Toxicology[JOURNAL]
Sun
200 papers
Analysis of the expression and function of ITGB6 in porcine intestinal epithelial cells upon deoxynivalenol exposure.
Wang H, Feng M, Xiao Y … +3 more , Wang J, Wu S, Bao W
Toxicology · 2026 Jan · PMID 41161376 · Publisher ↗
Deoxynivalenol (DON) frequently occurs in mould-contaminated crops and food, posing a significant threat to human and animal health. Identification of molecular targets against DON toxicity is critical for the developmen...
Deoxynivalenol (DON) frequently occurs in mould-contaminated crops and food, posing a significant threat to human and animal health. Identification of molecular targets against DON toxicity is critical for the development of novel strategies to control and prevent the toxic effects. Integrins regulate key cell survival signaling pathways and interact with E-cadherin in intestinal epithelial cells to regulate intestinal functions. Pigs are more sensitive to DON exposure than other farm animals, and porcine intestinal epithelial cell line (IPEC-J2) is a well-established model for studying DON toxicity. In this study, we treated IPEC-J2 cells with 1 μg/mL DON and observed a significant upregulation of Integrin β6 (ITGB6) at both the mRNA and protein levels. Further, we generated the ITGB6 knockout cells and found that ITGB6 knockout obviously alleviated DON-induced toxicity on cell viability. Moreover, ITGB6 knockout significantly decreased DON-induced reactive oxygen species level and cell apoptosis rate. Transcriptomic analysis revealed the differentially expressed genes between DON-treated ITGB6 knockout and control cells were significantly enriched in the PI3K/AKT signaling pathway. These results indicated the alleviating effect of ITGB6 depletion on DON-induced toxicity. Taken together, our findings provide new insight into the role of ITGB6 in the regulation of DON-induced toxicity, and suggest the potential of ITGB6 as a promising candidate for the development of novel strategies to prevent and control DON-induced toxicity.
Vascular endothelial growth factor-containing conditioned medium from PFOS-exposed human granulosa cells promotes endothelial angiogenesis in vitro.
Tomanic T, Samardzija Nenadov D, Stanic B … +3 more , Pogrmic-Majkic K, Radovic Pletikosic S, Andric N
Toxicology · 2026 Jan · PMID 41161375 · Publisher ↗
Perfluorooctanesulfonic acid (PFOS) is a persistent environmental pollutant associated with reproductive dysfunction. We investigated the acute effects of PFOS in HGrC1 human granulosa cells. Cells were initially exposed...
Perfluorooctanesulfonic acid (PFOS) is a persistent environmental pollutant associated with reproductive dysfunction. We investigated the acute effects of PFOS in HGrC1 human granulosa cells. Cells were initially exposed for 48 h to two concentrations of PFOS: 15 nM, representing levels found in human follicular fluid, and 10 µM, corresponding to serum concentrations observed in occupational exposure scenarios. Global mRNA sequencing revealed that exposure to 10 µM PFOS upregulated six genes, including vascular endothelial growth factor A (VEGFA). Different experimental conditions showed robust induction of this gene, with maximal increases at 25 µM PFOS after 6 and 12 h, without overt cytotoxicity. PFOS at 25 µM rapidly activated protein kinase B (AKT) and cAMP response element-binding protein (CREB), while inhibition of the phosphoinositide 3-kinase (PI3K)/AKT pathway prevented VEGFA mRNA upregulation. PFOS decreased VEGFA protein levels in cells, but induced VEGFA protein secretion into the medium of HGrC1 cells, independently of PI3K/AKT and protein kinase A (PKA) signaling. Conditioned media from PFOS-exposed HGrC1 cells enhanced the migration of both HGrC1 and human endothelial EA.hy926 cells and promoted endothelial tube formation in EA.hy926 cells. Immunodepletion of VEGFA from the conditioned media of PFOS-exposed HGrC1 cells returned parameters of tube formation to control levels, while recovery of VEGFA activity restored tube formation to levels observed after exposure to conditioned medium from PFOS-exposed HGrC1 cells. These results suggest that VEGFA is the key mediator of the observed pro-angiogenic effects in endothelial cells providing a novel insight into the mechanisms of PFOS action on ovarian function.
Cadmium accumulation in neuronal cells leads to essential metals imbalance and zinc transporters dysregulation.
Bovio F, Ferrian M, Franceschi A … +5 more , Melchioretto P, Porru S, Forcella M, Fusi P, Urani C
Toxicology · 2026 Jan · PMID 41139003 · Publisher ↗
The heavy metal cadmium (Cd), a natural element of the Earth's crust released into the environment through both natural processes and anthropogenic activities, is ranked 7th on the ATSDR Substance Priority List of hazard...
The heavy metal cadmium (Cd), a natural element of the Earth's crust released into the environment through both natural processes and anthropogenic activities, is ranked 7th on the ATSDR Substance Priority List of hazardous substances. Its low excretion rate from human body and its long biological half-life (10-30 years) lead to Cd heavy accumulation in organisms. Although Cd carcinogenicity is well recognized, the neurotoxicity and damage to the nervous system still require further investigation. The interference with essential element homeostasis, referred as dyshomeostasis, is one of Cd neurotoxic mechanisms and its interference on specific ions balance could play a key role in the process of neurodegenerative diseases. In this study Cd possible impact on the balance of essential elements was evaluated in human neural SH-SY5Y cells, by exposing the target cells to low Cd concentrations (0.1-5 µM) for 24 h, 48 h and 6 days. Cd accumulates inside the cells in a time and dose dependent manner with dysregulation of both zinc and iron homeostasis and induction of heme oxygenase 1 expression. Moreover, zinc transporters ZnT1 and ZnT2 are upregulated, while the iron transporter DMT1 is downregulated. In conclusion our data show that even low, sublethal cadmium concentrations are effective in inducing dyshomeostasis of essential metals involved in important neuronal functions.
Adolescent exposure to polylactic acid microplastics causes cardiac fibrosis by promoting cardiomyocyte senescence.
Pan C, Li S, Liu T … +4 more , Shi Y, Cai Z, Luo X, Xia S
Toxicology · 2026 Jan · PMID 41125161 · Publisher ↗
Population studies and animal experiments have indicated that exposure to microplastics (MPs) is closely related to adverse cardiovascular outcomes. However, as far as we know, all current studies on MPs-induced cardioto...
Population studies and animal experiments have indicated that exposure to microplastics (MPs) is closely related to adverse cardiovascular outcomes. However, as far as we know, all current studies on MPs-induced cardiotoxicity are limited to traditional petroleum-based plastics, and there is a blank for potential heart damage caused by 'bioplastics' made of polylactic acid (PLA) materials. This study investigated the cardiotoxicity of PLA-MPs in mice and its potential mechanism. Adolescent mice exposed to PLA-MPs for 28 days showed obvious cardiac developmental toxicity, manifested as disordered arrangement of myocardial cells, thinning of myocardial thickness and fibrosis. Further studies found that ferroptosis and senescence were observed in the hearts of adolescent mice exposed to PLA-MPs. In vitro, we used H9c2 cells to study the cellular internalization, senescence and ferroptosis effects of PLA-MPs. We found that PLA-MPs exposure increased the senescence characteristics of H9c2 cells, such as increased SA-β-Gal activity, up-regulated expression of senescence-associated proteins (p16, p21, γH2AX) and senescence-associated inflammatory factors. Moreover, we found that PLA-MPs caused ferroptosis in H9c2 cells with elevated ferrous iron. Subsequent studies found that Fer-1 inhibited ferroptosis signal and alleviated PLA-MPs-induced H9c2 cell senescence. In summary, our findings highlight the cardiotoxic effects of biodegradable PLA-MPs through ferroptosis and senescence pathways, and provide insights into the toxicological effects of biodegradable MPs on mammalian cardiovascular system capacity.
Investigation of hepatotoxicity of acrylamide using mass spectrometry-based proteomics and N-glycoproteomics in mouse model.
Xiang M, Tian Z
Toxicology · 2026 Jan · PMID 41110587 · Publisher ↗
Acrylamide is a widely used and distributed chemical proven to be a hepatotoxicant; however, the toxicological mechanisms on post-translational modifications regulation, which is most relevant to regulating the activity...
Acrylamide is a widely used and distributed chemical proven to be a hepatotoxicant; however, the toxicological mechanisms on post-translational modifications regulation, which is most relevant to regulating the activity of proteins, are largely unknown. Here we report mass spectrometry-based toxico-proteomics and N-glycoproteomics study of AA using ICR mouse model with the exposure experimental group and the wild-type control group. 16,640 peptides from 2,956 proteins and 19,613 intact N-glycopeptides from 3,515 N-glycoproteins were identified in proteomics and N-glycoproteomics, where 99 differentially expressed proteins and 303 differentially expressed intact N-glycopeptides from 150 N-glycoproteins were quantified. Functional annotation of differentially expressed proteins and N-glycoproteins enables identification of AA hepatotoxicity pathways of autophagy, apoptosis and inflammation through stresses of reactive oxygen species and endoplasmic reticulum. 11 potential N-glycoprotein biomarkers were filtered through interactome and functional network analysis, and 5 (UGT1A9, CTSD, PSAP, CES1F and CD163) of them with more than 50 % frequency occurrence in parallel reaction monitoring verification experiment. These results provide a deep and comprehensive understanding of AA hepatotoxicity, especially from the perspective of N-glycoproteins; in addition, the integrated proteomics and N-glycoproteomics pipeline can be extended to the study of other toxicants.
The role of DNA methylation in alcohol-mediated neurodevelopmental toxicity.
Gao J, Liu B, Chen H … +10 more , Xu P, Guo X, Yao D, Li X, Wang T, Wang Y, Yao H, Qiao S, Yuan J, Liu Y
Toxicology · 2026 Jan · PMID 41110586 · Publisher ↗
Alcohol induces neurodevelopmental toxicity through multiple biological processes, including DNA methylation and histone modifications in epigenetic regulation. Epigenetic mechanisms involving DNA chemical modifications...
Alcohol induces neurodevelopmental toxicity through multiple biological processes, including DNA methylation and histone modifications in epigenetic regulation. Epigenetic mechanisms involving DNA chemical modifications represent crucial molecular pathways that regulate gene expression during neurodevelopment, exhibiting high sensitivity to adverse lifestyle factors such as alcohol consumption, smoking, and stress. Prenatal alcohol consumption is a primary cause of fetal neurodevelopmental disorders. Alcohol alters DNA methylation and histone modification levels in the brain, which in turn disrupts the expression levels of related genes. This review focuses on how alcohol mediates neurodevelopmental toxicity by disrupting DNA methylation mechanisms. First, alcohol affects DNA methylation through the following pathways: (1) Inhibiting folate metabolism reduces the production of the methyl donor S-adenosylmethionine (SAM), thereby decreasing DNA methyltransferase (DNMTs) activity; (2) Induces oxidative stress, where reactive oxygen species (ROS) disrupt methylation status at CpG sites; (3) Directly alters the activity of DNMTs and TETs, leading to hypermethylation or hypomethylation in gene promoter regions. These abnormal methylation patterns significantly impact the differentiation neural stem cells (NSCs), neuronal migration and synapse formation, as well as the function of glial cells. Methylation abnormalities in neurodevelopment-related genes can trigger neuronal migration defects and synaptic plasticity disorders. Alcohol-induced methylation-related changes exhibit brain region specificity, involving areas such as the hippocampus, prefrontal cortex, and hypothalamus. Regarding intervention strategies, prenatal supplementation with methyl donors like folate and choline partially reverses alcohol-induced abnormal DNA methylation and improves neurodevelopmental outcomes. This study highlights the role of DNA methylation in alcohol-mediated neurotoxicity, providing a theoretical basis for elucidating the molecular mechanisms of FASD and developing targeted epigenetic therapeutic strategies.
Mediating roles of oxidative stress and nuclear factor kappa B signaling in benzyl butyl phthalate-aggravated allergic asthma.
Lei F, Xue R, Gu J … +4 more , Zhang M, Wu Q, Gong Y, Li C
Toxicology · 2026 Jan · PMID 41110585 · Publisher ↗
It has been proposed that benzyl butyl phthalate (BBP) exposure raises the risk of allergic asthma, but current research evidence is not sufficient to fully support this claim. Examining the function and mechanism of BBP...
It has been proposed that benzyl butyl phthalate (BBP) exposure raises the risk of allergic asthma, but current research evidence is not sufficient to fully support this claim. Examining the function and mechanism of BBP in exacerbating allergic asthma was the goal of this investigation. To create an allergic asthma model, 90 male Balb/c mice were randomly split into 6 groups, comprising of saline (control); OVA; 10 BBP + OVA; 100 BBP + OVA; 250 BBP + OVA; and 1250 BBP + OVA. To investigate if BBP makes allergic asthma worse in mice given OVA, we first examined lung histological sections and airway hyperresponsiveness (AHR). Second, we investigated oxidative stress, the signaling pathway of nuclear factor kappa B (NF-κB), and the inflammatory factors that are downstream of it to explore mechanism of BBP exacerbating allergic asthma.The results showed that, the enhanced pause (Penh) value in BBP + OVA group was remarkably greater in contrast to OVA group, indicating increased AHR, whereas worsening airway remodeling was observed in lung tissue slices. Both Penh and airway remodeling worsened as the BBP dose increased. In addition, exposure to BBP + OVA resulted in enhanced levels of markers related to the NF-κB signaling pathway and oxidative stress, decreases in Th1 inflammatory cytokine levels, and increases in Th2/Th17 inflammatory cytokine levels. Combined exposure to OVA and BBP worsened AHR and airway wall remodeling, and these impacts were correlated with oxidative stress and elevated secretion of IgE, NF-κB biomarkers, and Th1/Th2/Th17 cytokines. Therefore, we suggest that the primary mechanisms by which BBP aggravates allergic asthma through Th1/Th2/Th17 cytokine modulation include the NF-κB pathway and oxidative stress. It may be a potential drug target for the treatment of allergic asthma.
Oil mists and vapours: A review of exposure and toxicity, with dose descriptors from inhalation studies.
Hadrup N, Sørli JB, Frederiksen M … +8 more , Sharma AK, Kafert-Kasting S, Schuchardt S, Bitsch A, Clausen PA, Saber AT, Vogel U, Hougaard KS
Toxicology · 2026 Jan · PMID 41109551 · Publisher ↗
Inhalation of oil mists and vapours may induce adverse effects. Here we review the literature on human exposure to oil mists and vapours and their toxicity following inhalation exposure. We collected data on inhalation o...
Inhalation of oil mists and vapours may induce adverse effects. Here we review the literature on human exposure to oil mists and vapours and their toxicity following inhalation exposure. We collected data on inhalation of all types of oils, on all toxicity endpoints other than genotoxicity and cancer. Toxicological dose descriptors (no-observed-adverse-effect concentrations (NOAECs) and lowest-observed-adverse-effect concentrations (LOAECs)) were collected to identify exposure levels at which toxicity occurs. Occupational mean exposure concentrations typically range from 0.2 to 5 mg/m for mist and up to 36 mg/m for vapours during oil drilling. Affected toxicological endpoints in humans of exposure to refined oil include lung function, lung pathology (including fibrosis), asthma and irritation of nose and throat. Sudden death has been reported after acute exposure to hydrocarbon gas and vapour (e.g. during oil tank hatch operation, potentially involving oxygen deficiency). In animals, endpoints affected include lung function, lung pathology, increases in pulmonary immune cells, decreased body weight and in one study on monkeys also lethality. Dose descriptors in human studies with exposure to mineral oil mists included LOAECs as low as 0.3, 0.4. 0.5, 0.7 and 2.2 mg/m concerning lung function/respiratory symptoms. In general, higher dose descriptors were observed in animal studies, e.g. LOAECs for lung pathology of 50 mg/m in rats and 63 mg/m in monkeys. In conclusion, toxicological effects were observed in humans at occupationally relevant exposure levels. The collected data inform hazard assessment of airborne oil at the workplace and in society.
Toxicological potential of substances in spray-formulated degreasers and lubricants - With a literature review on asthma potentials of ammonia, maleic anhydride and methyl methacrylate.
Sørli JB, Shin HK, Frydendall KB … +4 more , Wedebye EB, Nikolov N, Frederiksen M, Hadrup N
Toxicology · 2026 Jan · PMID 41106493 · Publisher ↗
Spray-formulated engine/brake cleaners and lubricants form aerosols that can deposit in the airways where toxicity can occur. Characterisation of the ingredients' toxicity can help minimise the human risk. We recently pu...
Spray-formulated engine/brake cleaners and lubricants form aerosols that can deposit in the airways where toxicity can occur. Characterisation of the ingredients' toxicity can help minimise the human risk. We recently published a database of 376 ingredient substances in 82 spray-formulated engine/brake cleaners and lubricants available in the European Union (EU) and screened them for genotoxic and carcinogenic potentials. In the current work we expand this screening to include pulmonary toxicity, neurotoxicity, hepatotoxicity and reproductive and developmental toxicity. For this we used EU harmonised classification, quantitative structure activity relationship (QSAR) models and lists of suspected asthmagens. For asthmagens we reviewed the literature. Fifteen substances had an asthma induction potential, five of which had literature to support the potential, namely: aluminium powder, ammonia, chlorine, maleic anhydride and methyl methacrylate. Other potential asthma inducers were: 1,3,5-trimethylbenzene, 1,2,4-trimethylbenzene, benzyl alcohol, methyl-2-hydroxybenzoate, 1,4-dihydroxybenzene, 2-aminoethanol, 2-aminopropanol, 1,2-benzisothiazol-3(2 H)-on, hexyl dihydrogen phosphate and diethanolamine. The number of substances with potential for the other toxicities are: acute toxicity when inhaled (8 substances), aspiration toxicity (13), neurotoxicity (13), reproductive/developmental toxicity (34) and hepatotoxicity (76). The fractions of products containing substances with potential for the toxicities were: asthma (18 % of the products), acute toxicity when inhaled (12 %), neurotoxicity (55 %), reproductive/developmental toxicity (63 %) and hepatotoxicity (52 %). Finally, we discuss substances to be prioritised as of highest concern. In conclusion, we identified a substantial toxic potential with the employed screening methods. The data can be used in safe-by-design substitution of potentially toxic substances and inform hazard assessment of spray-formulated engine/brake cleaners and lubricants.
Deleterious effects of plastic component bisphenol a on mitochondrial function in human intestinal cells.
Perra G, Caddeo A, Sedda F … +5 more , Cao G, Isola R, Concas A, Perra A, Lai N
Toxicology · 2026 Jan · PMID 41106492 · Publisher ↗
Plastic compounds released into the environment can be accumulated in human tissues causing various health issues. It has been demonstrated that Bisphenol A (BPA), widely used in polycarbonate plastics and food packaging...
Plastic compounds released into the environment can be accumulated in human tissues causing various health issues. It has been demonstrated that Bisphenol A (BPA), widely used in polycarbonate plastics and food packaging, can accumulate in gastrointestinal (GI) tract, inducing oxidative stress, metabolic dysfunction, and other cellular disturbances, including mitochondrial damage. However, the mechanisms by which BPA affects the GI function and affects mitochondrial function in the absorptive cells of the intestine, are still not completely understood. The aim of this study is to investigate whether BPA enters intact human intestinal cells and affects mitochondrial electron transport chain (ETC) function. High-resolution respirometry (O2k system, OROBOROS) and fluorometry were used to assess mitochondrial respiration and membrane potential (mt-MP) in Caco-2 cells under acute exposure to BPA. Cellular respiration was stimulated with complex I (C-I), II (C-II), IV (C-IV) and β-oxidation substrates in both intact and permeabilized Caco-2 cells. Morphological analysis of cells exposed to BPA was performed by electron microscopy. In intact cells, respiration rate decreased in presence of BPA, thus confirming the detrimental effects of BPA on ETC. In permeabilized cells, BPA caused a decrease of respiratory activity in presence of C-I and C-II substrates following a reduction of the ETC oxidative capacity and a depolarization of mt-MP. Morphological analysis suggested that BPA can be internalized by endocytosis. The reduced respiration rate in both intact and permeabilized cells indicates that BPA reaches mitochondria even without membrane permeabilization. BPA compromises both oxidative phosphorylation (OxPhos) and mt-MP, thus leading to an impairment of energy metabolism that could contribute to pathological alterations of the gastrointestinal function.
Di-(2-ethylhexyl) phthalate exposure disrupts glucose homeostasis through inhibition of PI3K/Akt/FoxO1 pathway triggering β-cell dedifferentiation in male rats.
Shi D, Wang X, Zhao Y … +5 more , Zhao L, Lu S, Wang J, Han H, Zhang Z
Toxicology · 2026 Jan · PMID 41101618 · Publisher ↗
Di-(2-ethylhexyl) phthalate (DEHP), a widely used environmental endocrine disruptor, has been associated with an increased risk of Type 2 Diabetes Mellitus (T2DM). However, it remains unclear whether exposure to DEHP and...
Di-(2-ethylhexyl) phthalate (DEHP), a widely used environmental endocrine disruptor, has been associated with an increased risk of Type 2 Diabetes Mellitus (T2DM). However, it remains unclear whether exposure to DEHP and its active metabolite can disrupt metabolic homeostasis by inducing pancreatic β-cell dedifferentiation. To evaluate the effects of DEHP on glucose homeostasis and β-cell dedifferentiation, we established an in vivo exposure model using male SD rats, administered with varying concentrations of DEHP (0, 2, 20 and 200 mg/kg/day) over six weeks. Our findings suggest that DEHP exposure leads to elevated blood glucose levels, insulin resistance, and β-cell dedifferentiation, which are associated with the suppression of the PI3K/Akt/FoxO1 signaling pathway. Subsequent in vitro experiments demonstrated that exposure of INS-1 cells to mono (2-ethylhexyl) phthalate (MEHP), the primary bioactive metabolite of DEHP, impaired glucose-stimulated insulin secretion (GSIS). This impairment was associated with β-cell dedifferentiation, the nuclear translocation of FoxO1, and suppression of the PI3K/Akt signaling pathway. Notably, these detrimental effects were ameliorated by PI3K agonist treatment or the transfection of FoxO1 overexpression plasmids. Our findings indicate that DEHP induces β-cell dedifferentiation by inhibiting the PI3K/Akt/FoxO1 signaling pathway, thereby disrupting glucose homeostasis. These findings provide mechanistic insight into the disruption of glucose regulation following DEHP exposure.
From inhalation to systemic damage: Decoding the mechanistic cascade of silica nanoparticle-induced multi-organ toxicity.
Ban JQ, Ao LH, Gu HQ … +5 more , Wei YG, Tian Q, He X, Zhao H, Li J
Toxicology · 2026 Jan · PMID 41101617 · Publisher ↗
The increasing use of silica nanoparticles (SiNPs) has raised concerns about their biotoxicity. Since respiratory exposure is the primary route of human exposure to SiNPs, this study systematically investigated their dis...
The increasing use of silica nanoparticles (SiNPs) has raised concerns about their biotoxicity. Since respiratory exposure is the primary route of human exposure to SiNPs, this study systematically investigated their distribution and damaging effects in the lungs, heart, liver, and kidneys following tracheal drip injection. The results demonstrated that SiNPs distribute across these organs and induce mitochondrial damage, endoplasmic reticulum stress, and activate cell death pathways, including apoptosis, pyroptosis, and autophagy. The most significant damage occurred in the middle-dose group (6 mg/kg). The lungs, as the primary target organ, exhibited pronounced fibrotic changes, while fibrotic lesions were also observed in the heart, liver, and kidneys to varying degrees. These findings suggest that the observed injury mechanisms may collectively contribute to chronic inflammation and promote fibrosis. This study provides critical insights into the multi-organ toxicity of SiNPs, offering a foundation for their safety assessment.
TBPH promotes lung cancer proliferation via mTORC1 activation and altered lipid metabolism while inducing toxicological effects in pulmonary cells in vitro and in vivo.
Li Y, Niu J, Qi Q … +2 more , Liu C, Zhu Z
Toxicology · 2026 Jan · PMID 41093099 · Publisher ↗
Bis(2-ethylhexyl) 2,3,4,5-tetrabromophthalate (TBPH) is extensively utilized as an alternative to traditional options like polybrominated diphenyl ethers (PBDEs). TBPH is a ubiquitous environmental contaminant, having be...
Bis(2-ethylhexyl) 2,3,4,5-tetrabromophthalate (TBPH) is extensively utilized as an alternative to traditional options like polybrominated diphenyl ethers (PBDEs). TBPH is a ubiquitous environmental contaminant, having been detected in a wide range of environmental media, biota, and human tissues, raising concerns about its potential risks to ecological systems and human health. Considering the significant association between environmental toxins and lung cancer, assessing the impact of TBPH on lung cancer is essential. This study utilized lung cancer cells as in vitro model to evaluate the effects of TBPH. Our findings indicate that TBPH enhances lung cancer cell proliferation, as determined by CCK-8 and EdU assays. Further investigations revealed that TBPH facilitates lung cancer progression by activating the mTORC1 pathway, as confirmed by indirect immunofluorescence and Western blot analyses. Additionally, TBPH enhances lipid synthesis in lung cancer cells, altering their lipid metabolism, which may contribute to lung cancer development. On the contrary, we also evaluated the toxicological effects of TBPH on lung tissues and cells. TBPH exposure showed a range of toxicological effects on lung epithelial cells and lung tissues. TBPH exposure induces pyroptosis in lung cells. In summary, our findings suggest that low levels of TBPH promote tumor cell growth, However, TBPH exhibited toxicological effects in lung epithelial cells, highlighting its adverse impact on pulmonary toxicity.
Human proteome-wide molecular interaction analysis based on AlphaFold3 to evaluate toxicity between PFOS and its alternative F-53B.
Li H, Chen N, Yu B … +4 more , Peng Y, Yuan Y, Guo H, Zhang Z
Toxicology · 2026 Jan · PMID 41093098 · Publisher ↗
F-53B, primarily composed of 6:2 chlorinated polyfluoroalkyl ether sulfonate (Cl-PFESA) and 8:2 Cl-PFESA, has been widely used as an alternative to perfluorooctane sulfonic acid (PFOS), but emerging evidence indicates th...
F-53B, primarily composed of 6:2 chlorinated polyfluoroalkyl ether sulfonate (Cl-PFESA) and 8:2 Cl-PFESA, has been widely used as an alternative to perfluorooctane sulfonic acid (PFOS), but emerging evidence indicates that F-53B also exhibits toxicity and may not be a safe substitute. We conducted systematic molecular interaction analysis between three compounds - PFOS, 6:2 Cl-PFESA, and 8:2 Cl-PFESA - and 19,508 human proteins using AlphaFold3-predicted three-dimensional structures combined with AutoDock Vina molecular docking. Binding affinity distributions, compound-specific binding patterns, and functional enrichment analyses were performed to identify differential toxicity mechanisms. This study completed a total of 58,496 molecular docking calculations between the three compounds and human proteins. 8:2 Cl-PFESA demonstrated the strongest overall binding capacity, with top-ranked binding targets including emopamil-binding protein-like protein (EBPL) and lanosterol synthase (LSS). In comparison, PFOS showed highest-ranked binding to olfactory receptor 5D14 (OR5D14), while 6:2 Cl-PFESA preferentially bound to sulfotransferase 6B1 (SULT6B1). For ultra-strong binding targets with binding affinity ≤ -10.0 kcal/mol, 8:2 Cl-PFESA exhibited 413 targets, 6:2 Cl-PFESA showed 98 targets, and PFOS had 78 targets. Functional enrichment analysis revealed significant enrichment in olfactory transduction pathways across all compounds, suggesting potential impacts on chemosensory functions. Additionally, 8:2 Cl-PFESA showed preferential binding to cholesterol synthesis enzymes, while 6:2 Cl-PFESA demonstrated interactions with epigenetic regulatory enzymes, including histone deacetylase 11 (HDAC11) and sirtuin 6 (SIRT6). The findings suggest that F-53B, particularly its 8:2 Cl-PFESA component, may exhibit enhanced toxicity potential compared to PFOS across multiple molecular dimensions. These computational predictions require experimental validation through in vitro binding assays, cell-based toxicity tests, and in vivo studies.
Statin induces epithelial cell death and tissue barrier damage in renal tubule on chip.
Wang S, Liu Y, Wang D … +4 more , Zhang X, Pak HU, Qin J, Zhang X
Toxicology · 2026 Jan · PMID 41093097 · Publisher ↗
Although statins are widely used to reduce lipid levels, they can lead to cytotoxicity in various cell types when given at certain dosages. The effects of statins on kidney epithelial cells are speculated based on clinic...
Although statins are widely used to reduce lipid levels, they can lead to cytotoxicity in various cell types when given at certain dosages. The effects of statins on kidney epithelial cells are speculated based on clinical phenomena but remain unverified in animal models. Here, we described a human renal tubule chip that allows the evaluation of statin-induced cytotoxicity. The renal chip was constructed by co-culturing human proximal tubular epithelial cells and umbilical vein endothelial cells under fluidic flow. In this model, the effects of lovastatin (25 μM) on the cells over 48 h were tested using the CCK-8, lactate dehydrogenase leakage, permeability tests and ROS production assays. Our findings revealed that lovastatin reduced cell viability, increased lactate dehydrogenase leakage, and impaired barrier integrity while elevating ROS levels. Different from what we expected, lovastatin-treated epithelial cells exhibited exacerbated tubular injury and further increased ROS production following the addition of N-acetylcysteine or GSH. In contrast, sodium pyruvate attenuated lovastatin-induced ROS levels and barrier damage in the chip. These findings demonstrate that lovastatin induces oxidative stress via GSH, with ROS-mediated pathways driving tubular injury. This study establishes a platform for the in vitro assessment of drug cytotoxicity and the investigation of statin-related renal side effects.
Micro- and nanoplastic-induced mitochondrial dysfunction and organelle miscommunication: A toxicological perspective.
Maharana T, Taranath A, Fernandes CSE … +2 more , Mishra P, Muralidaran Y
Toxicology · 2026 Jan · PMID 41086899 · Publisher ↗
Microplastics and nanoplastics (MNPs) and their derivatives, pose significant environmental and biomedical risks due to their pronounced cellular toxicity. These particulates disrupt mitochondrial function and compromise...
Microplastics and nanoplastics (MNPs) and their derivatives, pose significant environmental and biomedical risks due to their pronounced cellular toxicity. These particulates disrupt mitochondrial function and compromise inter-organelle communication, leading to enhanced oxidative stress, calcium dysregulation, impaired ATP production, and activation of cellular stress responses including mitophagy and apoptosis. Mitochondrial dysfunction extends its impact to other organelles such as lysosomes, the endoplasmic reticulum (ER), and the nucleus, resulting in impaired organelle crosstalk, epigenetic modifications, and genomic instability. Plastic additives and adsorbed pollutants exacerbate these effects, further destabilizing cellular homeostasis and contributing to systemic pathologies encompassing metabolic disorders, neurodegeneration, cardiovascular dysfunction, and reproductive toxicity. This review synthesizes current mechanistic insights into the pathways mediating MNPs-induced mitochondrial and organelle dysfunction, emphasizing the critical role of disrupted mitochondrial dynamics, ER stress, and bioenergetic failure. Therapeutic strategies focusing on mitochondria-targeted antioxidants, ER stress modulators, and autophagy regulators show promise but require validation under environmentally relevant conditions. Addressing notable research gaps such as polymer diversity, chronic low-dose exposure, and co-contaminant effects through integrative, multi-disciplinary approaches will enhance understanding of long-term health impacts and inform effective mitigation strategies against the pervasive threat of MNPs pollution.
Integrated assessment of bisphenols, phthalates, and biocides for estrogenic and androgenic endocrine-disrupting properties.
Lee SH, Park Y
Toxicology · 2026 Jan · PMID 41075969 · Publisher ↗
The integrated assessment of estrogenic and androgenic endocrine disruption using a combination of receptor dimerization and transactivation assays is an effective approach for providing information the mechanistic actio...
The integrated assessment of estrogenic and androgenic endocrine disruption using a combination of receptor dimerization and transactivation assays is an effective approach for providing information the mechanistic action of chemical compounds that disrupt estrogen and androgen signaling pathways at the cellular level. This study integratedly evaluated the estrogenic and androgenic endocrine-disrupting properties of a total of 29 chemicals, including representative bisphenols, phthalates, and biocides, which are commonly exposed to humans. As a result, most bisphenols showed estrogenic agonist activity through transactivation via dimerization of estrogen receptors alpha and beta, while also exhibiting androgenic antagonist activity by inhibiting dihydrotestosterone-induced transactivation through interference with androgen receptor dimerization. Most phthalates also exhibited estrogenic agonist activity through transactivation via dimerization of estrogen receptors alpha and beta, and only some of them showed androgenic antagonist activity by interfering with androgen receptor dimerization and inhibiting dihydrotestosterone-induced transactivation. Biocides showed estrogenic and androgenic endocrine-disrupting properties through various mechanisms depending on their structural diversity. This integrated assessment effectively provided clues to the mechanism of action of endocrine-disrupting chemicals in estrogen and androgen signaling pathways at the cellular level, based on the adverse outcome pathway framework.
Polycyclic aromatic hydrocarbons-enriched diesel exhaust particles induced hypertrophy in rat primary neonatal cardiomyocytes and apoptotic cell death in H9c2 cardiomyocytes.
Wang CC, Tzeng HP, Hsieh MC … +2 more , Lan KC, Liu SH
Toxicology · 2026 Jan · PMID 41075968 · Publisher ↗
There is limited research about the direct effects of diesel exhaust particles (DEPs) on cardiomyocytes. The respirable DEPs asorbed many organic substances such as polycyclic aromatic hydrocarbons (PAHs). Here, we used...
There is limited research about the direct effects of diesel exhaust particles (DEPs) on cardiomyocytes. The respirable DEPs asorbed many organic substances such as polycyclic aromatic hydrocarbons (PAHs). Here, we used the standard DEPs, enriched in PAHs and their derivatives, from the National Institute of Standards and Technology of the United States and extracted the organic compounds of DEPs (DEPEs) to examine the effects and mechanisms of DEPEs on rat primary neonatal cardiomyocytes (NRCMs) and rat embryonic H9c2 cardiomyocytes. No cytotoxicity was found at DEPEs concentrations up to 25 μg/mL in NRCMs. By evidence of immunofluorescence of desmin, cellular protein content, and mRNA levels of brain natriuretic peptide and β-myosin heavy chain, the cell hypertrophy was induced by DEPEs in NRCMs. DEPEs induced cytotoxicity in H9c2 cells at the concentration of 15 μg/mL and up. DEPEs exposure significantly induced apoptosis and protein expression of phosphorylated JNK and endoplasmic reticulum stress markers glucose-regulated protein 78 and C/EBP-homologous protein in H9c2 cells. Altogether, the direct effects of PAHs-enriched DEPEs include cytotoxic effects observed in H9c2 cells at higher concentrations and hypertrophic effects in NRCMs at concentrations without cytotoxicity. These results provide the better understanding of direct effects of DEPs on cardiomyocytes.
Microplastics and nanoplastics, emerging pollutants, increased the risk of pulmonary fibrosis in vivo and in vitro: A comparative evaluation of their potential toxicity effects with different polymers and size.
Dou JY, Liu S, Wang CY … +5 more , Dai X, Lian LH, Cui ZY, Nan JX, Wu YL
Toxicology · 2026 Jan · PMID 41075967 · Publisher ↗
With the increasing consumption of plastic products, microplastics (MPs) and nanoplastics (NPs), as new environmental pollution, pose a huge potential threat to human health. The different polymers and sizes of MPs and N...
With the increasing consumption of plastic products, microplastics (MPs) and nanoplastics (NPs), as new environmental pollution, pose a huge potential threat to human health. The different polymers and sizes of MPs and NPs are important factors determining the distribution and pathways of particulate organisms, thereby affecting their toxicity. The study explored the pulmonary toxicity and potential mechanism of MPs (1 μm) and NPs (100 nm) of polystyrene (PS), polyethylene (PE), or polypropylene (PP) in vivo and in vitro. Intratracheal injection of MPs/NPs (10 mg/kg, once every six days, continued four times) in mice induced pulmonary histopathological changes, raised α-SMA and collagen I expressions, the TIMP-1/MMP13 ratio, epithelial-mesenchymal transition (EMT)-related proteins, recruited immune cells and increased pro-inflammatory cytokine secretion, especially in PS-NPs group. MPs/NPs (PS, PE or PP) exhibited cytotoxicity in human lung epithelial BEAS-2B, and MPs/NPs (50 μg/mL, 8 h) up-regulated α-SMA, Vimentin, and IL-1β expressions. PS-NPs raised YAP1 and inhibited FXR expression in mice or BEAS-2B, compared with other polymers or diameters. In PS-NPs-induced BEAS-2B, Verteporfin (YAP1 antagonist, 0.2 μM) or GW4064 (FXR agonist, 2 μM) reduced α-SMA, Vimentin, and IL-1β expressions, while Gugglesterone (FXR antagonist, 50 μM) increased above protein expressions. Meanwhile, FXR deficiency increased YAP1 activity and fibrogenesis in PS-NPs-induced BEAS-2B. Collectively, MPs/NPs exposure elevates the risk of pulmonary fibrosis, and FXR-YAP1 axis dysregulation may underlie their toxicity mechanisms. Among the tested polymers, PS exhibits stronger pulmonary toxicity and cytotoxicity compared to PE or PP, and NPs of the same polymer demonstrate greater pulmonary toxicity than MPs.
The dysbiosis of gut microbiota attributes to the impairment of blood-brain barrier in rats triggered by cadmium.
Wang T, Huang X, Lu L … +10 more , Luo X, Wang Y, Ma Y, Tong X, Zou H, Gu J, Liu X, Bian J, Liu Z, Yuan Y
Toxicology · 2026 Jan · PMID 41075966 · Publisher ↗
Cadmium (Cd) is a non-biodegradable heavy metal with a long biological half-life that is detrimental to human health. As Cd can increase blood-brain barrier (BBB) permeability and disturb the gut microbiota, the relation...
Cadmium (Cd) is a non-biodegradable heavy metal with a long biological half-life that is detrimental to human health. As Cd can increase blood-brain barrier (BBB) permeability and disturb the gut microbiota, the relationship between the BBB and gut microbiota disturbance induced by Cd consumption remains unclear. This study aims to identify whether Cd-induced gut microbiota dysbiosis is associated with rat BBB injury and investigate the possible mechanism. Here, we conducted analyses of variations in the composition of the gut microbiota and its metabolites, as well as BBB permeability and the results of the Morris water maze test, in rats treated with Cd by gavage. Fecal microbiota transplantation was performed to verify the role of the microbiota in altering BBB permeability induced by Cd. The results showed that Cd disturbed the gut microbiota, decreasing the levels of short-chain fatty acids (SCFAs). Furthermore, Cd-induced BBB permeability was substantiated by FITC-dextran leakage, ultrastructural observations, and diminished Claudin-5, Occludin, and ZO-1 protein expression, all of which were mitigated by FMT. In vitro, sodium butyrate (SOB) alleviated Cd-induced oxidative stress and increased the expression levels of GPX4 and FTH. Taken together, these findings suggest that Cd disrupts the microbiota and SCFAs components in rats, thereby contributing to BBB damage. SOB prevents Cd-induced BBB damage by suppressing ferroptosis in microvascular endothelial cells. This exhaustive study considerably enhances our comprehension of the health hazards posed by Cd to the central nervous system via the gut-brain axis.
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