Toxicology[JOURNAL]
Sun
200 papers
Microplastic-induced alterations in the intestinal environment: Aging as a modulating factor.
Sánchez A, Ríos D, Martínez M … +4 more , Monedero V, Zúñiga M, Vélez D, Devesa V
Toxicology · 2026 May · PMID 41672195 · Publisher ↗
Microplastics (MPs) present in the diet can affect the intestinal environment. Alterations in gut microbiota, as well as oxidative stress and inflammation in intestinal tissue, have been reported. However, most studies r...
Microplastics (MPs) present in the diet can affect the intestinal environment. Alterations in gut microbiota, as well as oxidative stress and inflammation in intestinal tissue, have been reported. However, most studies rely on commercial microspheres and non-aged particles, which do not reflect realistic environmental exposure. Environmental aging can modify MP properties and potentially their toxicity. The aim of this study was to evaluate the in vivo intestinal toxicity of a subchronic oral exposure to MPs derived from PVC packaging samples that have undergone an aging process. Female BALB/c mice were exposed by oral gavage to aged or non-aged PVC MPs (0.02 mg/day) for 70 days. Intestinal toxicity was assessed by measuring oxidative stress markers (ROS/RNS, lipid peroxidation, reduced glutathione), inflammatory cytokines (IL-1β, TNF-α), histological alterations, gut microbiota composition and metabolism (short-chain fatty acids, SCFAs), and fecal albumin. Microplastic accumulation in intestinal tissue was determined using microwave-assisted digestion and µRaman spectroscopy. Exposure to both aged and non-aged PVC MPs increased oxidative stress, with higher ROS/RNS (20-43 %) and lipid peroxides (27-34 %), and promoted inflammation, with elevated IL-1β (229 %) and TNF-α (68-163 %). Histological analysis showed reduced crypt depth and increased mucus-secreting cells. MPs also altered gut microbiota composition and reduced SCFA levels (32-82 %). Notably, intestinal toxicity differed between aged and non-aged MPs. Overall, subchronic exposure to PVC MPs disrupts intestinal homeostasis through oxidative and inflammatory mechanisms and microbiota dysbiosis, with toxicity influenced by particle aging.
Micro-nanoplastics in the central nervous system: Evidence, mechanisms and perspectives.
Pei Z, Zhong H, Li X … +2 more , Guo S, Wang T
Toxicology · 2026 May · PMID 41662903 · Publisher ↗
Environmental exposure to micro-nanoplastics (MNPs) has emerged as a significant concern for neurological health. This review synthesizes evidence that MNPs translocate the blood-brain barrier (BBB) and induce neurotoxic...
Environmental exposure to micro-nanoplastics (MNPs) has emerged as a significant concern for neurological health. This review synthesizes evidence that MNPs translocate the blood-brain barrier (BBB) and induce neurotoxicity through mechanisms including oxidative stress, neuroinflammation, mitochondrial dysfunction, and neurotransmitter disruption. In rodent models, these disturbances lead to pathological and behavioral deficits relevant to neurodegeneration, neurodevelopmental disorders, and psychiatric conditions. Critically, we evaluate emerging clinical studies confirming the presence of MNPs within human central nervous system tissues and fluids. Our review then provides a critical appraisal of these human studies, highlighting their methodological limitations and inconsistent application of quality assurance/quality control (QA/QC) protocols, which currently constrain robust exposure assessment and causal inference. While clinical correlations exist between MNP levels and markers of BBB integrity, cognitive function, and stroke severity, establishing causality requires standardized detection methods and rigorous QA/QC integrated with longitudinal cohort studies. Generating such reliable evidence is paramount for informing public health strategies aimed at mitigating plastic exposure.
PFOS promotes Alzheimer's disease through aggravating the cell apoptosis and AKT/GSK3β/NF-κB/NLRP3 pathway mediated inflammation.
Li M, Ping X, Song H … +3 more , Sun J, Yang Q, Gao LN
Toxicology · 2026 May · PMID 41655940 · Publisher ↗
Perfluorooctane sulfonate (PFOS) and its alternatives are widely utilized in industrial and commercial applications. Nevertheless, their environmental persistence and widespread detection in diverse matrices in recent ye...
Perfluorooctane sulfonate (PFOS) and its alternatives are widely utilized in industrial and commercial applications. Nevertheless, their environmental persistence and widespread detection in diverse matrices in recent years have raised significant public health concerns. Studies reported that exposure to PFOS in cerebrospinal fluid will increase the risk of cognitive decline in humans. However, the underlying toxicological mechanism is still unclear. The aim of this study was to elucidate the possible toxic targets and potential molecular mechanisms of Alzheimer's disease (AD) induced by PFOS exposure through network toxicology, molecular docking and in vitro verification. Firstly, the results of network toxicology suggested that the mechanisms of PFOS-induced AD were mainly associated with the PI3K-AKT, neurodegeneration, apoptosis and NOD-like receptor signaling pathways. Subsequently, molecular docking simulations confirmed a strong binding interaction between PFOS and the key targets including SRC, ESR1, CASP3, BCL2, ERBB2, and TNF. Finally, we used HT22 and SH-SY5Y cell lines to validate the toxic effects of PFOS and found that PFOS aggravated neuronal cell apoptosis and AKT/GSK3β/NF-κB/NLRP3 pathway mediated inflammatory damages. Briefly, these findings indicated that PFOS exposure could affect the proliferation of neural cells by activating apoptosis and inflammatory related signaling pathways, thus promoting the occurrence and development of AD. This study provides a theoretical basis for understanding the molecular mechanisms involved in PFOS-induced neurotoxicity.
ROS-driven rewiring of Hippo-inflammation-polycomb axis by PFOA in 2D and 3D lung epithelial models.
Thakur M, Mutyala D, Amoliga AA … +2 more , Kondati R, Batra S
Toxicology · 2026 Jun · PMID 41654163 · Publisher ↗
Perfluorooctanoic acid (PFOA), a persistent organic pollutant and prominent member of the per- and polyfluoroalkyl substances (PFAS) family, continues to raise global concern due to its bioaccumulation and potential for...
Perfluorooctanoic acid (PFOA), a persistent organic pollutant and prominent member of the per- and polyfluoroalkyl substances (PFAS) family, continues to raise global concern due to its bioaccumulation and potential for chronic human exposure. While hepatic and systemic toxicities of PFOA are well documented, its effects on lung epithelial integrity/homeostasis, particularly at environmentally relevant concentrations, remain incompletely understood. In this study, we investigated the cellular and molecular responses to PFOA in A549 human adenocarcinoma epithelial cells (alveolar type-II like cells) cultured under submerged monolayer (2D) and 3D air-liquid interface (ALI) condition, representing systemic and barrier-relevant exposure models respectively. Cells were exposed to 10-1000 nM PFOA for 24 h, during which we observed robust induction of pro-inflammatory mediators including- transcription factors (NF-κB and STAT3), pattern recognition receptors (TLR4 and RAGE), cytokine/chemokine production (IL-6, IL-8, CCL2, CCL5), and damage-associated molecular patterns (HSP70, HMGB1). To determine whether these inflammatory responses were linked to broader stress‑adaptation and epigenetic reprogramming, we further examined pathways governing post-transcriptional and translational control, mechanistic signaling, and chromatin regulation. PFOA appear to induce translational stress responses as evidenced by increased stress granule and P-body formation. Alterations in Hippo signaling characterized by YAP/TAZ induction and nuclear translocation was also observed in our experimental models. PFOA-challenged cells exhibited enhanced expression of Polycomb Repressive Complex components, along with increased repressive histone marks (H3K27me3, H2AK119Ub). Additionally, concurrent modulation of HDACs and SIRT family members together with these Polycomb-associated changes, suggests stress adaptive epigenetic reprogramming. Oxidative stress emerged as a key upstream mediator of both the epigenetic and Hippo pathway disruptions, as pretreatment with 1 mM N-acetylcysteine (NAC) effectively attenuated these effects. Despite these molecular alterations, epithelial cell migration capacity remains unaffected under acute exposure. Our results provide key mechanistic insight into PFOA-mediated disruption of redox homeostasis, immune/Hippo signaling, and epigenetic plasticity in A549 lung epithelial cells, and identify potential biomarkers to support future biomonitoring efforts and environmental exposure and risk assessment.
Toxicological effects of PM-derived and PM-relevant mixture of chlorinated paraffins on A549/THP-1 co-culture cells.
Huang JW, Chu C, Yang M … +9 more , Hakkarainen H, Hensel AK, Jin NX, Roponen M, Leskinen A, Komppula M, Liang D, Dong GH, Jalava P
Toxicology · 2026 May · PMID 41654162 · Publisher ↗
Chlorinated paraffins (CPs) are complex mixture of chlorinated straight-chain hydrocarbons, including short-, medium-, and long-chain CPs (SCCPs, MCCPs, and LCCPs), to which humans are exposed environmentally. Although P...
Chlorinated paraffins (CPs) are complex mixture of chlorinated straight-chain hydrocarbons, including short-, medium-, and long-chain CPs (SCCPs, MCCPs, and LCCPs), to which humans are exposed environmentally. Although PM-bound CPs were positively associated with asthma and related symptoms, the toxicological effects of CPs on the respiratory system remain limitedly understood. CPs were extracted from PM samples collected in three cities in southern China, representing distinct SCCPs, MCCPs, and LCCPs profiles. The A549/THP-1 co-culture cells, an in vitro respiratory model, were exposed to PM-derived extracts containing CPs (CP extract). The gradient was established according to the extract dosage calibrated based on its quantified SCCP content with environmentally relevant concentrations. Cell viability, oxidative stress, inflammatory factors, cell cycle distribution, and genotoxicity were assessed. CP extracts reduced cell viability, increased pro-inflammatory factors concentrations, induced cell cycle arrest and DNA damage. Furthermore, CP mixtures were prepared using standards to simulate PM-relevant compositions. But the results showed weak toxicological effects of CP mixtures, suggesting CPs play a relatively weak role or CPs exhibit toxicological effects through alternative pathways. Interesting, varying compositional ratios of SCCPs, MCCPs, and LCCPs may induce different cytotoxic effects. These findings provide in vitro evidence for explaining adverse effects of PM-bound CPs on A549/THP-1 cells. More research is needed to clarify the respiratory toxicological effects of CPs.
Physiologically relevant 3D CRISPR screening enhances mechanistic insight into chemical toxicity compared to 2D screening.
Kim C, Zhu Z, Tagmount A … +3 more , Barbazuk WB, Bacher R, Vulpe CD
Toxicology · 2026 May · PMID 41643803 · Full text
CRISPR-based approaches can complement other genomics-based toxicology studies by enabling causal interrogation of gene function modulating chemical-induced toxicity. Moreover, CRISPR screens enable scalable and systemat...
CRISPR-based approaches can complement other genomics-based toxicology studies by enabling causal interrogation of gene function modulating chemical-induced toxicity. Moreover, CRISPR screens enable scalable and systematic identification of functional pathways involved in cellular response to chemical exposure. Cell-based functional toxicogenomics approaches using CRISPR provide a potential powerful tool for the development of mechanism-driven new approach methodologies (NAMs) for toxicodynamic and toxicokinetic hazard screening to enable more effective risk assessment. To improve the physiological relevance of in vitro functional toxicogenomics, we developed a three-dimensional (3D) CRISPR screening platform using HepG2/C3A spheroids cultured in a continuously rotating bioreactor (ClinoStar). We evaluated the potential utility of a 3D CRISPR screen as compared to conventional 2D screen using a custom CRISPR sgRNA library representing common loss-of-function genetic variants in the human population and exposure to the well characterized DNA damaging toxicant, doxorubicin. The 3D platform identified more genes and pathways in which variants have previously been associated with doxorubicin toxicity in clinical studies than the 2D system. These results support the utility of 3D CRISPR screening to identify physiologically relevant genetic determinants underlying chemical toxicity.
A comparative toxicological evaluation of nicotine and its analog 6-methyl nicotine in E-cigarette aerosol utilizing a 3D in vitro human respiratory model.
Effah F, Sengupta M, Sun Y … +7 more , Faizan MI, Kaur G, Raghu R, Elzein A, Marczylo T, Strongin RM, Rahman I
Toxicology · 2026 May · PMID 41628686 · Full text
Under the U.S. Tobacco Regulatory Act of 2020, all novel nicotine-containing products require a Premarket Tobacco Product Application (PMTA) and FDA authorization before they can be marketed. However, lengthy PMTA review...
Under the U.S. Tobacco Regulatory Act of 2020, all novel nicotine-containing products require a Premarket Tobacco Product Application (PMTA) and FDA authorization before they can be marketed. However, lengthy PMTA review timelines have prompted some manufacturers to replace traditional nicotine with 6-methyl-nicotine (6-MN), a non-tobacco-derived analog that delivers comparable psychoactive effects while evading existing regulatory pathways. Despite its growing market presence as a purportedly "safer" alternative, the toxico-pharmacokinetic profile of 6-MN remains poorly characterized. This study assessed the toxicity after exposure to nicotine or 6-MN-containing e-liquid aerosols using a 3D EpiAirway tissue model. RT-qPCR analyses revealed differential effects on transcripts associated with DNA damage (53BP1, ATR), inflammation (NF-κB1), and cancer (MYCBP). Morphological evaluation of the airway tissues exposed to either aerosol showed an increase in epithelial thickness, a decrease in E-cadherin protein levels, increased goblet cell hypertrophy, evidenced by positive PAS staining and elevated mucus (MUC5AC protein) production, and a reduction in Occludin protein (part of the tight junction complex), which is suggestive of epithelial remodeling. Exposure to PG/VG aerosols alone significantly increased the release of MIP-1α, IFN-γ, and IL-4. Conversely, spearmint-flavored aerosols containing 6-MN or nicotine decreased several pro-inflammatory cytokines, significantly reducing TNF-α, Eotaxin, MCP-1, RANTES, and G-CSF levels, potentially via NF-κB and ERK1/2 pathways. Our findings reveal differential toxicological and chemical profiles for nicotine and 6-MN aerosols; however, flavorings may confer similar cytotoxicity, as measured by LDH and metabolic activity, in 6-MN formulations as they do in those with nicotine. Thus, 6-MN is not a "safer" nicotine alternative.
Nanoplastics induce SH-SY5Y cell damage through oxidative stress and disruption of amino acid metabolism.
Ma T, Liu Y, Sun J … +8 more , Fang Y, Wang Y, Li X, Su N, Liu M, Zhao Z, Wu J, Bai J
Toxicology · 2026 May · PMID 41621474 · Publisher ↗
With the pervasive environmental distribution of plastics, their fragmentation into nanoplastics (NPs) has raised growing concerns regarding potential biological toxicity, particularly in neuronal cells. This study inves...
With the pervasive environmental distribution of plastics, their fragmentation into nanoplastics (NPs) has raised growing concerns regarding potential biological toxicity, particularly in neuronal cells. This study investigated the toxic effects and underlying mechanisms of NPs on SH-SY5Y cells. Five types of NPs were first systematically characterized using scanning electron microscopy (SEM), hydrodynamic diameter measurement, and Zeta potential analysis. Cell internalisation of fluorescently labelled NPs was observed using confocal microscopy. Cell viability was assessed across different NP concentrations to determine the optimal exposure dose. In vitro exposure to the five types of nanoplastics (PE-NPs, PET-NPs, PMMA-NPs, PP-NPs, and PS-NPs) resulted in differential reductions in SH-SY5Y cell viability. Notably, the PE-NPs and PP-NPs treatment groups exhibited a more significant decrease in cell viability, whereas the PET-NPs and PMMA-NPs treatment groups showed a relatively mild reduction in cell viability. Oxidative stress indicators (ROS, MMP, LDH, MDA, GSH, and SOD) were measured, and apoptosis was evaluated by TUNEL and EdU assays. Transcriptome sequencing was performed on PE- and PP-exposed cells, followed by GO/KEGG enrichment analyses; differentially expressed genes were validated via RT-qPCR, Western blotting, and amino acid content detection. Characterisation results showed that NPs were uniformly spherical particles (∼200 nm) with high aqueous stability (zeta potential: -30 to -20 mV) and could be internalized by SH-SY5Y cells. NPs reduced cell viability in a concentration-dependent manner, with 400 μg/mL selected for subsequent experiments. NP exposure increased reactive oxygen species (ROS) levels, impaired mitochondrial function, induced apoptosis, and disrupted cell proliferation in SH-SY5Y cells. Transcriptomic and validation results revealed that NPs disrupted amino acid and one-carbon unit metabolism. Collectively, NPs induce SH-SY5Y cell damage through oxidative stress, apoptosis, and amino acid metabolism disorder. These findings provide insights into NP-induced neuronal toxicity, laying the groundwork for further studies on the health risks of NPs and the development of targeted protective strategies.
Arsenite sensitizes to ferroptosis by disrupting selenium metabolism and reducing GPx4 expression.
Takashima H, Makino R, Taguchi H … +9 more , Ito J, Mishima E, Takenaka Y, Akiyama Y, Sumi D, Conrad M, Tomikoka Y, Toyama T, Saito Y
Toxicology · 2026 May · PMID 41592620 · Publisher ↗
Arsenic (As), an environmental toxicant commonly found in groundwater, exerts its toxic effects primarily through oxidative stress. Selenium (Se) plays a crucial role in counteracting oxidative stress by promoting the sy...
Arsenic (As), an environmental toxicant commonly found in groundwater, exerts its toxic effects primarily through oxidative stress. Selenium (Se) plays a crucial role in counteracting oxidative stress by promoting the synthesis of Se-containing antioxidant enzymes, such as glutathione peroxidases (GPx). To elucidate the impact of As on cellular Se metabolism, we investigated the effects of inorganic arsenic on cultured cells (HT-1080, Jurkat, and SH-SY5Y). Our findings indicate that As(III) disrupts Se metabolism and inhibits Se-induced GPx expression. By comparing different Se sources (selenoprotein P, selenocysteine, and selenite), we determined that As(III) primarily interferes with Se metabolism downstream of selenite, an inorganic form of Se. Notably, exposure to As(III) reduced Se incorporation into RNA, suggesting inhibition of Sec-tRNA synthesis, a critical step in selenoprotein biosynthesis. Additionally, As(III) increased cellular susceptibility to ferroptosis, a form of oxidative stress-driven lipid peroxidation-mediated cell death primarily regulated by GPx4. Supporting this, genetic deletion of PRDX6, a recently identified regulator of cellular Se metabolism, further suppressed selenoprotein expression and exacerbated As(III)-induced ferroptosis. These findings provide new insights into the toxicological mechanisms of As compounds, highlighting their role in disrupting Se metabolism and potentially mitigating the side effects associated with arsenic-based anticancer therapies.
Persistent organic pollutants: Neurotoxic mechanisms and insights from organoid models.
Ji Z, Chen L, Ming D
Toxicology · 2026 May · PMID 41580186 · Publisher ↗
Persistent Organic Pollutants (POPs) pose significant global environmental health risks due to their persistence, bioaccumulation, and long-range transport. Exposure to POPs has been linked to a range of neurological dis...
Persistent Organic Pollutants (POPs) pose significant global environmental health risks due to their persistence, bioaccumulation, and long-range transport. Exposure to POPs has been linked to a range of neurological disorders, including cognitive impairment, neurodevelopmental abnormalities, and neurodegenerative diseases. This review examines the neurotoxic effects of various POP categories, such as flame retardants, pesticides, plasticizers, and preservatives, and explores the underlying molecular mechanisms. It also highlights the potential of brain organoids as a more physiologically relevant experimental platform. Although organoid models offer improved translational value, their capacity to fully replicate the complexity of the human nervous system remains limited, necessitating further technical refinement and interdisciplinary collaboration. The integration of organoid technology into environmental toxicology is anticipated to enhance the accuracy and efficiency of neurotoxicity assessment, thereby supporting the development of robust health risk evaluation frameworks and informing evidence-based environmental policy.
Cigarette smoke exposure disrupts the blood-testis barrier and negatively impacts reproductive capacity in mice.
Zhong Y, Wei X, Yasin Z … +2 more , Huang Y, He L
Toxicology · 2026 May · PMID 41577289 · Publisher ↗
Maintaining normal testicular structure and function is closely related to the blood-testis barrier (BTB). Meanwhile, cigarette smoke extract (CSE) affects testicular function. However, whether CSE mediates BTB damage an...
Maintaining normal testicular structure and function is closely related to the blood-testis barrier (BTB). Meanwhile, cigarette smoke extract (CSE) affects testicular function. However, whether CSE mediates BTB damage and the underlying mechanism(s) are unclear. This study investigates the effects of CSE on the BTB in mice by focusing on changes in hormone levels. CSE was prepared and administered intranasally at different concentrations to 6-8-week-old male Balb/c mice for five weeks. After cigarette smoke components successfully entered and accumulated in the mice, the seminiferous tubules of the testes were atrophied, spermatogenic cell arrangement became disordered, sperm quality declined, and spermatogenesis was impaired. Furthermore, CSE exposure disrupted the hypothalamic-pituitary-gonadal axis. CSE also damaged the ultrastructure of the BTB, leading to impaired integrity and increased permeability. The associated disruption of BTB function was caused by inhibiting key proteins, including occludin, Zonula occludens-1(ZO-1), N-cadherin, β-catenin, and connexin-43, correlated with hormonal changes. Collectively, these findings suggest that cigarette smoke exposure disrupts BTB structure and function by altering hormone levels and suppressing the expression of BTB-related proteins, affecting spermatogenesis and male reproductive capacity.
Could cannabigerol protect against neuroinflammation? Insights from an in vitro microglial study.
Santos JMD, Machado AK, Bick DLU … +4 more , Sagrillo MR, Del Bel EA, Machado AK, Santos ACD
Toxicology · 2026 Mar · PMID 41548647 · Publisher ↗
Cannabigerol (CBG), a non-psychotropic cannabinoid from Cannabis sativa, has been investigated for its anti-inflammatory potential. However, its toxicological profile and the mechanisms underlying its effects are still p...
Cannabigerol (CBG), a non-psychotropic cannabinoid from Cannabis sativa, has been investigated for its anti-inflammatory potential. However, its toxicological profile and the mechanisms underlying its effects are still poorly understood. This experimental study evaluated the safety and anti-inflammatory efficacy of CBG in BV-2 microglial cells, in a model of neuroinflammation. BV-2 cells were exposed to CBG concentrations ranging from 0.01 to 100 μM for 24 h to investigate non-cytotoxic doses. Colorimetric and fluorometric assays were performed in triplicate to assess cellular viability (MTT), the production of reactive oxygen species (ROS) and nitric oxide (NO), genotoxicity (GEMO and Alkaline Comet assay), and Caspase-1 gene expression. Cell morphology was also monitored microscopically. The results revealed that CBG 100 μM was highly cytotoxic, reducing cell viability by about 80 % and significantly increasing NO (approximately 400 %) and ROS (approximately 900 %) levels. Additionally, CBG was shown to be genotoxic in the GEMO assay at various concentrations, with 10 μM and 100 μM inducing DNA damage of approximately 200 % and 300 %, respectively. However, no genotoxicity was identified in the Comet assay. At higher concentrations, CBG also promoted the activation of microglia, altering their morphology. In a neuroinflammation model, CBG was unable to attenuate the increase in ROS levels induced by NLRP3 activation and promoted an increase in Caspase-1 gene expression. Despite a favorable safety profile at low doses, CBG exhibits inconsistent anti-inflammatory effects and can be genotoxic depending on the dose and exposure conditions.
PM2.5 induces cardiac defects by triggering endoplasmic reticulum stress mediated through the impairment of SIRT6 deacetylase activity.
Liu J, Wang Y, Su S … +5 more , Liu R, Wang J, Xie S, Yin C, Zhang E
Toxicology · 2026 Mar · PMID 41544926 · Publisher ↗
A growing body of research suggests that maternal exposure to fine particulate matter (PM2.5) is linked to congenital heart disease in the offspring. Endoplasmic reticulum stress (ERS) has been established as a cause of...
A growing body of research suggests that maternal exposure to fine particulate matter (PM2.5) is linked to congenital heart disease in the offspring. Endoplasmic reticulum stress (ERS) has been established as a cause of the cardiac developmental toxicity of PM2.5. Silent information regulator 6 (SIRT6) which serves as a protective element against environmental pollutants, was closely associated with cardiovascular conditions. However, the precise underlying molecular mechanisms remain unclear. Pregnant mice were exposed to PM2.5 or sterile saline through oropharyngeal aspiration, proteomic analysis of fetal cardiac tissue was performed. Co-immunoprecipitation analysis was used to examine the interaction of SIRT6 and PERK. We observed that maternal exposure to PM2.5 caused abnormal cardiac development in offspring, accompanied by a marked reduction in the expression of NKX2.5. In the AC16 cardiomyocyte model, exposure to PM2.5, contributed to a marked increase in cardiomyocyte apoptosis. Moreover, proteomic analysis revealed a significant disruption in protein processing in the endoplasmic reticulum. We further demonstrated that the expression of PERK and activity of the PERK/eIF2α/CHOP signaling pathway were significantly upregulated, along with a notable increase in PERK acetylation levels. More importantly, we confirmed the interaction between SIRT6 and PERK. Concurrently, a significant reduction in SIRT6 expression was detected alongside elevated H3K9 acetylation after exposure to PM2.5. The treatment of AC16 cells with the SIRT6 activator UBCS039 significantly attenuated PM2.5-induced PERK activation and cardiomyocyte apoptosis. Our results reveal that PM2.5 induces the downregulation of SIRT6, which promotes PERK hyperacetylation and activates the PERK/eIF2α/CHOP pathway, triggering ERS, ultimately resulting in abnormal cardiac development in offspring.
The regulatory roles of BMAL1 in TDCIPP-induced autophagy and apoptosis in HT22 cells.
Liu Y, Liang R, Xu B
Toxicology · 2026 Mar · PMID 41544481 · Publisher ↗
Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), a common organophosphate flame retardant, is extensively used in various consumer products and has emerged as an environmental pollutant. Recent studies have documented the...
Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), a common organophosphate flame retardant, is extensively used in various consumer products and has emerged as an environmental pollutant. Recent studies have documented the neurotoxic effects of TDCIPP, highlighting its ability to promote neuronal apoptosis and induce autophagy. Nonetheless, the underlying regulatory mechanisms remain poorly understood. The present study observed an upregulation of Brain and Muscle ARNT-Like 1 (BMAL1) in TDCIPP-treated mouse HT22 cells, indicating that BMAL1 may play a critical role in TDCIPP-induced neuronal autophagy and apoptosis. Furthermore, the impact of BMAL1 knockdown on TDCIPP-induced autophagy and apoptosis in HT22 cells was explored using Western blot (WB) and flow cytometry (FACS) analysis. The results demonstrated that TDCIPP exposure modulated the expression levels of BMAL1 and autophagy-related proteins and increased the phosphorylation of mTOR. The suppression of BMAL1 expression resulted in decreased AMPK expression, thereby blocking cell autophagy. Collectively, the results highlight the role of BMAL1 in the cell death mechanism induced by TDCIPP through the AMPK signaling pathway in HT22 cells. Therefore, the present study provides a new perspective and evidence on the mechanism of TDCIPP-induced neurotoxicity in HT22 cells.
Corrigendum to "Titanium nanoparticles provoke ferritinophagy-mediated ferroptosis via inhibition of the Nrf2-HO-1 signaling pathway in osteocytes'' [Toxicology 519 (January) (2026) 154324, doi:10.1016/j.tox.2025.154324].
Zhu R, Zhang Y, Wang Y … +4 more , Bao X, Zhang L, Fang J, Mao H
Toxicology · 2026 Mar · PMID 41530019 · Publisher ↗
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PFHxS exposure causes osteoarthritis through the innate immune signaling pathway mediated by lipid peroxidation.
Chen X, Zeng H, Chen G … +1 more , Yang H
Toxicology · 2026 Mar · PMID 41525832 · Publisher ↗
PFHxS have been widely used and detected in the environment. The toxicological effects of PFHxS exposure on cartilage tissues and cells are not fully clear. The objective of this work was to study the toxicological effec...
PFHxS have been widely used and detected in the environment. The toxicological effects of PFHxS exposure on cartilage tissues and cells are not fully clear. The objective of this work was to study the toxicological effects of PFHxS on cartilage. We investigated these effects using both in-vitro and in-vivo models. In the in-vitro model, we exposed chondrocytes to environmentally relevant concentrations of PFHxS. In the in-vivo model, we assessed cartilage damage using various staining methods, including toluidine blue, alcian blue, and safranin-fast green staining. In chondrocytes, PFHxS exposure decreased cell viability and induced inflammatory and oxidative stress responses.Further experiments showed that PFHxS induced lipid peroxidation, increased Fe²⁺ levels, and significantly decreased the expression of GPX4 and xCT, indicating the induction of ferroptosis. Oxidative stress also led to large-scale production of ds-DNA and activation of the cGAS-STING signaling pathway.In the in-vivo model, PFHxS exposure caused damage to cartilage tissues, as evidenced by the tissue staining.Similarly, in vivo findings showed that PFHxS induced ferroptosis-like characteristics in cartilage tissues, including decreased GPX4 and xCT and increased iron ion levels. This study is the first to reveal that the environmental pollutant PFHxS causes extracellular matrix degradation and functional damage to chondrocytes by inducing ferroptosis and activating the cGAS-STING inflammatory pathway. These findings establish a theoretical basis for a potential association between PFHxS environmental exposure and cartilage-degenerative diseases.
Impact of PM on cardiorespiratory mortality: A study in the capitals of Brazilian amazon rainforest.
de Oliveira Silveira G, de Lima Brum R, Tavella RA … +3 more , da Silva Bonifácio A, Fernandes RC, da Silva Júnior FMR
Toxicology · 2026 Mar · PMID 41521015 · Publisher ↗
Wildfire-related air pollution represents an escalating health threat in the Brazilian Amazon, where fine particulate matter (PM) concentrations frequently exceed safe levels (5 µg/m). This study quantified long-term PM...
Wildfire-related air pollution represents an escalating health threat in the Brazilian Amazon, where fine particulate matter (PM) concentrations frequently exceed safe levels (5 µg/m). This study quantified long-term PM exposure and its impact on cardiorespiratory mortality across the seven Amazonian capitals, Belém, Boa Vista, Macapá, Manaus, Palmas, Porto Velho, and Rio Branco, between 2018 and 2023. In addition, disease-specific outcomes including chronic obstructive pulmonary disease (COPD), lung cancer (LC), and ischemic heart disease (IHD) were assessed. Daily PM data were obtained from the CAMS reanalysis, and mortality records from the Brazilian Health Data Platform. Health impacts were estimated using the WHO AirQ+ log-linear model. Annual mean PM ranged from 10.47 µg.m (Palmas, 2020) to 49.69 µg.m (Porto Velho, 2021), exceeding the WHO guideline of 5 µg.m in all cities. Most capitals experienced over 100 days per year above the 15 µg.m daily guideline, and significant correlations were observed between wildfire counts and PM in Porto Velho (r = 0.24) and Rio Branco (r = 0.21). Between 2018 and 2023, approximately 5472 (95 % CI: 4595-6711) deaths from circulatory diseases and 2621 (95 % CI: 864-4278) from respiratory diseases were attributable to PM exposure. COPD accounted for 627 (95 % CI: 462-781) deaths, LC for 427 (95 % CI: 314-534), and IHD for 304 (95 % CI: 150-467). The highest burdens occurred in Belém, Manaus, and Porto Velho. These findings demonstrate that persistent smoke from seasonal fires has become a critical environmental health crisis in the Amazon, demanding urgent action to prevent deforestation, reduce emissions, and protect population health.
In vivo and in vitro toxicokinetics including metabolism, isozyme mapping, and monoamine oxidase inhibition of three (2-aminopropyl)benzo[b]thiophene (APBT) psychedelics.
Wagmann L, Brandt SD, Kavanagh PV … +1 more , Meyer MR
Toxicology · 2026 Mar · PMID 41519460 · Publisher ↗
3-(2-Aminopropyl)benzo[b]thiophene (3-APBT), 5-APBT, and 6-APBT are recently identified psychedelics and entactogens that activate serotonin 2 receptor subtypes and lead to a head-twitch response in mice. The present stu...
3-(2-Aminopropyl)benzo[b]thiophene (3-APBT), 5-APBT, and 6-APBT are recently identified psychedelics and entactogens that activate serotonin 2 receptor subtypes and lead to a head-twitch response in mice. The present study characterized their toxicokinetics, metabolism, and monoamine oxidase (MAO) inhibition using liquid chromatography-high-resolution tandem mass spectrometry. Metabolites were tentatively identified in urine from male Wistar rats collected over 24 h after oral administration (2 mg/kg body weight) and in incubations with pooled human liver S9 fraction (25 µM after 1 and 6 h). Phase I isoenzyme mapping and MAO inhibition were assessed using individual incubations with 11 human monooxygenases or recombinant human MAO-A and MAO-B. Hydroxylation was the predominant phase I biotransformation, primarily catalyzed by cytochrome P450 (CYP) 1A2, CYP2D6, CYP3A4, and CYP3A5, while N-acetylation, glucuronidation, and sulfation were observed as phase II reactions. The metabolic patterns were similar to those of related 5- and 6-(2-aminopropyl)benzofuran analogues, and the involvement of multiple CYP isozymes suggested a reduced toxicity risk e.g., by CYP-mediated drug-drug interactions. However, all three APBT isomers strongly inhibited MAO-A (IC of 5-APBT 0.4 µM, 6-APBT 0.6 µM, and 3-APBT 4 µM) but only weakly MAO-B (IC 23-49 µM). Given that the MAO-A inhibition strengths of 5-APBT and 6-APBT were in the range of model inhibitors, clinically relevant MAO-A inhibition and associated interaction risks and toxic effects cannot be excluded. These data provide a toxicokinetic basis to support the clinical and forensic interpretation of exposures to APBT and related sulfur-based psychedelics.
Hepatotoxicity: Mechanisms and animal-free prediction models.
Sanz-Serrano J, Suter-Dick L
Toxicology · 2026 Mar · PMID 41519459 · Publisher ↗
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In vitro hepatic metabolism and associated binding of enniatin B.
Le Hegarat L, Dubreil E, Le Yondre N … +3 more , Martin S, Bree F, Henri J
Toxicology · 2026 Mar · PMID 41506395 · Publisher ↗
Enniatin B (ENNB), a secondary metabolite produced by various Fusarium species, frequently contaminates cereals, which constitutes the main dietary source of human exposure. Critical toxicodynamic and toxicokinetic data...
Enniatin B (ENNB), a secondary metabolite produced by various Fusarium species, frequently contaminates cereals, which constitutes the main dietary source of human exposure. Critical toxicodynamic and toxicokinetic data gaps currently impede a robust and accurate risk assessment. The primary objective of this study was to characterize the in vitro toxicokinetic profile of ENNB. We investigated its clearance using human and mouse liver microsomes (HLM and MLM), as well as 2D and 3D HepaRG cell models. To facilitate reliable in vitro-in vivo extrapolation (IVIVE), we also determined key parameters: plasma protein binding, binding to microsomes and HepaRG cells, CYP450 inhibition, and the identification of HepaRG metabolites. Binding studies revealed a very high binding of ENNB to human plasma proteins and a high binding to inactivated human liver microsomes and HepaRG cells. The predicted in vivo hepatic clearance (cl) of ENNB, calculated using the in vitro results from MLM, HLM, and HepaRG 2D indicated a low hepatic first pass effect. Interestingly, no observable disappearance of ENNB was found in the HepaRG 3D model. Our findings on ENNB-mediated CYP inhibition in HLM, in combination with literature results, suggest a potential for CYP3A4/5-related auto-inhibition. Finally, we successfully performed a putative identification of 13 Phase I metabolites using the human HepaRG cell line. In conclusion, the low hepatic first pass effect could imply a high oral bioavailability in vivo if intestinal barrier passage is significant, as predicted elsewhere. However, this could be counteracted by transport limited hepatic clearance that should be further investigated and a pre-systemic first-pass effect already demonstrated in vitro.
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