attenuated while chemokine production (CCL2, CCL5, CXCL8) was enhanced, suggesting macrophage-mediated modulation of epithelial responses and immune cell recruitment potential. In an air-liquid interface coculture model, these early responses were associated with dendritic cell-like activation of THP-1 cells, marked by OX40L upregulation, indicating Th2-skewing potential. Overall, the findings support interacting epithelial-immune key events relevant to respiratory sensitization and highlight the value of incorporating epithelial-immune interactions into new approach methods (NAMs) based hazard assessment. SHORT SUMMARY: 4,4'-Methylene diphenyl diisocyanate (MDI) induced epithelial metabolic changes in vitro and promoted a partial M2a-like immunomodulatory macrophage response associated with alterations in central carbon metabolites. In epithelial-macrophage co-culture, macrophages attenuated metabolic responses while enhancing chemokine production, suggesting modulation of epithelial responses and immune cell recruitment potential. In an air-liquid interface co-culture model, these early events were associated with dendritic cell-like activation of THP-1 cells, marked by OX40L upregulation and indicative of Th2-skewing potential. Together, the findings support interacting key events relevant to proposed adverse outcome pathway concepts for respiratory sensitization and highlight candidate biomarkers and mechanistically relevant cellular responses that may support human-relevant NAM development for low-molecular-weight respiratory sensitizers.
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