Toxicology[JOURNAL]
Sun
200 papers
Dysregulation of xenobiotic metabolism and mitochondrial dysfunction exacerbate acetaminophen-induced hepatotoxicity in human antigen R-deficient male mice.
Eppler N, Jones E, Ahamed F … +16 more , Raja N, Akakpo JY, Lebofsky M, He L, Vats I, Ghosh P, Yu Y, Thomas K, McCoin C, Thyfault J, Wu X, Xu L, Cui W, Wang R, Jaeschke H, Zhang Y
Toxicology · 2026 Sep · PMID 42061604 · Full text
Acetaminophen (APAP) overdose is a leading cause of acute liver failure worldwide. The RNA-binding protein Human antigen R (HuR) is a multifunctional post-transcriptional regulator that plays a pivotal role in cellular s...
Acetaminophen (APAP) overdose is a leading cause of acute liver failure worldwide. The RNA-binding protein Human antigen R (HuR) is a multifunctional post-transcriptional regulator that plays a pivotal role in cellular stress responses, including those triggered by APAP toxicity. This study investigated the protective role and mechanisms of HuR in APAP-induced hepatotoxicity in male mice. Hepatocyte-specific HuR-deficient (HuR) mice on a C57BL/6 N background and wild-type (WT) littermates were treated with 200 mg/kg APAP, and liver tissues were collected at 2, 6, and 24 h post-treatment. APAP exposure increased hepatic HuR mRNA expression and induced both HuR cleavage and the formation of a higher-molecular-weight HuR species, which correlated with injury severity. Compared with WT controls, HuR mice exhibited markedly increased susceptibility to hepatotoxicity at both 2 and 6 h. Metabolite profiling revealed altered APAP metabolism and reduced expression of glutathione S-transferases (Gsts) in HuR livers, consistent with impaired detoxification and increased APAP-protein adduct formation. Fourier-transform infrared (FTIR) spectroscopy further identified early biochemical alterations between genotypes as early as 2 h after APAP exposure. HuR deficiency also resulted in pronounced mitochondrial structural abnormalities and dysfunction, accompanied by reduced expression of mitochondrial fission and fusion proteins (Drp1 and Mfn2), increased mitochondrial protein release, and enhanced hepatocyte death. Mechanistically, HuR inhibition and overexpression studies demonstrated its regulatory role in genes involved in detoxification and mitochondrial integrity. Ribonucleoprotein immunoprecipitation (RNP-IP) confirmed direct binding of HuR to mRNAs encoding mitochondrial dynamics proteins (Drp1, Mfn2), detoxification enzymes (Gsta4, Gstm6), and antioxidant regulators (Nrf2, Gclc, Gclm). Collectively, these findings identify hepatocyte HuR as a critical regulator of xenobiotic metabolism and mitochondrial function and establish the essential role of HuR in early protection against APAP-induced hepatotoxicity.
Long-chain chlorinated paraffins (LCCPs) exposure induces testicular aging damage by triggering mitochondrial dysfunction.
Tian X, Kong Y, Ma S … +4 more , Xu C, Zhang R, Deng H, Lan H
Toxicology · 2026 Sep · PMID 42061603 · Publisher ↗
LCCPs is a widely recognized environmental pollutant, and its hazards to the environment and organisms have attracted significant attention. Toxicological research on LCCP's effects on the male reproductive system is lim...
LCCPs is a widely recognized environmental pollutant, and its hazards to the environment and organisms have attracted significant attention. Toxicological research on LCCP's effects on the male reproductive system is limited, with mechanisms not well understood. This study investigates LCCPs exposure's impact on testicular cell senescence and its regulatory mechanisms using GC-1 and TM4 testicular cell models. This study utilized techniques such as Western blot analysis, flow cytometry, indirect immunofluorescence, and confocal microscopy. We evaluated senescence-associated markers, such as SA-β-Gal staining and the proteins p16 and p21, demonstrating that LCCPs treatment significantly induced senescence in testicular cells. LCCPs increased ROS and inflammatory cytokines (IL-6, IL-8, TNF-α) while reducing mitochondrial membrane potential (MMP). Mechanistic studies demonstrated that LCCPs significantly hindered TFEB's nuclear translocation, consequently inhibiting the expression of genes associated with TFEB-regulated lysosomal biogenesis. This led to lysosomal dysfunction and reduced mitophagy of damaged mitochondria. Ultimately, dysfunctional mitochondria released large amounts of double-stranded DNA (dsDNA), excessively activating the pyroptosis pathway and promoting cellular pyroptosis. Similarly, in vivo experiments revealed that LCCPs increased the expression of inflammatory markers and reduced collagen levels in mouse testicular tissues, in line with the results observed in vitro. In conclusion, our findings indicate that LCCPs exposure induces testicular cell senescence in both in vitro and in vivo environments. This research lays a crucial groundwork for future investigations into the toxicological characteristics of LCCPs.
Integrated cellular and molecular evidence of Amitraz-induced oxidative stress in SH-SY5Y spheroids.
Franco-Campos F, Taroncher M, Rodríguez-Carrasco Y … +1 more , Ruiz MJ
Toxicology · 2026 Aug · PMID 42036009 · Publisher ↗
Amitraz (AMZ), a formamidine acaricide widely used in apiculture, is frequently detected in honey at concentrations exceeding regulatory limits; however, its toxicological mechanisms in human systems remain poorly charac...
Amitraz (AMZ), a formamidine acaricide widely used in apiculture, is frequently detected in honey at concentrations exceeding regulatory limits; however, its toxicological mechanisms in human systems remain poorly characterized. In this study, a spheroidal SH-SY5Y model was employed to investigate AMZ-induced oxidative stress under conditions that closely mimic structural and functional complexity of the in vivo models. Spheroids were exposed three concentrations of AMZ (IC, IC/2, and IC/3) for 24 h. The levels of cytotoxicity, oxidative stress parameters, and antioxidant responses were evaluated. AMZ exposure resulted in spatially heterogeneous cell death within the spheroid structure and a significant increase in intracellular reactive oxygen species (ROS) at the highest concentration. No significant changes were detected in mitochondrial superoxide production or mitochondrial membrane potential under the experimental conditions tested. At the level of transcription, AMZ (IC/2 and IC induced a selective upregulation of antioxidant and cytoprotective genes, including HMOX1, NQO1, and GPX1. Overall, AMZ induces a spatially heterogeneous oxidative stress response in SH-SY5Y spheroids, characterized by intracellular redox imbalance, without mitochondrial involvement. The findings of this study underscore the significance of employing three-dimensional models to achieve a more profound comprehension of the deleterious effects that pesticides exert on complex organisms, such as spheroids, in contrast to the two-dimensional model that is presently utilized for this purpose.
Targeting CX3CR1 inhibits silica-induced epithelial-mesenchymal transition and pulmonary fibrosis in mice via the NF-κB signaling pathway.
Zhang J, Wang Y, Huo C … +7 more , Jiao X, Zeng X, Li J, Zhu Z, Wang Y, Tian L, Wang Y
Toxicology · 2026 Aug · PMID 42034183 · Publisher ↗
Silicosis is the most severe occupational disease, with complex fibrotic mechanisms and a lack of effective therapies. Macrophage CX3CR1 has recently been found to play an important role in fibrosis diseases, and our pre...
Silicosis is the most severe occupational disease, with complex fibrotic mechanisms and a lack of effective therapies. Macrophage CX3CR1 has recently been found to play an important role in fibrosis diseases, and our previous studies have revealed that silica induced epithelial-mesenchymal transition (EMT) via macrophages and EMT was closely related to silicosis fibrosis. However, whether macrophage CX3CR1 is involved in silica-induced EMT and pulmonary fibrosis remains unclear. This study aimed to clarify the role and mechanism of macrophage CX3CR1 in silica-induced EMT and pulmonary fibrosis. A silicosis model was established in two types of transgenic mice (Cx3cr1-knockout and Sftpc-EGFP mice), and CX3CR1 was inhibited via gene knockout and pharmacological intervention. Results showed that silica up-regulated CX3CR1 and induced EMT in alveolar epithelial cells while inhibiting CX3CR1 significantly alleviated EMT and fibrosis. In vitro two types of Cx3cr1 siRNA were used in RAW264.7 cells, and it showed that targeting CX3CR1 suppressed silica-induced EMT in MLE-12 cells. Transcriptomic analysis revealed enrichment of the NF-κB pathway in vivo. In vitro experiments further confirmed that combined inhibition of CX3CR1 and NF-κB synergistically alleviated silica-induced EMT. These findings indicate that the CX3CR1-NF-κB axis plays an important role in silica-induced EMT and pulmonary fibrosis, and targeting CX3CR1 inhibits silica-induced epithelial-mesenchymal transition and pulmonary fibrosis in mice via the NF-κB signaling pathway, providing new insights for the prevention and treatment of silicosis.
Cadmium-induced hepatotoxicity: Interconnecting molecular and cellular pathways.
Ezhilarasan D, Sharmila M
Toxicology · 2026 Aug · PMID 42031159 · Publisher ↗
Cadmium (Cd) is a persistent environmental toxicant with a prolonged biological half-life that accumulates in the liver following oral, intraperitoneal, or inhalational exposure. Experimental studies in murine models dem...
Cadmium (Cd) is a persistent environmental toxicant with a prolonged biological half-life that accumulates in the liver following oral, intraperitoneal, or inhalational exposure. Experimental studies in murine models demonstrate that Cd-induced hepatotoxicity is driven by interconnected mechanisms involving oxidative stress, mitochondrial dysfunction, inflammation, DNA damage, energy imbalance, and disruption of lipid homeostasis. After entering hepatocytes via metal transporters, Intracellularly, Cd binds to metallothioneins as a primarly detoxification mechanism; however, excessive exposure overwhelms this detoxification system, allowing free Cd to accumulate in mitochondria and the endoplasmic reticulum (ER), thereby initiating cellular dysfunction. Oxidative stress represents a central mechanism of Cd toxicity. Cd increases reactive oxygen species, lipid peroxidation, and reactive nitrogen intermediates while suppressing antioxidant defenses, including superoxide dismutase, catalase, glutathione, and related enzymes. This impairment is closely linked to inhibition of the nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) pathway, resulting in disrupted redox homeostasis and enhanced hepatic inflammation and fibrogenesis. Concurrently, Cd disrupts mitochondrial respiration, membrane potential, and bioenergetics, and activates ER stress signaling, further exacerbating metabolic dysfunction and potentially contributing to metabolic dysfunction-associated steatotic liver disease. Cd exposure also stimulates inflammatory pathways, including TLR4/NF-κB signaling and NLRP3 inflammasome activation, promoting cytokine production and immune cell infiltration. Moreover, multiple regulated cell death mechanisms such as apoptosis, ferroptosis, pyroptosis, and autophagy dysfunction along with genotoxic and epigenetic alterations, aggravate liver injury. Collectively, these findings highlight oxidative stress-mediated DNA damage, impaired repair mechanisms, and genomic instability as key contributors to Cd-induced hepatotoxicity.
Nicotine alters alveolar-barrier integrity by blocking autophagy and occludin trafficking.
Sabo AN, Filaudeau E, Lebert A … +4 more , Da Silva S, Becker G, Monassier L, Kemmel V
Toxicology · 2026 Aug · PMID 42031158 · Publisher ↗
Tobacco smoke inhalation disrupts the integrity of the alveolar-capillary barrier (ACB) and contributes to the pathogenesis of multiple chronic pulmonary diseases as chronic obstructive pulmonary disease (COPD). Nicotine...
Tobacco smoke inhalation disrupts the integrity of the alveolar-capillary barrier (ACB) and contributes to the pathogenesis of multiple chronic pulmonary diseases as chronic obstructive pulmonary disease (COPD). Nicotine, a major component of both cigarette smoke and electronic cigarette (e-cigarette) aerosol, is predominantly deposited on the alveolar surface, where it is rapidly absorbed, yet its specific contribution to ACB dysfunction remains insufficiently characterized. Our objective was to decipher the effects of nicotine across a wide concentration range (2.5 µM to 250 mM) on the modulation of the ACB in vitro. To this end, the following endpoints were investigated: cell viability (MTS and BrdU assays), cytotoxicity (LDH assay), mitochondrial oxidative stress (MitoSOX assay) and barrier integrity using Trans-Epithelial/Endothelial Electric Resistance (TEER) following exposure to increasing nicotine concentrations. Autophagic flux (LC3B-II, p62 and LAMP2 protein expression and localization) and occludin modulation and trafficking were also examined and compared with the effects of bafilomycin A1. Nicotine exposure slowed cell proliferation and enhanced mitochondrial reactive oxygen species (ROS) production, effects that were partially reversed by N-acetyl-cysteine (NAC). Nicotine inhibited autophagic flux through a mechanism distinct from that of bafilomycin A1, and this inhibition was partially reversed by NAC. In parallel, nicotine compromised barrier integrity, inducing a TEER decrease associated with occludin internalization and defective lysosomal degradation and recycling. These findings identify nicotine as an independent disruptor of ACB integrity, acting through oxidative stress, impaired autophagy and junctional remodeling, mechanisms relevant to smoking-related pulmonary diseases beyond COPD, including those associated with e-cigarette use.
Long-term exposure to N-(phosphonomethyl)glycine is associated with cancer stem cell-like properties in hormone-responsive breast cancer cells.
Soto-Jiménez D, Carrillo-Beltrán D, Pérez-Moreno P … +2 more , Quezada-Romegialli C, Muñoz JP
Toxicology · 2026 Sep · PMID 42025940 · Publisher ↗
N-(phosphonomethyl)glycine, commonly known as glyphosate, is the most extensively used herbicide worldwide. Its widespread application in agriculture has led to continuous human exposure through food residues, contaminat...
N-(phosphonomethyl)glycine, commonly known as glyphosate, is the most extensively used herbicide worldwide. Its widespread application in agriculture has led to continuous human exposure through food residues, contaminated water, and occupational contact. Although its carcinogenic risk remains inconclusive, mechanistic studies suggest endocrine-related signaling, oxidative stress, and epigenetic disruption may influence tumor biology. This study investigated whether prolonged exposure to glyphosate, at concentrations within the reported human exposure range, is associated with the acquisition of stem-like features and therapy tolerance in breast cancer cells. Estrogen receptor (ER)-positive MCF7 and triple-negative MDA-MB-231 cells were continuously exposed to 0.1 μM glyphosate for 8 weeks under non-cytotoxic conditions. Stemness and aggressiveness were assessed using mammosphere assays, soft-agar colony formation, migration assays, and doxorubicin dose-response testing, complemented by Western blot analysis of stemness-associated transcription factors. Chronic exposure increased mammosphere formation efficiency in both lines, accompanied by remodeling of stemness regulators, including increased Sox2 with reduced Nanog in MCF7 cells, alongside elevated β-catenin. Functionally, long-term exposure enhanced migratory behavior and anchorage-independent growth, and reduced doxorubicin sensitivity in MCF7 cells, with clonogenic persistence under doxorubicin challenge. These findings indicate that sustained exposure to glyphosate, at a concentration within the reported human exposure range, is associated with features consistent with a cancer stem-like and adaptive phenotype in breast cancer cells.
CD44 expression in renal tubules during maladaptive repair is a potential marker for the transition from acute kidney injury to chronic kidney disease in rats.
Matsushita K, Akane H, Akagi JI … +4 more , Morikawa T, Mizuta Y, Ogawa K, Toyoda T
Toxicology · 2026 Aug · PMID 42019744 · Publisher ↗
Renal tubular epithelial cells (TECs) are major targets of drug-induced kidney injury, a cause of acute kidney injury (AKI). Although TEC regeneration aids recovery, maladaptive repair promotes fibrosis and chronic kidne...
Renal tubular epithelial cells (TECs) are major targets of drug-induced kidney injury, a cause of acute kidney injury (AKI). Although TEC regeneration aids recovery, maladaptive repair promotes fibrosis and chronic kidney disease (CKD). CD44 has been reported to localize predominantly to dilated/atrophic TECs in the fibrotic lesions of rat CKD models, suggesting enrichment in failed-repair TECs, but its dynamics during the AKI-to-CKD transition are unclear. We examined CD44 across rat models spanning adaptive repair and AKI-to-CKD transition induced by renal ischemia/reperfusion (I/R; 30 or 60 min) or cisplatin nephrotoxicity (2 or 6 mg/kg, i.p.) through day 28. In the AKI-to-CKD transition settings (I/R 60 min and cisplatin 6 mg/kg), CD44 was induced in dilated/atrophic TECs before fibrosis. Re-analysis of mouse I/R single-cell RNA-seq confirmed Cd44 enrichment in maladaptive TEC clusters. In the cisplatin model, serum CD44 rose early and remained elevated after conventional markers normalized, paralleling renal CD44 induction. Microarray profiling of microdissected dilated/atrophic TECs revealed a matrix-associated signature. Immunohistochemistry showed reduced aquaporin 1, vimentin induction, and that CD44 tubules remained enclosed by a laminin-positive basement membrane. Pathway analysis predicted CD44 as a putative upstream regulator of fibrosis-related genes including Fn1; increased Fn1 mRNA in dilated/atrophic TECs with peritubular fibronectin accumulation suggested a possible tubular contribution to matrix deposition. Together, these findings support tissue CD44 as a candidate marker of maladaptive tubular repair during the AKI-to-CKD transition and suggest serum CD44 as a candidate circulating indicator in cisplatin nephrotoxicity.
Acute alcohol exposure induces reproductive behavior defects, subfertility, brain transcriptomic changes of parental zebrafish and malformation in their offspring.
Peng L, Lei JY, Meng YY … +2 more , Li SC, Dai XY
Toxicology · 2026 Aug · PMID 42002020 · Publisher ↗
Alcohol is a prevalent addictive substance and the consequences of alcohol abuse pose a significant public health concern. Despite its prevalence and pervasiveness in the modern world, the underlying mechanisms mediating...
Alcohol is a prevalent addictive substance and the consequences of alcohol abuse pose a significant public health concern. Despite its prevalence and pervasiveness in the modern world, the underlying mechanisms mediating alcohol's deleterious effects on vertebrate reproductive behaviors remain poorly understood due to its complex pharmacology. Using adult zebrafish (Danio rerio) as a model, we investigated the effects of 40-minute acute alcohol exposure (0.25%, 0.50%, 0.75% vol/vol) on reproductive behaviors, fecundity, offspring development, and brain transcriptomes. Results show that acute alcohol exposure impairs courtship behaviors in a dose-dependent manner, along with significantly suppressed fecundity at 0.75% alcohol group. Additionally, parental exposure also induces offspring deformities and growth retardation. The brain transcriptomic analysis shows that 127 co-upregulated genes and 113 co-downregulated genes in female brain, 58 co-upregulated genes and 91 co-downregulated genes in male brain; GO/KEGG analyse further reveal the key signaling pathways and genes involved in alcohol-induced reproductive impairment, with sexually dimorphic transcriptomic patterns observed in the brains of male and female zebrafish. This study demonstrates that acute alcohol exposure of parental zebrafish can influence brain function, courtship behavior, and offspring development, providing insights into the reproductive toxicity of alcohol.
Ethylene glycol poisoning induces nephrolithiasis including complement-fibrinogen-related renal tubular injury in rats.
Unuma K, Isa S, Noritake K … +3 more , Yamada A, Aki T, Tojo A
Toxicology · 2026 Aug · PMID 41991143 · Publisher ↗
Renal tubular damage is one of the hallmarks of ethylene glycol (EG) poisoning and is associated with calcium oxalate crystals in the kidney. We firstly conducted transcriptome analysis to search novel mechanisms of rena...
Renal tubular damage is one of the hallmarks of ethylene glycol (EG) poisoning and is associated with calcium oxalate crystals in the kidney. We firstly conducted transcriptome analysis to search novel mechanisms of renal toxicity during EG intoxication (8 g/kg body weight, orally, 2 and 5 days) in rat kidney. Biochemical parameters in urine as well as blood plasma showed transient kidney injury that peaked at 2 days and recovered by 5 days after the administration of EG. Transcriptome analysis indicated the inductions of all fibrinogen genes (Fga, Fgb, and Fgg) and several complement components on day 2 and 5, respectively, suggesting the possible involvement of complement-fibrinogen in renal tubular injury. Immunostaining showed C3c and fibrinogen to be increased in renal tubules on day 2 of EG intoxication, confirming that the complement-fibrinogen axis may play a role in EG-related nephrolithiasis. Transmission electron microscopy (TEM) of proximal tubules showed fluid accumulations that may include EG metabolite oxalate, as well as autophagosomes containing ribosomes on days 2-5 of EG administration. TEM also indicated brush border injury in the proximal tubules, confirming renal injury after EG administration. These results revealed that the increase of complement components and fibrinogen results in aberrant deposition of these products. These findings should be beneficial for understanding the pathogenesis of EG-induced nephrolithiasis.
Mechanistic study on propoxate-induced neurotoxicity and addictive potential via blood-brain barrier disruption and GABAergic pathway activation.
Cao R, Ding S, Cai J … +4 more , Zhang J, Liu X, Ren Y, Liu C
Toxicology · 2026 Aug · PMID 41962649 · Publisher ↗
In recent years, propoxate (PPO), a structural analogue of etomidate (ETO), has been illicitly added to e-cigarette liquids, while its neurotoxic and addictive mechanisms remain unclear. In this study, 8-week-old male C5...
In recent years, propoxate (PPO), a structural analogue of etomidate (ETO), has been illicitly added to e-cigarette liquids, while its neurotoxic and addictive mechanisms remain unclear. In this study, 8-week-old male C57BL/6 J mice were used to evaluate the toxic and addictive effects of 3 mg/kg and 5 mg/kg PPO exposure through behavioral tests, molecular biology, and molecular docking. The results showed that PPO induced conditioned place preference, reduced locomotor activity, and anxiety- and depression-like behaviors. It accumulated dose-dependently in the brain and other tissues and increased blood-brain barrier (BBB) permeability by significantly downregulating tight junction-related genes (Ocln, Tjp1, Cldn5) and interfering with the ZO-1/Occludin complex via direct binding. PPO also induced oxidative stress, local inflammation, and neuronal apoptosis in the hippocampus and striatum. In addition, GABA_A receptor α1 expression was upregulated in the hippocampus, and PPO was found to bind to the α/γ2 subunit interface of the receptor, potentially modulating its function. Transcriptomic analysis further confirmed that PPO mediates neurotoxicity and addictive potential by suppressing genes associated with tight junction proteins and disrupting the GABAergic system. This study reveals the dual mechanisms underlying PPO-induced neurotoxicity and addiction, providing a molecular-level explanation for its environmental and public health risks.
Endocrine and metabolism modulating effects of paracetamol: From in vitro signaling to in vivo metabolic reprogramming in male mice.
Entezari B, Bozdag D, Buhur A … +3 more , Sabuncuoglu S, Yavasoglu A, Gurer-Orhan H
Toxicology · 2026 Aug · PMID 41946439 · Publisher ↗
Obesity is a major global health challenge associated with a cluster of comorbidities, including metabolic syndrome and type 2 diabetes, necessitating a deeper understanding of the environmental factors contributing to t...
Obesity is a major global health challenge associated with a cluster of comorbidities, including metabolic syndrome and type 2 diabetes, necessitating a deeper understanding of the environmental factors contributing to this epidemic. This study investigated the in vitro adipogenic/lipogenic potential of paracetamol and its in vivo endocrine and metabolic modulating effects following prenatal exposure. Using the 3T3-L1 preadipocyte model, cells were exposed to paracetamol at physiologically relevant concentrations. Results demonstrated that paracetamol promoted lipid accumulation and upregulated G3PDH activity. Furthermore, low concentrations significantly increased the protein expression of key adipogenic regulators (PPARγ, C/EBPα, LPL, and SREBP1), suggesting interference with transcriptional cascades governing adipogenesis and lipogenesis. To assess in vivo effects, pregnant CD1 mice were exposed to paracetamol at three human relevant doses (Cmax/10, Cmax, and Cmax×10). In male F1 offspring, prenatal exposure resulted in increased anogenital distance and a higher incidence of sperm morphological abnormalities, indicating reproductive developmental alterations despite unchanged circulating hormone levels. Metabolically, offspring exhibited dyslipidemia characterized by elevated serum triglycerides and total cholesterol. Although body weight and glucose tolerance remained unaffected, lipidomic profiling of epididymal adipose tissue revealed pronounced remodeling, including the accumulation of neutral lipids and altered membrane phospholipid composition. This was accompanied by the upregulation of the adipogenic genes Pparγ, Lpl, and Fasn in adipose tissue. Collectively, these findings suggest that paracetamol may act as an endocrine modulator and metabolic disruptor when exposed prenatally, inducing latent metabolic dysregulation that may predispose offspring to metabolic syndrome later in life, even in the absence of overt obesity.
A semi-automated workflow to quantify γ-H2AX DNA damage in pulmonary cell models and lung tissue sections.
Cherriere M, Oger M, De Araujo S … +15 more , Nasser F, Rival B, Butigieg X, Favier AL, Floreani M, Lecomte A, Robidel F, Rodrigues S, Barbier G, Peiffer J, Valente M, Lacroix G, François S, Loret T, Dekali S
Toxicology · 2026 Aug · PMID 41941935 · Publisher ↗
The quantification of DNA double-strand breaks via γ-H2AX immunolabeling is a cornerstone of genotoxicity assessment, yet classical nucleus-based counting is frequently constrained by cell morphology, high confluence, an...
The quantification of DNA double-strand breaks via γ-H2AX immunolabeling is a cornerstone of genotoxicity assessment, yet classical nucleus-based counting is frequently constrained by cell morphology, high confluence, and complex tissue architectures. To overcome these limitations, we developed and validated a semi-automated image analysis workflow that combines manual scoring with an optimized tool using two key metrics: the number of positive nuclei and the surface area of γ-H2AX foci. Validated across diverse biological systems, hAELVi, HPMEC-ST1.6 R cells and rat lung tissue sections exposed to varying genotoxic stressors, γ-irradiation (1 Gy), etoposide (10 µg·mL⁻¹), or bleomycin (2 U·kg⁻¹), our approach demonstrates excellent concordance with manual counting where segmentation is feasible. Specifically, the workflow was optimized to allow precise nucleus-based segmentation for the hAELVi model and tissue lung sections. However, for models where segmentation is not feasible, such as HPMEC-ST1.6 R, the surface-based metric was exclusively applied. Crucially, this surface-based metric successfully captured DNA damage induction in complex samples where per-nucleus segmentation was previously impossible. By providing a scalable, versatile alternative that bridges the gap between traditional cell culture assays and lung tissue sections, this methodology represents a standardized workflow for evaluating genotoxic stress in experimental contexts that were previously inaccessible to conventional quantification.
Reduced NR2F6 expression reshapes the VPA-induced transcriptome in human hepatocytes and increases lipid accumulation.
Guo K, Verheijen M, van Herwijnen M … +2 more , Caiment F, van den Beucken T
Toxicology · 2026 Aug · PMID 41936854 · Publisher ↗
Valproic acid (VPA) is an antiepileptic drug associated with hepatic steatosis, yet the transcriptional regulators determining cellular susceptibility to VPA remain incompletely defined. In a time-series RNA-sequencing a...
Valproic acid (VPA) is an antiepileptic drug associated with hepatic steatosis, yet the transcriptional regulators determining cellular susceptibility to VPA remain incompletely defined. In a time-series RNA-sequencing analysis of primary human liver spheroids, NR2F6 emerged as one of the nuclear regulators predicted to shape the hepatocellular response to VPA. In parallel, a shRNA screen targeting 42 nuclear receptors in HepG2 cells independently identified NR2F6 as a sensitizer of VPA toxicity. Functional validation in HepG2 and HepaRG models demonstrated that NR2F6 knockdown significantly increased VPA-induced lipid accumulation, whereas lipid accumulation triggered by oleic and palmitic acid remained unaffected, indicating a VPA-specific steatogenic vulnerability. To characterize NR2F6-dependent transcriptional programs, we performed RNA-sequencing in shNR2F6 and shGFP HepaRG cells exposed to VPA for 72 h. Although VPA was the principal driver of transcriptional variance, reduced NR2F6 expression markedly amplified the VPA-induced transcriptomic response. shNR2F6 cells exhibited coordinated upregulation of nuclear-encoded oxidative phosphorylation genes across Complexes I, III, IV, and V, while mitochondrial genome-encoded subunits remained unchanged, suggesting nuclear-driven mitochondrial compensation. NR2F6 knockdown also altered key lipid-associated pathways, including reduced induction of CPT1A and exaggerated induction of PLIN2, linking NR2F6 deficiency to impaired fatty-acid import and enhanced lipid-droplet accumulation. Together, these results identify NR2F6 as a key modulator of hepatocellular adaptation to VPA, linking nuclear receptor signaling to mitochondrial and lipid-metabolic remodeling and revealing a previously unrecognized regulatory node in drug-induced steatosis.
Application of HepaRG mono- and HepaRG:THP-1 cocultures as immune responsive hepatotoxicity models.
van Slobbe GJJ, Busch M, Bakker W … +2 more , Govers C, Bouwmeester H
Toxicology · 2026 Aug · PMID 41921650 · Publisher ↗
Embedding immune responsiveness is relevant for hepatotoxic testing strategies, as inflammation can affect the kinetics of compounds by modulation of drug-metabolizing enzymes and transporters (DMETs), and because inflam...
Embedding immune responsiveness is relevant for hepatotoxic testing strategies, as inflammation can affect the kinetics of compounds by modulation of drug-metabolizing enzymes and transporters (DMETs), and because inflammation is thought to explain some cases of idiosyncratic drug-induced liver injury (iDILI). Therefore, this study applied HepaRG monocultures and HepaRG:THP-1 macrophage cocultures as immune responsive hepatotoxicity models. To induce inflammation, HepaRG and THP-1 macrophages in mono- and coculture were stimulated with lipopolysaccharide (LPS) combined with interferon gamma (IFNγ). Proinflammatory cytokines interleukin (IL)6, IL8, IL1β and tumor necrosis factor alpha (TNFα) were quantified to verify an inflamed-like state. Our results showed that LPS and IFNγ elicited an inflamed-like state in both culture models, characterized by an increase in cytokine secretion. Next, mRNA expression and activity of DMETs was assessed in the stable and inflamed mono- and coculture model. Inflammation reduced the mRNA expression and activity of cytochrome P450 (CYP) enzymes, but did not reduce the mRNA expression and activity of efflux transporters in HepaRG mono- and cocultures. Finally, models were exposed to iDILI drugs diclofenac (200 µM), trovafloxacin (100 µM) and clozapine (75 µM), whereafter cell viability and cytotoxicity was measured. The iDILI drugs induced a synergistic decrease in viability in inflamed HepaRG mono- and cocultures, which showcases predictivity of the model for iDILI hepatotoxic reactions. In conclusion, HepaRG cells in monoculture and in coculture with THP-1 macrophages showed similar inflammation-driven effects on the selected endpoints, which shows that both models are promising tools to evaluate inflammation-driven effects on toxicokinetic and toxicodynamic endpoints.
POLA1 mediates hexavalent chromium-induced ovarian tumor progression through replication stress and DNA damage response.
Guo H, Sun Z, Li M … +2 more , Yao S, Yan L
Toxicology · 2026 Aug · PMID 41921649 · Publisher ↗
Hexavalent chromium (Cr(VI)), a recognized environmental carcinogen, yet its role in promoting gynecological malignancies remains mechanistically unclear. Here, we demonstrate that chronic, low-dose hexavalent chromium (...
Hexavalent chromium (Cr(VI)), a recognized environmental carcinogen, yet its role in promoting gynecological malignancies remains mechanistically unclear. Here, we demonstrate that chronic, low-dose hexavalent chromium (Cr(VI)) exposure (0.1 μM) drives ovarian tumorigenesis by inducing replication stress and DNA damage response (DDR) activation. We identify the DNA polymerase α catalytic subunit POLA1 as a critical mediator of this process. In human ovarian cancer SKOV3 cells, long-term Cr(VI) exposure (4-8 weeks) triggered S-phase accumulation, γH2AX elevation, and ATR/ATM activation, events dependent on POLA1 recruitment to chromatin. Crucially, genetic ablation of POLA1 reversed Cr(VI)-induced replication stress and suppressed tumor proliferation both in vitro and in vivo. These findings reveal a novel Cr(VI)-POLA1-DNA damage axis in environmental carcinogenesis, highlighting POLA1 as a potential target for preventive intervention in metal-induced malignancies.
Corrigendum to: "Benzo[a]pyrene exposure promotes RIP1-mediated necroptotic death of osteocytes and the JNK/IL-18 pathway activation via generation of reactive oxygen species" [Toxicology, 476, June 2022, 153244].
Zhang T, Shen Y, Zhu R … +4 more , Shan W, Li Y, Yan M, Zhang Y
Toxicology · 2026 Aug · PMID 41905831 · Publisher ↗
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Response to the Letter to the Editor regarding "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 Aug · PMID 41905504 · Publisher ↗
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Mitochondrial perspectives on environmental pollutant-induced male reproductive toxicity.
Feng Q, Gong Z, Yan B … +3 more , Guo B, Guo J, Liu S
Toxicology · 2026 Aug · PMID 41887453 · Publisher ↗
With rapid industrialization and urbanization, environmental pollutants have emerged as a major threat to male reproductive health, and declining semen quality and rising rates of male infertility have now become a globa...
With rapid industrialization and urbanization, environmental pollutants have emerged as a major threat to male reproductive health, and declining semen quality and rising rates of male infertility have now become a global public health concern. Owing to its high energetic demand and specialized cellular organization, the testis is especially vulnerable to pollutants, with mitochondria serving as a principal target because they coordinate energy metabolism and apoptotic control. Here we synthesize evidence on how heavy metals, air pollutants, organic pollutants, endocrine-disrupting chemicals, micro(nano)plastics, pesticides, and mycotoxins injure testicular mitochondria and the mechanisms involved. Current evidence indicates that these pollutants compromise spermatogenesis and androgen production via convergent mitochondrial pathways, including oxidative stress, metabolic disruption, mitochondria-dependent apoptosis, imbalance of mitochondrial dynamics, suppressed biogenesis, and dysregulated mitophagy. Importantly, these mechanisms are not independent, since individual pathways may dominate under specific exposure scenarios, yet they can also intersect and mutually reinforce one another to generate a multistep cascading network that culminates in reproductive injury. Therefore, mitochondrial dysfunction represents a central convergent node through which pollutants drive male reproductive toxicity. Future work should prioritize low-dose, long-term, and mixture exposure models, integrate multi-omics approaches with testicular organoid platforms, define key regulatory pathways, identify early biomarkers, and evaluate mitochondria-targeted interventions to support environmental risk assessment and prevention of male reproductive injury.
Comment on "Nicotine drives acute epithelial injury in region-specific human airway models at the air-liquid interface after e-cigarette aerosol exposure".
Mokkapati A, Thakkar R, Rani A … +1 more , Puri D
Toxicology · 2026 Jun · PMID 41887452 · Publisher ↗
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