Toxicology[JOURNAL]
Sun
200 papers
Fluorene‑9‑bisphenol‑associated endoplasmic reticulum stress linked to oxidative stress, apoptosis and autophagy in SH‑SY5Y cells.
Wang H, Hu Y, Bi X … +3 more , Li Z, Lan X, Zhang H
Toxicology · 2026 Jun · PMID 41865970 · Publisher ↗
Fluorene-9-bisphenol (BHPF), an alternative to bisphenol A (BPA), is widely used to make polyester polymers and serves as an important organic intermediate in synthetic plastics. While diverse toxic effects of BHPF have...
Fluorene-9-bisphenol (BHPF), an alternative to bisphenol A (BPA), is widely used to make polyester polymers and serves as an important organic intermediate in synthetic plastics. While diverse toxic effects of BHPF have been documented in the literature, its effects on neurons, potential neurotoxicity, and underlying molecular mechanisms remain unclear. In this study, we reported that BHPF (10, 25 µM) inhibited neuronal SH-SY5Y cell viability, increased lactate dehydrogenase (LDH) release, and induced cell death in a dose-dependent manner. BHPF exposure increased intracellular reactive oxygen species (ROS) and mitochondrial reactive oxygen species (mtROS) levels, decreased mitochondrial membrane potential, reduced the expression of cytochrome C oxidase subunit 4 (COX4) and mitochondrial protein 1 (MFN1), but upregulated Bax, Caspase-3, Caspase-8 and initiated apoptosis. In addition, BHPF treatment led to the accumulation of acidic vacuoles in the cells and increased the expression of autophagy regulatory proteins, including Beclin-1, LC3II, ATG5 and p62. Moreover, BHPF could trigger endoplasmic reticulum stress (ER stress), and ER stress inhibitor taurodeoxycholate (TUDCA) reversed the BHPF-induced oxidative stress, apoptosis and autophagy. Thus, our in vitro data indicate that ER stress may be linked to the oxidative stress, apoptosis, and autophagy observed in nerve cells following BHPF exposure. These findings offer preliminary insights into cellular processes that could help elucidate the potential role of nerve cells in BHPF-associated degenerative diseases.
Polystyrene microplastics induce skeletal muscle atrophy through disruption of anabolic signaling and mitochondrial function.
Choi SY, Yeo J, Heo YJ … +4 more , Lee HI, Nam MK, Yoo SA, Lee MK
Toxicology · 2026 Jun · PMID 41865969 · Publisher ↗
Polystyrene microplastics (PS-MPs) have emerged as pervasive environmental contaminants with growing concerns regarding their potential adverse effects on human health; however, their impact on skeletal muscle homeostasi...
Polystyrene microplastics (PS-MPs) have emerged as pervasive environmental contaminants with growing concerns regarding their potential adverse effects on human health; however, their impact on skeletal muscle homeostasis remains poorly understood. In this study, we investigated the effects of PS-MPs on muscle atrophy and the underlying molecular mechanism using differentiated C2C12 myotubes. Cells were exposed to 1 μm PS-MPs for 24 h, which resulted in a dose-dependent increase in intracellular reactive oxygen species levels at concentrations of 100-500 μg/mL. PS-MPs significantly upregulated the gene and protein expression of muscle atrophy-related markers, including myostatin, atrogin-1, and MuRF1, and increased polyubiquitinated proteins, while markedly suppressed muscle protein synthesis-related markers such as MyoD1, MyoG, and MHC, as well as overall protein synthesis, as determined by puromycin labeling. Mechanistically, PS-MPs remarkably downregulated IGF-1-PI3K-Akt-mTOR signaling pathway, while concomitantly activating AMPK and FoxO3α signaling. Intracellular accumulation of PS-MPs was accompanied by mitochondrial swelling and cristae disruption. Consistently, PS-MPs induced mitochondrial dysfunction, as evidenced by mitochondrial depolarization, decreased ATP production, and reduced expression of PGC-1α, NRF1, TFAM, and OXPHOS proteins. Oxidative stress responses were further characterized by the upregulation of Keap1 and the suppression of NRF2 and HO-1 expression. PS-MPs alone elicited a muscle atrophy phenotype comparable to that caused by dexamethasone, and co-exposure synergistically enhanced the expression of atrogin-1, MuRF1, and myostatin genes. In conclusion, these findings demonstrate that PS-MPs disrupt muscle homeostasis by inhibiting IGF-1-PI3K-Akt signaling, promoting oxidative stress, and impairing mitochondrial integrity, confirming PS-MPs as a previously unrecognized environmental hazard that may contribute to muscle atrophy.
Silica-induced telomere dysfunction promotes pulmonary fibrosis through the activation of the cGAS-STING pathway.
Qian Q, Pan S, Li X … +5 more , Gong X, Jiang Z, Zhang X, Lou J, Feng L
Toxicology · 2026 Jun · PMID 41864539 · Publisher ↗
OBJECTIVE: This study aims to elucidate whether silica (SiO₂) induces alveolar epithelial cell senescence through telomere shortening, and to explore the involvement of TERF1 and its subsequent activation of the cGAS-STI...
OBJECTIVE: This study aims to elucidate whether silica (SiO₂) induces alveolar epithelial cell senescence through telomere shortening, and to explore the involvement of TERF1 and its subsequent activation of the cGAS-STING pathway in the development of pulmonary fibrosis. METHOD: Silicosis was induced in male C57BL/6 mice through intratracheal instillation of silica. Lung tissues collected on days 7, 14, and 28 were assessed by H&E staining, qPCR (telomere length and gene expression), and senescence markers (SA-β-Gal staining, p16/p21 immunohistochemistry). In vitro, BEAS-2B cells (including TERF1-modified) were exposed to SiO₂ (short- and long-term), and the expression level of CST complex, telomere stability genes, shelterin complex, and components of cGAS-STING pathway were analyzed by qPCR or Western blot. RESULTS: An abnormal increase in cellular senescence was observed in the lung tissues of mice with silica-induced silicosis, accompanied by telomere shortening and downregulation of CST complex, telomere-stabilizing genes, and shelterin complex. In BEAS-2B cells, SiO₂ suppressed proliferation and promoted senescence in a dose- and time-dependent manner. Deficiency in TERF1 exacerbated telomere damage, led to the accumulation of cytoplasmic free DNA, and increased cellular senescence, whereas overexpression of TERF1 maintained telomeric homeostasis and attenuated cellular senescence. SiO₂ also activated the cGAS-STING pathway, suggesting its involvement in fibrotic signaling. CONCLUSION: Our study found that TERF1 deficiency is key in SiO₂-induced fibrosis, linking telomere instability to cGAS-STING activation through cytosolic DNA. Increasing TERF1 expression restored telomere balance and blocked fibrosis, offering a new therapeutic target.
Exposure to microplastics and liver oncogenesis: A comprehensive review on molecular mechanisms and pathogenic pathways.
Li W, Wang Z, Chen J … +1 more , Ying S
Toxicology · 2026 Jun · PMID 41864538 · Publisher ↗
Microplastics have become a serious environmental pollutant that enter different ecosystems and eventually the human body through direct exposure to the environment. This infiltration is a major health risk, especially f...
Microplastics have become a serious environmental pollutant that enter different ecosystems and eventually the human body through direct exposure to the environment. This infiltration is a major health risk, especially for the liver, which is a primary metabolic organ highly sensitive to the harmful effects of microplastics. There are many ways that these particles can cause liver damage, such as disrupting metabolism, inducing oxidative stress, causing mitochondrial dysfunction, causing inflammation, changing gene expression, and activating abnormal signaling pathways. Even in the absence of hepatic fibrosis or cirrhosis, the carcinogenic potential of microplastics may exert its effects through different pathways. In addition, microplastics can act as efficient vectors for the transport of heavy metals, organic pollutants, and pathogenic microorganisms, thereby synergistically amplifying the toxic effects of these agents and increasing health risks. The complex interactions between microplastics and various pathological processes underscore their critical role in the development of hepatocellular carcinoma. Future research endeavors should focus on elucidating the long-term health impacts of microplastic exposure to devise effective public health policies and preventive strategies.
Epigenetic approaches by analysis of circulating miRNAs and global DNA methylation in veterinarians occupationally exposed to volatile anesthetics.
Grassi TF, Silva MAP, Destro MV … +6 more , Minutentag IW, Reis PP, De Martinis BS, Cappetta M, Braz LG, Braz MG
Toxicology · 2026 Jun · PMID 41856424 · Publisher ↗
Exposure to waste anesthetic gases (WAGs) is an underestimated occupational hazard in veterinary operating rooms (VORs), where insufficient ventilation and the absence of scavenging systems remain common worldwide. Veter...
Exposure to waste anesthetic gases (WAGs) is an underestimated occupational hazard in veterinary operating rooms (VORs), where insufficient ventilation and the absence of scavenging systems remain common worldwide. Veterinarians occupationally exposed to WAGs have been poorly investigated to date. Addressing this critical gap, we present the first integrative study evaluating circulating microRNAs (miRNAs), global DNA methylation, and urinary anesthetic quantification in veterinarians occupationally exposed to WAGs isoflurane and sevoflurane. In a case-control design, plasma profiling revealed 11 dysregulated miRNAs in the exposed group (n = 29) compared to the control group (n = 28) based on nominal p-values (p < 0.05), as part of an exploratory screening approach, including seven upregulated miRNAs meeting a predefined fold-change criterion (FC≥1.5). Among these, hsa-miR-1252-5p and hsa-miR-520f-3p showed robust discriminatory performance based on Receiver Operating Characteristic (ROC) curve analysis (AUC≥0.70). Functional enrichment analysis highlighted epigenetic regulators as major network hubs. For hsa-miR-1252-5p, hubs included EP300, TP53, CREBBP, HDAC1 and SIRT1, linking miRNAs modulation to histone acetylation/deacetylation, DNA damage response, apoptosis, and stress regulation. For hsa-miR-520f-3p, included MAPK1, TNRC6B, MECP2 and KMT2A, associated with cell signaling pathways, proliferation and epigenetic regulation. Global DNA methylation levels did not differ significantly between groups, suggesting that exposure under the evaluated conditions may not trigger genome-wide alterations. Occupational exposure was confirmed by urinary quantification of isoflurane and sevoflurane, indicating highly polluted workplaces. In conclusion, although global DNA methylation remained unchanged, WAG exposure was associated with modulation of circulating miRNAs, and our findings suggest that hsa-miR-1252-5p and hsa-miR-520f-3p emerge as potential biomarkers of effect associated to WAG occupational exposure in veterinarians who work in inadequately equipped VORs.
Co-exposure to polystyrene nanoplastics and cadmium induces apoptosis in intestinal cells: Role of the IP3R/Ca²⁺/STAT3 signaling pathway.
Yang H, Wu L, Niu S … +5 more , Guo M, Liu C, Wu T, Cui M, Xue Y
Toxicology · 2026 Jun · PMID 41833704 · Publisher ↗
The widespread use of plastic products has elevated nanoplastics (NPs) pollution to a critical global concern, with polystyrene nanoplastics (PS-NPs) and cadmium (Cd) emerging as common environmental contaminants whose c...
The widespread use of plastic products has elevated nanoplastics (NPs) pollution to a critical global concern, with polystyrene nanoplastics (PS-NPs) and cadmium (Cd) emerging as common environmental contaminants whose co-occurrence and combined toxicity increasingly alarm the scientific community. The intestine, as the main xenobiotic exposure site, is a primary target for PS-NPs and Cd exposure-individually or combined. While PS-NPs and Cd's individual intestinal toxicity mechanisms are well-studied, their combined effects remain poorly understood, especially at the molecular level. This study investigated the combined effects of environmentally relevant concentrations of PS-NPs and Cd on intestinal apoptosis and the regulatory role involving the IP3R/Ca /STAT3 pathway using both C. elegans and Caco-2 cell models. In C. elegans, 72-hour PS-NPs (10 μg/L) and Cd (5 μg/L) co-exposure induced developmental retardation, intestinal structural abnormalities, and dysregulated expression of apoptosis-related genes along with key components of the IP3R/Ca/STAT3 pathway. Parallel experiments in Caco-2 cells demonstrated that 24-hour co-treatment with PS-NPs (20 μg/mL) and Cd (0.25 μg/mL) significantly elevated apoptosis rates and triggered endoplasmic reticulum stress. Molecular analyses revealed these effects were mediated through increased IP3R phosphorylation, elevated cytosolic Ca concentrations, and enhanced phosphorylation of the downstream effector STAT3. Notably, pharmacological inhibition of IP3R (2-APB, 10 μM), Ca²⁺ chelation (BAPTA, 10 μM), or STAT3 phosphorylation (stattic, 5 μM) significantly attenuated PS-NPs and Cd-induced apoptosis. These results establish the IP3R/Ca²⁺/STAT3 axis as a pivotal regulatory switch governing intestinal apoptosis under NP-heavy metal co-exposure, providing mechanistic foundations for environmental risk assessment of combined pollutant exposure.
Keratinocytes exposed to Ozone induce a bystander oxinflammatory response in dermal fibroblasts.
Sarandy MM, Guiotto A, Ivarsson J … +2 more , Pecorelli A, Valacchi G
Toxicology · 2026 Jun · PMID 41831636 · Publisher ↗
While ozone (O₃) is widely recognized for its respiratory effects and its detrimental impact on skin health has been well demonstrated, the mechanisms underlying dermal damage remain incompletely understood. This study i...
While ozone (O₃) is widely recognized for its respiratory effects and its detrimental impact on skin health has been well demonstrated, the mechanisms underlying dermal damage remain incompletely understood. This study investigates the biological effects of O₃ on human skin using both clinical and in vitro approaches, focusing on the interactions between O₃-exposed keratinocytes and unexposed fibroblasts, to investigate a potential bystander effect. Fifteen healthy volunteers underwent repeated forearm exposure to O₃, and skin biopsies were analyzed for extracellular matrix components and oxidative stress markers. In parallel, keratinocytes were exposed to O₃ in vitro, and their conditioned medium was applied to dermal fibroblasts to evaluate viability, oxidative stress, DNA damage, aryl hydrocarbon receptor (AhR) activation, and matrix metalloproteinase-9 (MMP-9) activity. After O₃ exposure, human skin biopsies revealed decreased expression of key extracellular matrix (ECM) components, including tropoelastin, elastin and collagen III, as well as increased levels of 8-OHdG and AhR. Mechanistic in vitro investigations revealed that conditioned medium from O₃-treated keratinocytes reduced fibroblast viability, and triggered oxidative stress, mitochondrial ROS production, lipid peroxidation, and DNA damage in unexposed dermal fibroblasts. These changes were accompanied by AhR activation and increased MMP-9 activity, leading to ECM protein degradation. Collectively, these findings identify a previously underappreciated paracrine pathway through which O₃-induced oxidative mediators propagate damage from the epidermis to the dermis. This mechanism provides new insight into how environmental O contributes to skin aging and structural deterioration, highlighting the broader cutaneous health implications of air pollution exposure.
Polyvinyl chloride microplastics exposure accelerates endometrial cancer progression via regulating AHR/CYP1A1 signaling pathway.
Zhang L, Chen D, Fan R … +5 more , Chen L, Chen H, Wu M, Liu J, Lin X
Toxicology · 2026 Jun · PMID 41825789 · Publisher ↗
Endometrial cancer (EC) is one of the most prevalent gynaecological cancers among women. Despite the advent of advanced therapeutic approaches, the mortality rate of EC has not declined but rather shows an increasing tre...
Endometrial cancer (EC) is one of the most prevalent gynaecological cancers among women. Despite the advent of advanced therapeutic approaches, the mortality rate of EC has not declined but rather shows an increasing trend, which is closely associated with its rising incidence. No viable strategies have been established to curb the rising incidence of EC. Polyvinyl hloride microplastics (PVC-MPs) represent ubiquitous environmental contaminants. Increasing evidences demonstrate the carcinogenic potential of PVC-MPs exposure. However, PVC-MPs specific role and mechanisms in EC remain unelucidated. This study provides the first comprehensive evidence that PVC-MPs exacerbate EC progression by activating the AHR/CYP1A1 pathways, driving proliferation, migration, invasion. The tumor-promoting effects of PVC-MPs were further validated in primary human endometrial cancer cells and mouse models (including both cell line-derived xenograft and patient-derived xenograft), substantially strengthening the robustness and translational relevance of our study. Collectively, these findings establish PVC-MPs as an environmental risk factor for EC and identify AHR/CYP1A1 signaling pathway as potential therapeutic targets to mitigate the adverse effects of microplastic exposure, developing preventive interventions in exposed populations against EC (Graphic abstract).
The role of autophagy in mycotoxin-induced toxicity: A review.
Xu Y, Liu M, Chen J … +5 more , Liu Z, Ma S, Liu Y, Yan G, Xu X
Toxicology · 2026 Jun · PMID 41802625 · Publisher ↗
Mycotoxins are widespread toxic secondary metabolites produced by fungi, posing substantial health risks to humans and animals. Recent studies have highlighted the crucial role of autophagy in mediating mycotoxin-induced...
Mycotoxins are widespread toxic secondary metabolites produced by fungi, posing substantial health risks to humans and animals. Recent studies have highlighted the crucial role of autophagy in mediating mycotoxin-induced toxicity. As a highly conserved intracellular degradation pathway, autophagy maintains cellular homeostasis by selectively removing damaged organelles and misfolded protein aggregates. However, its function in the context of mycotoxin exposure is dualistic: it can act either as a protective mechanism or contribute to detrimental cellular outcomes. This review focuses on recent advances in understanding the role of autophagy in mycotoxin-induced toxicity and discusses potential intervention strategies by targeting the autophagy pathway.
Mitochondrial toxicity of emerging disinfection byproduct 2,6-dichloro-1,4- benzoquinone in renal proximal tubule cells: Oxidative phosphorylation impairment and metabolic reprogramming.
Chen Y, Xu T, Gu L … +2 more , Guo X, Yin D
Toxicology · 2026 Jun · PMID 41802624 · Publisher ↗
2,6-Dichloro-1,4-benzoquinone (DCBQ), an emerging aromatic disinfection byproduct (DBP) frequently detected in drinking water, has raised increasing concern regarding its potential renal toxicity. However, its toxic effe...
2,6-Dichloro-1,4-benzoquinone (DCBQ), an emerging aromatic disinfection byproduct (DBP) frequently detected in drinking water, has raised increasing concern regarding its potential renal toxicity. However, its toxic effects at environmentally relevant concentrations and the underlying mechanisms remain unclear. In this study, human renal proximal tubule epithelial cells (RPTEC/TERT1) were exposed to intrarenal-equivalent levels of DCBQ (10, 100, and 1000 μg/L) to investigate mitochondrial toxicity under a worst-case exposure scenario. DCBQ induced mitochondrial dysfunction, characterized by impaired oxidative phosphorylation, reduced ATP production, decreased coupling efficiency, and disruption of electron transport chain (ETC) function. Suppression of ETC Complex I and III, together with aberrant activation of Complex II, was associated with increased reactive oxygen species generation and altered superoxide dismutase levels. In addition, DCBQ significantly disrupted the tricarboxylic acid cycle, as evidenced by decreased citrate, increased fumarate, and inhibited metabolic enzyme activity. Enhanced glycolysis further indicated metabolic reprogramming in response to mitochondrial impairment induced by DCBQ exposure. Collectively, these findings demonstrated that mitochondrial dysfunction and metabolic remodeling represent central mechanisms underlying DCBQ-induced toxicity in renal cells at environmentally relevant exposure levels, highlighting the importance of reassessing the health risks of chronic low-dose exposure to emerging DBPs.
Nicotine drives acute epithelial injury in region-specific human airway models at the air-liquid interface after e-cigarette aerosol exposure.
Kose O, Mercier C, Pourchez J
Toxicology · 2026 Jun · PMID 41796715 · Publisher ↗
Electronic cigarette aerosols are complex mixtures whose respiratory toxicity depends on formulation chemistry and regional deposition. This study investigated how nicotine presence, nicotine protonation state, and propy...
Electronic cigarette aerosols are complex mixtures whose respiratory toxicity depends on formulation chemistry and regional deposition. This study investigated how nicotine presence, nicotine protonation state, and propylene glycol/vegetable glycerin (PG/VG) ratio shape acute epithelial injury under controlled air-liquid interface (ALI) exposure. Well-defined e-liquid formulations differing in PG/VG ratio (70/30 or 30/70, w/w), nicotine concentration (0 or 20 mg/mL), and nicotine form (freebase or salicylic-acid salt) were aerosolized using a fourth-generation pod-based device and delivered at the ALI to human epithelial models representing the pharynx (Detroit 562), bronchi (Calu-3), and distal-airway (NCI-H441, alveolar type II-like). Cells were exposed to low and high aerosol doses corresponding to 2 and 20 puffs, resulting in deposited surface doses of approximately 33 and 330 µg/cm², respectively, as quantified gravimetrically. Cytotoxicity, epithelial barrier integrity, and inflammatory signaling were assessed 24 h post-exposure. Nicotine emerged as the primary driver of acute epithelial injury. Toxicity was modulated by formulation chemistry: freebase nicotine elicited more pronounced barrier-disruptive responses than the corresponding nicotine salt, while nicotine salts induced comparatively modest inflammatory signaling. PG-rich formulations amplified toxicity, particularly in distal airway-like cells. In contrast, pharyngeal epithelial cells remained largely unresponsive under identical conditions. Pro-inflammatory responses, assessed by interleukin-8 release, were limited and observed at high deposited doses. Overall, these findings demonstrate that acute e-cigarette aerosol toxicity under ALI conditions is nicotine-driven and influenced by nicotine speciation, solvent composition, and airway region, highlighting the importance of region-specific ALI models and surface-based dosimetry for toxicological assessment of inhaled products.
In vitro inhibition of monoamine transport by amphetamine-like pre-workout supplement ingredients.
Pinckaers NET, Sawicka PD, Wopken JP … +5 more , Blankesteijn WM, van Schooten FJ, Opperhuizen A, Vrolijk M, Westerink RHS
Toxicology · 2026 Jun · PMID 41796714 · Publisher ↗
Phenethylamine (PEA) and alkylamine (AA) analogues are a prominent group of pre-workout food supplement ingredients. They are structurally related to the stimulant amphetamine and to the endogenous catecholamines noradre...
Phenethylamine (PEA) and alkylamine (AA) analogues are a prominent group of pre-workout food supplement ingredients. They are structurally related to the stimulant amphetamine and to the endogenous catecholamines noradrenaline and dopamine, implying potential cardiovascular and psychological effects. This study systematically investigated the inhibitory potential of 12 PEAs and 4 AAs identified in pre-workout supplements on the human dopamine transporter (hDAT), human noradrenaline transporter (hNET) and human serotonin transporter (hSERT) that are stably overexpressed in HEK 293 cells. All PEAs and AAs tested, except DMAE, inhibited substrate uptake by one or more monoamine transporters. Overall, the substances displayed the highest potency and efficacy at hNET, followed by hDAT and with considerably weaker effects on hSERT. At hNET, potency values (IC) ranged from 0.5 µM to 123 µM, with maximal inhibition (E) ranging from -59.2% to -120%. Inhibition of substrate uptake by hDAT occurred with IC values between 4.0 and 95.8 µM and E values between -66.8% and -135%. For hSERT 50% inhibition was observed at concentrations ranging from 2.6 µM to 131 µM, with maximal effect between 85.3% and -64.8%. These findings indicate a potential for sympathetic activation and behavioral rewarding and reinforcing effects. Notably, the in vitro potency and efficacy of several PEAs and AAs were comparable to those of the well-known illicit stimulants amphetamine and cocaine. Together, these findings highlight the urgent need to further characterize pharmacokinetic and pharmacodynamic properties of these pre-workout supplement ingredients to support robust risk assessment and informed regulatory decision-making regarding the safety of pre-workout supplement ingredients.
Fertility decline induced by subchronic exposure to an atrazine-mesotrione mixture in male Wistar rats.
Guimarães-Ervilha LO, Lopes IDS, Assis MQ … +12 more , Bento IPDS, Iasbik-Lima T, Faria JVL, Almeida LMR, Carvalho RPR, Coimbra JLP, Silva RCD, Soares FAF, Toma APMF, Costa GMJ, Clarindo WR, Machado-Neves M
Toxicology · 2026 Jun · PMID 41796713 · Publisher ↗
A commercial atrazine-mesotrione mixture (Calaris®) is widely used in agriculture due to its improved weed control. However, toxicological data on this combination remain elusive, especially regarding its effects on mamm...
A commercial atrazine-mesotrione mixture (Calaris®) is widely used in agriculture due to its improved weed control. However, toxicological data on this combination remain elusive, especially regarding its effects on mammalian health. Herein, we investigated the effects of subchronic exposure to 2 and 20 mg Kg of Calaris® in male Wistar rats, focusing on reproductive parameters. Eighty days of daily exposure to 20 mg Kg of Calaris® elicited nitrosative stress and ionic disturbance in the hypothalamus, and low serum LH levels. In the testis, the highest dose disrupted the activity of antioxidant enzymes, total and Mg-ATPases, interfered with the homeostasis of Fe, Zn, Mg, and Se, and damaged the DNA of testicular cells. Although the number of normal seminiferous tubules was higher than that of abnormal tubules, alterations in epithelium height and luminal diameter reflected the low number of spermatids and daily sperm production. Spermatozoa were exposed to an oxidative and nitrosative environment in the proximal epididymis and a nitrosative stress in its distal portion. Rats exposed to the highest dose exhibited low sperm motility and midpiece mitochondria activity, besides a high rate of preimplantation loss after mating with healthy females. Their fetuses, in turn, showed a low anogenital distance, suggesting possible epigenetic and/or endocrine effects. Calaris® at low dose caused less damage than the highest dose, primarily affecting the nitrosative and ionic balance of the tissues. Our findings raise concerns about the long-term safety of pesticide mixtures, underscoring the need to understand environmental risk assessments for combined agrochemical exposures.
Redox imbalance and glutathione metabolism disruption drive neodymium - induced neurotoxicity in microglia.
Wang J, Qin X, Feng L … +6 more , Han Y, Wang Z, Wang N, Zhang J, Zhou Z, Chang X
Toxicology · 2026 Jun · PMID 41796712 · Publisher ↗
Neodymium (Nd), a rare earth element widely used in clean energy and electronic technologies, has raised increasing concern for its potential neurotoxic effects. Microglia, the primary immune cells of the central nervous...
Neodymium (Nd), a rare earth element widely used in clean energy and electronic technologies, has raised increasing concern for its potential neurotoxic effects. Microglia, the primary immune cells of the central nervous system, are particularly sensitive to environmental chemicals. In this study, we investigated the effects of neodymium nitrate [Nd(NO₃)₃] on microglial physiology and metabolism using integrated cellular and metabolomic analyses. Nd exposure disrupted microglial homeostasis by impairing proliferation, suppressing phagocytosis, and promoting M1-type proinflammatory polarization. Accumulation of reactive oxygen species (ROS) and depletion of glutathione indicated pronounced oxidative stress and redox imbalance, accompanied by mitochondrial damage and ATP loss. Untargeted metabolomics revealed concentration-dependent metabolic reprogramming, with early perturbations in glutathione metabolism and the glyoxalase system as central events driving oxidative and inflammatory responses. Among the differentially altered metabolites, S-lactoylglutathione and glutathione showed the highest sensitivity and strongest correlation with inflammatory phenotypes. Downregulation of glyoxalase enzymes (GLO1 and GLO2) further confirmed compromised antioxidant capacity and impaired detoxification. Collectively, these findings demonstrate that Nd induces microglial dysfunction through disruption of the glutathione-glyoxalase redox axis, providing new mechanistic insight into how rare earth element exposure may contribute to neurotoxicity.
Bridging AI advancements with risk assessment needs: A journey towards effective use and regulatory acceptance.
Kolesnyk S, Souza JP, Bearth A … +4 more , Aicher L, Wilks MF, Mosig A, Fritsche E
Toxicology · 2026 Jun · PMID 41786018 · Publisher ↗
In recent years, the development of artificial intelligence (AI), including machine learning (ML) and deep learning (DL), has not only captured the attention of scientists, industry, and society due to its vast potential...
In recent years, the development of artificial intelligence (AI), including machine learning (ML) and deep learning (DL), has not only captured the attention of scientists, industry, and society due to its vast potential, but also sparked debates regarding the reliability, transparency, and legal as well as ethical implications of AI systems and tools. At the same time, toxicology is undergoing a paradigm shift toward New Approach Methodologies (NAMs). The implementation of NAMs necessitates an evolution of chemical risk assessment (CRA) approaches, giving rise to the concept of next-generation risk assessment (NGRA). It also transforms the field of regulatory toxicology into a data-rich discipline entailing the generation and management of increasingly large and complex datasets. For data handling and interpretation, these changes require effective integration of AI tools in chemical testing and assessment. In this narrative review, we examine the current landscape of AI applications relevant to CRA and NGRA. These tools can be broadly categorized into two domains: evidence management and evidence generation. They might support the discovery of toxicological mechanisms, biomarker identification, Adverse Outcome Pathway (AOP) development, and modeling of toxicokinetic and toxicodynamic processes as well as exposure assessment. Finally, we identify areas where further progress is required to ensure the successful integration of AI tools into CRA by extending beyond technical validation and guiding the development of detailed criteria for their regulatory acceptance.
From in vitro to in vacuo: a call for space toxicology research.
Cools B, Vinken M
Toxicology · 2026 Jun · PMID 41740917 · Publisher ↗
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Proquinazid, a new-generation fungicide, induces DNA damage and apoptosis via oxidative stress process in liver and kidney tissues of adult Wistar rats.
Rich S, Rjiba K, Ayed I … +4 more , Torrens C, Babajko S, Taihi I, Abid S
Toxicology · 2026 Jun · PMID 41734831 · Publisher ↗
Proquinazid (PROQ) is a new fungicide used against powdery mildew infections, but little is known about PROQ toxicity. The aim of this study was to investigate the effects of PROQ in liver and kidney. Male Wistar rats we...
Proquinazid (PROQ) is a new fungicide used against powdery mildew infections, but little is known about PROQ toxicity. The aim of this study was to investigate the effects of PROQ in liver and kidney. Male Wistar rats were daily exposed for 28 days to 1, 2, 4, and 8 mg PROQ / kg body weight, corresponding to No-Observable Adverse Effect Level (NOAEL)/ 2, NOAEL, NOAEL × 2, and NOAEL × 4, respectively. PROQ caused histopathological disruptions in both hepatic and renal functions associated with increased plasmatic activities of alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and transaminases (AST and ALT), and levels of creatinine, uric acid, and urea. Oxidative stress analysis showed that PROQ induced an increase in malondialdehyde (MDA) and protein carbonyl levels with a conspicuous disruption of superoxide dismutase, catalase, glutathione S-transferase and glutathione peroxidase activities. Oxidative stress generation was accompanied with DNA damage assessed by comet and TUNEL assays. PROQ down-regulated Bcl-2 and PCNA expression and up-regulated p53, Bax and caspase-3 expression evaluated by immunohistochemistry and western blotting. Overall, our outcomes highlighted that PROQ is a hepatotoxic and nephrotoxic fungicide that exerts its toxic effects through disruption of oxidative balance which causes genotoxic damage leading to apoptotic cell death.
Polystyrene nanoplastics disrupt iron homeostasis by promoting FPN1 ubiquitination in GC-2spd(ts) cells.
Cui X, Shang Y, Ding L … +7 more , Zhang Z, Deng Y, He T, Xu B, Fu X, Du X, Han H
Toxicology · 2026 Jun · PMID 41722726 · Publisher ↗
Nanoplastics are emerging environmental pollutants ubiquitously found in natural ecosystems. Although studies have shown that nanoplastics can accumulate in the testes of mice and affect spermatogenic cells, the specific...
Nanoplastics are emerging environmental pollutants ubiquitously found in natural ecosystems. Although studies have shown that nanoplastics can accumulate in the testes of mice and affect spermatogenic cells, the specific toxicological mechanisms remain unclear. To investigate the specific mechanism by which polystyrene nanoplastics induce ferroptosis in mouse spermatocyte-derived GC-2spd(ts) cells and subsequently lead to male reproductive toxicity, this study exposed mouse germ cell lines (GC-1 spg and GC-2spd(ts)) to PS-NPs of two sizes (50 nm and 90 nm). Cell viability assays indicated that GC-2spd(ts) cells were more sensitive to PS-NPs exposure. Transcriptomic and proteomic analyses revealed that PS-NPs exposure induced intracellular reactive oxygen species (ROS) accumulation and significant alterations in related pathways, specifically activating the ferroptosis signaling pathway. Further mechanistic studies demonstrated that PS-NPs disrupted intracellular iron homeostasis, leading to the accumulation of labile Fe , enhanced lipid peroxidation, depletion of the antioxidant glutathione, and mitochondrial dysfunction. At the molecular level, PS-NPs upregulated the expression of iron uptake-related proteins and significantly downregulated the iron exporter protein ferroportin1 (FPN1). In-depth investigation revealed that PS-NPs did not affect the transcriptional level of FPN1 but promoted FPN1 protein degradation by enhancing its ubiquitination modification, subsequently via the proteasome-dependent pathway. This process resulted in blocked cellular iron efflux, iron ion accumulation, and ultimately triggered ferroptosis. This study elucidates the molecular mechanism by which PS-NPs regulate FPN1 degradation through the ubiquitin-proteasome pathway, disrupt iron metabolic homeostasis, and thereby induce ferroptosis in germ cells, providing novel experimental evidence for assessing the male reproductive toxicity of nanoplastics.
Cl-PFESA disrupts thyroid hormone secretion in human thyrocytes and nonmonotonic effects of iodide co-exposure.
Teng M, Zhuang J, Yang L … +4 more , Chen Y, Andersen ME, Zhang Q, Qu W
Toxicology · 2026 May · PMID 41722725 · Publisher ↗
Chlorinated polyfluoroalkyl ether sulfonic acids (Cl-PFESAs, F-53B) are widespread environmental pollutants that have been introduced as emerging alternatives to perfluorooctane sulfonate. They are suspected to have thyr...
Chlorinated polyfluoroalkyl ether sulfonic acids (Cl-PFESAs, F-53B) are widespread environmental pollutants that have been introduced as emerging alternatives to perfluorooctane sulfonate. They are suspected to have thyroid-disrupting effects, however, their impact on human thyroid hormone (TH) synthesis and the underlying mechanisms remain poorly understood. Using Cl-PFESAs at concentrations relevant to children's serum levels, in the present study we found that Cl-PFESA mixture significantly elevated thyroxine (T4) and triiodothyronine (T3) synthesis in human thyroid follicular epithelial cells (Nthy-ori 3-1)-contrasting with the hypothyroid effect reported in animal studies. We further demonstrated that mechanistically Cl-PFESAs activated transcription factor paired box gene 8 (PAX8) at environmentally relevant concentrations, upregulating thyroglobulin, thyroid peroxidase, and catalase while downregulating sodium iodide symporter. PAX8 knockdown completely abolished Cl-PFESA-induced upregulation of thyroid-specific transcription factors and TH hypersecretion, confirming that PAX8 plays a central role in mediating the TH-stimulating effect of Cl-PFESA. Furthermore, co-exposure with iodide exhibited a nonmonotonic effect: low-to-medium iodide levels (100-300 μg/L) enhanced Cl-PFESA-stimulated TH secretion, whereas high levels (≥600 μg/L) suppressed it. Taken together, this study revealed a novel, human thyrocyte-specific hyperthyroid effect of Cl-PFESA at children serum relevant concentrations and a PAX8-mediated molecular mechanism. Our findings provide crucial toxicological evidence for the human health risk that this class of emerging PFAS alternatives may pose and its potential complications by iodine intake status.
Prenatal arsenic exposure and gene expression in fetal liver, heart, lung, and placenta.
Rychlik KA, Sanchez SS, Kashiwagi C … +6 more , Liao JS, Mathur A, Illingworth EJ, Kleensang A, Maertens A, Sillé FCM
Toxicology · 2026 May · PMID 41679378 · Full text
Prenatal arsenic exposure has been linked to a myriad of negative health effects. There is relatively little insight into the mechanisms and signaling alterations across different fetal organs that drive long-term immune...
Prenatal arsenic exposure has been linked to a myriad of negative health effects. There is relatively little insight into the mechanisms and signaling alterations across different fetal organs that drive long-term immune-related issues following prenatal arsenic exposure. Therefore, the effects of this exposure window on gene expression in the liver, placenta, heart, and lung of gestation day (GD) 18 C57BL/6 mouse fetuses were investigated. From two weeks prior to mating until tissue collection at GD18, mice were exposed to 0 or 100 ppb sodium (meta) arsenite in drinking water, ad libitum. Genes of interest were analyzed by RT-qPCR, complemented with untargeted Agilent 44 K microarray analysis. Data cleanup and analysis was performed in RStudio. Differentially expressed mRNAs were queried in the String Database and using Cytoscape to create interaction networks and identify significantly enriched biological pathways. A total of 251, 165, 158, and 41 genes were significantly altered in the liver, placenta, heart, and lung, respectively, when treated samples were compared to controls. Many altered pathways were immune-related, supporting prior research. Most notably, gene expression of Gbp3, a key player in the cellular response to interferon gamma, was found to be reduced in placentas of male fetuses exposed to arsenic compared to controls (p = 0.0237). IMPACT: This is the first study comparing alterations in gene expression across multiple organs following prenatal exposure to environmentally relevant levels of arsenic. These findings, elucidating the multi-organ impact of prenatal arsenic exposure on predominantly immune-related pathways, further our mechanistic understanding of the long-term health effects observed in early-life arsenic-exposed populations.
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