Toxicology[JOURNAL]
Sun
200 papers
In Silico molecular insights into CYP3A-mediated monensin detoxification across species.
Pedroni L, Gehring R, Dorne JCM … +3 more , Girolami F, Nebbia C, Dellafiora L
Toxicology · 2026 Jan · PMID 41072751 · Publisher ↗
Monensin is an ionophore antibiotic widely used in veterinary medicine, known for its marked species-specific toxicity with Equus caballus being the most sensitive species, Sus scrofa partially tolerant, while Gallus gal...
Monensin is an ionophore antibiotic widely used in veterinary medicine, known for its marked species-specific toxicity with Equus caballus being the most sensitive species, Sus scrofa partially tolerant, while Gallus gallus is the most tolerant. It has been reported that such variability may depends on differences in CYP3A-mediated metabolism, particularly related to the O-demethylation reaction, which plays a key role in monensin detoxification. In this study, we applied a 3D modelling-based pipeline, including molecular docking, dynamics simulations and machine learning driven post-processing analysis, to investigate the interaction of monensin with CYP3A isoforms from chickens, pigs, and horses. The data collected unveiled interspecies and isoform-specific differences in both monensin binding and stability within CYP3A isoforms, providing a molecular basis for the species-related toxicity profile and O-demethylation efficiency previously described. These results were also corroborated by differences in terms of amino acid residues shaping the tested CYP3A catalytic sites. These findings provide mechanistic insights into interspecies variability regarding monensin detoxification and highlight the impact of in silico approaches on mechanistic toxicology studies related to risk assessment.
Induction of human cytochrome P450 enzyme activities by metabolism disrupting chemicals in the hepatic cell line HepaRG.
Person E, Cabaton NJ, Urien L … +10 more , Lacroix MZ, Kamstra JH, Mediouni L, Kubickova B, Jamin A, Chevolleau S, Hoffmann S, Legler J, Jacobs MN, Zalko D
Toxicology · 2026 Jan · PMID 41067530 · Publisher ↗
Metabolism disrupting chemicals (MDCs) are a class of endocrine disrupting substances that promote metabolic changes leading to metabolic disorders in humans. Central to assessing their adverse effects is the need to bet...
Metabolism disrupting chemicals (MDCs) are a class of endocrine disrupting substances that promote metabolic changes leading to metabolic disorders in humans. Central to assessing their adverse effects is the need to better understand their modes of action (MoA). Cytochrome P450 (CYP) enzymes play a major role in xenobiotic metabolism, but also catalyse many endogenous metabolic reactions. Therefore, modulation of CYP functionality may impact homeostasis, contributing to adverse outcomes. At the functional level, alteration of the activity of human CYPs by MDCs largely remains unexplored. In this study we investigated the capability of six candidate MDCs, bisphenol A (BPA), perfluorooctanoic acid (PFOA), tributyltin (TBT), dichlorodiphenyldichloroethylene (p,p'-DDE), triclosan (TCS) and triphenylphosphate (TPP) to induce CYP1A2, CYP2B6 and CYP3A4 activities in the human hepatic HepaRG cell line. The CYP induction test method previously validated for pharmaceuticals was optimised and selected MDCs were tested in the context of the European Horizon 2020 GOLIATH project. Induction was revealed using a cocktail of CYP-selective probe substrates, followed by probe metabolite quantification by mass spectrometry. All MDCs except TCS induced CYP activities. PFOA, TBT, p,p'-DDE and TPP induced CYP1A2, TPP being the most potent inducer. BPA, PFOA, TBT and TPP induced CYP2B6, PFOA being the most potent inducer. BPA, PFOA, TBT, p,p'-DDE and TPP all induced CYP3A4, p,p'-DDE and BPA being the most potent inducers. These results highlight the capability of candidate MDCs to induce key CYP activities in a human relevant hepatic model, paving the way for a better understanding of MDCs mechanisms of action.
Particulate matter extracted from human anthracotic tissues induces inflammatory markers in co-culture of lung cells and macrophages.
Frias DP, Vieira GL, Smelan J … +7 more , De Lacerda JPA, Cardoso da Silva PS, Sussa FV, Carvalho-Oliveira R, Saldiva PHN, Mauad T, Macchione M
Toxicology · 2026 Jan · PMID 41062014 · Publisher ↗
Anthracosis, characterized by black pigmentation in the lungs and tracheobronchial tree due to inhaled carbon particles, has been linked to urban air pollution. This study analyzed the chemical composition of particulate...
Anthracosis, characterized by black pigmentation in the lungs and tracheobronchial tree due to inhaled carbon particles, has been linked to urban air pollution. This study analyzed the chemical composition of particulate matter extracted from anthracotic tissue (APE) and its effects on human bronchial cells (BEAS-2B) and lung adenocarcinoma cells (A549) in co-culture with M1 or M2 macrophages. Diesel exhaust particles (DEP) served as a positive control. APE was extracted from lung and lymph nodes at Capital Death Verification Service (SVO) and chemically characterized for polycyclic aromatic hydrocarbons (PAHs) and inorganic elements like metals and sulfur. DEP contained more complex PAHs and higher levels of iron, sulfur, and zinc than APE. Pulmonary cell's metabolism decreased after exposure to APE, also co-culture macrophage viability. Macrophage immunophenotyping revealed heterogeneity, with M1 and M2 markers present in mono- and co-cultures, but APE exposure induced a pro-inflammatory M1 profile. Cytokine analysis showed significant increases in IL-1β, TNF-α, IL-6, and IL-8 levels after APE exposure, but not DEP. Gene expression of CYP1A1 and CYP1B1, associated with xenobiotic responses, increased after DEP exposure but remained unaffected by APE. Both APE and DEP caused mild modulation of cell cycle markers p53 and EGFR. These findings suggest APE is a metabolized particle, but not inert, inducing a pro-inflammatory response in pulmonary cells. Differences between APE and DEP effects likely stem from compositional variations: DEP's higher PAHs amount elicited a xenobiotic response, whereas APE's lower-weight PAHs triggered pronounced cytokine release.
Copper exposure induces autophagy and angiogenesis in liver cell via ATF4 activation independent of TFEB.
Zhang M, Zhang YG, Shi YT … +6 more , Qu XC, Li YH, Miao JX, Sun GM, Ge P, Liu BQ
Toxicology · 2026 Jan · PMID 41052668 · Publisher ↗
Copper (Cu) pollution has become as a significant global environmental concern, leading to excessive Cu accumulation in humans and disrupting cellular homeostasis. As a key catalytic cofactor, Cu is involved in essential...
Copper (Cu) pollution has become as a significant global environmental concern, leading to excessive Cu accumulation in humans and disrupting cellular homeostasis. As a key catalytic cofactor, Cu is involved in essential biological processes, including oxidative stress detoxification, angiogenesis, pigmentation, and peptide hormone production. However, excessive copper exposure has been linked to various cellular pathological processes. This study demonstrated that copper exposure induced autophagy in hepatocytes in a dose- and time-dependent manner, independent of starvation. Additionally, copper stimulated transcriptional activation of autophagy-lysosome-related and pro-angiogenic factors, including vascular endothelial growth factor (VEGF), predominantly through the activation of the stress-responsive protein ATF4, while bypassing the canonical transcription factor TFEB. These findings suggest that ATF4-driven autophagy and VEGF signaling may synergistically modulate paracrine communication in the liver microenvironment, potentially contributing to angiogenic processes. These findings reveal copper's impact on liver cell functions through ATF4-mediated autophagy and angiogenesis, suggesting that ATF4 could serve as a potential therapeutic target for further exploration.
Chronic oral exposure to chlorpyrifos disrupts hepatic epigenetic regulation and induces metabolic dysfunction in mice.
Mansukhani M, Ganguli N, Majumdar SS … +1 more , Sen Sharma S
Toxicology · 2026 Jan · PMID 41046031 · Publisher ↗
Organophosphate pesticides (OPs) have found extensive use in agriculture due to their short half-lives and relatively low persistence in the environment. In recent years, a growing body of evidence has linked OPs, includ...
Organophosphate pesticides (OPs) have found extensive use in agriculture due to their short half-lives and relatively low persistence in the environment. In recent years, a growing body of evidence has linked OPs, including chlorpyrifos (CPF), to endocrine, reproductive, and metabolic dysfunction, raising significant public health concerns. Although CPF has been linked to various toxic effects, the epigenetic mechanisms underlying CPF-induced hepatotoxicity remain poorly understood. In the present study, mice were orally exposed to CPF (2 or 20 mg/kg body weight), and the effects on hepatic function were assessed. CPF exposure resulted in pronounced hepatotoxicity characterized by increased oxidative stress, impaired mitochondrial function and dysregulated expression of genes involved in oxidative phosphorylation. Notably, CPF exposure significantly depleted hepatic choline levels and downregulated the expression of genes involved in the regulation of DNA methylation, including Dnmt1, Mthfr and Tet2. The decline in hepatic choline was correlated with hypomethylation of the hepatic genome in CPF-exposed mice. CPF also elevated serum corticosterone in mice, reinforcing its role as an endocrine disruptor. This hormonal disruption was associated with dysregulated glucose homeostasis as evidenced by glucose intolerance, elevated hepatic glycogen and altered hepatic expression of the glucose transporter Glut2. Together, the findings from this study provide novel mechanistic insights into the epigenetic and metabolic effects of CPF-induced hepatotoxicity.
Involvement of ARTS in bisphenol A-induced apoptosis of mouse Leydig cells.
Yang Y, Yang S, Zhang M … +2 more , Xu L, Chen J
Toxicology · 2026 Jan · PMID 41046030 · Publisher ↗
As a widely used organic chemical raw material in the world, bisphenol A (BPA) can induce apoptosis in mouse Leydig cells, yet the underlying mechanism remains insufficiently elucidated. Herein, we confirmed that BPA cou...
As a widely used organic chemical raw material in the world, bisphenol A (BPA) can induce apoptosis in mouse Leydig cells, yet the underlying mechanism remains insufficiently elucidated. Herein, we confirmed that BPA could induce apoptosis of TM3 cells, accompanied with the upregulation of apoptosis-related protein in the TGF-β signaling pathway (ARTS). Overexpression of ARTS promoted apoptosis of TM3 cells, while ARTS depletion attenuated BPA-induced apoptosis of the cells, indicating that ARTS plays a key role in BPA-induced apoptosis of mouse Leydig cells. Subsequently, BPA was found to increase the expression of transcription factor p53 in the cells. Interestingly, overexpression of p53 enhanced the expression of ARTS and induced apoptosis of TM3 cells, while knockdown of p53 by siRNA attenuated the upregulation of ARTS and the induction of apoptosis caused by BPA, implying that BPA induces apoptosis of mouse Leydig cells through p53/ARTS signals. In addition, we also found that oxidative stress was involved in BPA-induced apoptosis of TM3 cells through p53/ARTS signals. Taken together, these findings suggest that BPA-triggered oxidative stress activates p53/ARTS signaling pathway, thereby inducing apoptosis of mouse Leydig cells.
The correlation between lung surfactant function inhibition in vitro and the effect on breathing of mice during inhalation exposure - A study of spray-formulated engine/brake cleaners and lubricating products.
Sørli JB, Sengupta SR, Hadrup N
Toxicology · 2026 Jan · PMID 41022194 · Publisher ↗
Moving parts in motors require maintenance, both lubrication for smooth operation and de-greasing for cleaning and repair. Since these motor parts are hard to reach, cleaning and lubrication products are often applied by...
Moving parts in motors require maintenance, both lubrication for smooth operation and de-greasing for cleaning and repair. Since these motor parts are hard to reach, cleaning and lubrication products are often applied by spraying. However, the aerosol spray of the product can potentially reach the breathing zone of the worker and end up in the lungs. We investigated eight products and two single ingredients for their acute effects on the lungs. The effects of the aerosolized substances were tested in an in vitro model for lung surfactant function inhibition. The in vitro results were then compared to the effects of the aerosolized substances on the breathing parameters of exposed mice, measured in whole-body plethysmographs. No-observed-adverse-effect-concentrations were set based on the endpoint of reduction in tidal volume. When a reduction in tidal volume was used as the ´true´ result, the in vitro test for lung surfactant inhibition was 80 % accurate at predicting if the substance affected tidal volume in exposed mice. The ranking of test substances were similar between the in vivo and in vitro results with the exception of (2-methoxymethylethoxy)propanol (substance A). This substance did not inhibit lung surfactant function, but was potent at reducing tidal volume in mice. In conclusion, lung surfactant function inhibition in vitro can be used as a screening tool for acute effects of ingredients in- or formulated -spray products on the lungs.
2-Ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB) triggers Z-DNA-binding protein 1(ZBP1)- (Receptor-interacting serine/threonine-protein kinase 3) RIP3 mediated programmed necrosis in hepatic cells by inducing mitochondrial left-handed helix (Z-DNA) release.
Yu M, Jinchao L, Jinlai L … +3 more , Yanyan J, Lili L, Xinpeng W
Toxicology · 2026 Jan · PMID 40992649 · Publisher ↗
Traditional Polybrominated Diphenyl Ethers (PBDEs) have been gradually banned due to their significant health impacts. As a substitute, the novel brominated flame retardant 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB) h...
Traditional Polybrominated Diphenyl Ethers (PBDEs) have been gradually banned due to their significant health impacts. As a substitute, the novel brominated flame retardant 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB) has been extensively utilized in industrial and consumer products. TBB has been detected in various environmental media, organisms, and humans, suggesting potential health risks. However, existing toxicological studies on TBB are still limited. The liver is one of the most important target organs in toxicological research. Therefore, we explored the toxicological effects of TBB on liver. Therefore, a series of corresponding biochemical experiments were conducted to evaluate the toxicological effects of TBB. Firstly, CCK8 and EdU assays indicated that TBB blocked the proliferation of hepatocytes. Cell cycle analysis demonstrated that TBB inhibited cell cycle progression; Secondly, TBB treatment causes mitochondrial damage by detection of mitochondrial membrane potential. Further work found that TBB led to programmed necrosis, which is mediated by ZBP1. Mechanistically, we found that TBB induced mitochondrial damage, as evidenced by impaired mitochondrial membrane potential, followed by mitochondrial genome instability and subsequent generation/release of mitochondrial Z-DNA, which subsequently drives both cell death and inflammatory responses. In conclusion, this study investigated the toxicological effects of the novel brominated flame retardant (TBB), these findings indicate that limiting TBB usage should be prioritized in future studies.
Oral exposure to tire rubber-derived contaminant 6PPD and 6PPD-quinone induces intestinal toxicity in mice.
Fang L, Xu J, Fang C … +1 more , Jin Y
Toxicology · 2025 Dec · PMID 40976059 · Publisher ↗
N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) is a commonly used rubber protectant that continuously enters the environment via groundwater. Its oxidation product, N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylened...
N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) is a commonly used rubber protectant that continuously enters the environment via groundwater. Its oxidation product, N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPDQ), has garnered significant concern due to its reported toxicity in animals. This study aims to evaluate the intestinal toxicity and potential metabolic impact of 6PPD and 6PPDQ in mice following oral exposure to various doses. Our results demonstrate that both compounds compromise the intestinal barrier, as evidenced by significant increases in the expression of tight junction proteins (claudin-1 and occludin) and mucin protein (MUC2). These changes suggest an impairment of both the physical and chemical barriers of the intestine. Following exposure, there was a marked increase in pro-inflammatory cytokines (IL-6, IL-22, and NOD-1), indicating an inflammatory response associated with the disruption of lipid metabolism and macrophage polarization. Specifically, the shift from M2 to M1 macrophage polarization correlates with increased expression of M1 markers despite no change in the M1/M2 ratio over prolonged exposure. Furthermore, 6PPD exposure significantly reduced gut microbiota richness and evenness, with more pronounced changes observed in the 6PPDQ-treated group. Correlation analysis suggested that these microbial shifts may influence host carnitine and lipid metabolism pathways. Ultimately, both 6PPD and 6PPDQ exposure led to elevated levels of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL) in the bloodstream, attributed to decreased TC esterification. These findings highlight the potential long-term health risks associated with environmental exposure to 6PPD and 6PPDQ, particularly concerning gut integrity and metabolic dysregulation. SYNOPSIS: This study investigates the toxicity of 6PPD and its transformation product 6PPDQ, revealing their detrimental effects on intestinal health, disruption of gut microbiota, and alterations in lipid metabolism, highlighting significant implications for both environmental and human health.
Deciphering the quantitative relationship between NRF2 and SRXN1 through semi-mechanistic computational modeling.
Sharma RP, Loonstra-Wolters L, Ter Braak B … +5 more , Niemeijer M, White A, van de Water B, Middleton AM, Beltman JB
Toxicology · 2026 Jan · PMID 40972999 · Publisher ↗
Nuclear factor erythroid 2-related factor 2 (NRF2) plays a vital role in the regulation of various antioxidant response element (ARE) genes, which control physiological processes such as oxidative stress, autophagy, prol...
Nuclear factor erythroid 2-related factor 2 (NRF2) plays a vital role in the regulation of various antioxidant response element (ARE) genes, which control physiological processes such as oxidative stress, autophagy, proliferation and apoptosis to maintain cellular homeostasis. It is not understood in detail how the NRF2 program acquires its flexibility with respect to regulation of its downstream targets. Various NRF2 binding partners and cofactors specific to ARE genes are involved in this regulation, and are potentially condition-specific (e.g., type of stressor) and dependent on non-canonical signaling pathways (i.e., crosstalk). Here, we explored the quantitative relationship between NRF2 and sulfiredoxin 1 (SRXN1), a bona fide key NRF2 target gene. We developed a semi-mechanistic mathematical model based on time course experimental data of NRF2 and SRXN1 protein expression in HepG2 cells following single or repeated exposure to NRF2 activating soft electrophiles (sulforaphane, andrographolide, ethacrynic acid or CDDO-me) at a wide concentration range. We showed that a nonlinear mixed effect modeling approach with partially hierarchical parameters accurately captures the observed experimental dynamics. Our analysis highlights that NRF2 requires a cofactor or post-translational modification to regulate its activity as a transcription factor. Moreover, this modulation of the transcription factor activity of NRF2 is time-, compound- and exposure scenario specific. We conclude that a complete understanding of NRF2-mediated ARE genes activation requires detailed dynamic information on NRF2 binding partners and cofactors.
Reflections on the NIEHS Virtual Consortium funding mechanism (ViCTER) and what it has taught us about the future of transdisciplinary science.
Veiga-Lopez A, Stevens HE, Rand M … +7 more , Tjalkens R, Claus Henn B, Marsit CJ, Bernstein AI, Bonner MR, Hoffmann HM, Meliker JR
Toxicology · 2025 Dec · PMID 40972998 · Full text
In environmental health science, collaboration across disciplines is often encouraged but rarely specifically solicited through funding mechanisms. The United States National Institute of Environmental Health Sciences (N...
In environmental health science, collaboration across disciplines is often encouraged but rarely specifically solicited through funding mechanisms. The United States National Institute of Environmental Health Sciences (NIEHS) Virtual Consortium for Translational/Transdisciplinary Environmental Research (ViCTER) program fostered and promoted early-stage transdisciplinary collaborations among basic, clinical, and population-based researchers in the environmental health field. ViCTER awards are typically three-year R01 grants that include at least one NIEHS-funded PI and engage partners from distinct disciplines or institutions. By design, ViCTER created space for scientifically diverse research teams, including epidemiologists, clinicians, toxicologists, molecular biologists, often across multiple institutions, to work side-by-side, not sequentially, to address complex environmental challenges. This commentary reflects on how ViCTER catalyzed scientific advances, transformed careers, and created a model for the future of translational environmental health research.
Hexafluoropropylene oxide homologues, the novel alternatives to PFOA, induce mitochondrial dysfunction and cytotoxicity in Leydig cells through disrupting SIRT1/PGC-1α signaling pathway.
Le ML, Xue JY, Wu LH … +5 more , Zhao XY, Ding J, Yuan YY, Wan YQ, Zhang DL
Toxicology · 2025 Dec · PMID 40972997 · Publisher ↗
Hexafluoropropylene oxide (HFPO) homologues (HFPOs), specifically HFPO-dimeric acid (DA), HFPO-trimeric acid (TA) and HFPO-tetrameric acid (TeA), have emerged as industrial replacements for phased-out perfluorooctanoic a...
Hexafluoropropylene oxide (HFPO) homologues (HFPOs), specifically HFPO-dimeric acid (DA), HFPO-trimeric acid (TA) and HFPO-tetrameric acid (TeA), have emerged as industrial replacements for phased-out perfluorooctanoic acid (PFOA), garnering considerable attention due to their environmental ubiquity and bioaccumulation potential. Nevertheless, the reproductive toxicity of HFPOs remains incompletely characterized, particularly regarding their endocrine-disrupting effect and the underlying mechanisms involving Leydig cell dysfunction. In this study, we investigated the cytotoxic influences of HFPOs on TM3 Leydig cells, focusing on mitochondrial function and dynamics, oxidative stress, and apoptosis. Our findings demonstrated that exposure to HFPOs significantly compromised mitochondrial function and fusion-fission dynamics by disrupting the SIRT1/PGC1α signaling pathway. The mitochondrial dysfunction further triggered excessive ROS production and apoptosis, ultimately impairing TM3 Leydig cell viability and testosterone secretion. However, supplementation with the SIRT1 agonist SRT1720 relieved the inhibitory effect of HFPOs on SIRT1/PGC1α signaling pathway and reversed the expression of apoptosis-associated proteins (BAX/BCL2), oxidative stress-associated proteins (SOD1/SOD2), as well as proteins associated with mitochondrial fusion (MFN2/OPA1) and fission (DRP1/FIS1). These results elucidated the involvement of the SIRT1/PGC1α pathway in mediating the cytotoxicity of HFPOs. Notably, the activation of SIRT1 mitigated HFPO-induced toxicity in the TM3 cells, highlighting its potential in safeguarding testicular cells from the damage caused by HFPOs exposure.
Perinatal neurodevelopmental effects of endocrine disruptors: Insights from metabolome mapping in the rat hippocampus.
Evangelista S, Lichtensteiger W, Schlumpf M … +5 more , Rancan L, Paredes SD, Linillos-Pradillo B, Lamoree MH, Leonards PEG
Toxicology · 2025 Dec · PMID 40967503 · Publisher ↗
Metabolism is critical for neurodevelopment, yet the mechanisms by which endocrine-disrupting chemicals (EDCs) contribute to neurodevelopmental disorders remain poorly defined. Using a rat model, we investigated hippocam...
Metabolism is critical for neurodevelopment, yet the mechanisms by which endocrine-disrupting chemicals (EDCs) contribute to neurodevelopmental disorders remain poorly defined. Using a rat model, we investigated hippocampal metabolomic responses at postnatal day 6 following maternal exposure to six structurally diverse EDCs (bisphenol F, permethrin, butyl benzyl phthalate, triphenyl phosphate, perfluorooctane sulfonic acid, and DINCH) from pre-mating through lactation. Targeted steroid, thyroid, and neurosteroid hormones, neurotransmitters, and untargeted lipidomics were profiled to map disrupted pathways. The analysis revealed sex-specific, chemical-specific, and shared metabolic signatures of developmental neurotoxicity. Key affected endpoints across chemicals included corticosterone, pregnenolone sulfate, and N-acylethanolamine lipids, confirming hormonal disruption while uncovering novel non-EATS (estrogen, androgen, thyroid, and steroidogenesis) pathways and mechanisms of action. These findings provide new insights into EDC-mediated disruption of hippocampal development and identify potential molecular biomarkers that may support future mechanistic research and chemical risk assessment.
Mechanistic toxicity profiling of chemicals: A comparative study in 2D and 3D HepaRG models using high-content analysis.
Saleh M, Hogeveen K, Fessard V … +1 more , Le Hégarat L
Toxicology · 2026 Jan · PMID 40967502 · Publisher ↗
Humans and the environment are exposed to a diverse range of chemicals, many of which are introduced through the human activities. This growing chemical burden has given rise to concerns related to their potential advers...
Humans and the environment are exposed to a diverse range of chemicals, many of which are introduced through the human activities. This growing chemical burden has given rise to concerns related to their potential adverse effects. Traditionally, chemical toxicity evaluation has relied on animal tests that are time consuming, expensive, pose ethical concerns, and may not be directly extrapolated to humans. This highlights the urgent need to develop New Approach Methodologies (NAMs) to evaluate chemical- associated toxicity. Since the liver is a primary target organ for xenobiotics, our objective is to use both 2D and 3D HepaRG models combined with High-Content Analysis (HCA) for chemical mechanistic toxicity profiling. HepaRG models were exposed to eight chemicals (Chlorothalonil, Tebuconazole, Thioacetamide, Benzoyl peroxide, Diethyl maleate, clofibrate, indeno[1,2,3-cd]pyrene, 3-methylcholanthrene) for 72 h with daily media renewal. Cellular endpoints including cytotoxicity, oxidative stress, mitochondrial dysfunction, lipid accumulation and the pro-inflammatory response were quantified. Additionally, four chemicals were added in this study to test chemicals having different MOA and to demonstrate the sensitivity of the 3D HepaRG spheroid model (FICZ, Diuron, 12-O-Tetradecanoylphorbol-13-acetate, Azoxystrobin). Our findings revealed that 3D HepaRG cells exhibited more pronounced positive responses to chemical treatment compared to the 2D HepaRG cells. In addition to the chemical-specific toxicity profiling generated by HCA, we identified correlations between different cellular alterations such as mitochondrial dysfunction, dysregulated lipid metabolism and oxidative stress in the treated 3D HepaRG spheroids. Overall, this approach proposed in this study provides a rapid, human-relevant in vitro method that enhances the predictive power of NAMs for chemical associated toxicity.
Neurological alterations in adult female rats developmentally exposed to a glyphosate-based herbicide: Potential role of the immune system.
Gallegos CE, Bartos M, Gumilar F … +7 more , Jodar DNN, Lencinas I, Bras C, García BN, Delbés JA, Dominguez S, Baier CJ
Toxicology · 2025 Dec · PMID 40953766 · Publisher ↗
Despite the increasing evidence about the adverse consequences of early exposure to Glyphosate (Gly) and Gly-based herbicides (GlyBHs) on the central nervous system (CNS), little is known about the effects of this herbic...
Despite the increasing evidence about the adverse consequences of early exposure to Glyphosate (Gly) and Gly-based herbicides (GlyBHs) on the central nervous system (CNS), little is known about the effects of this herbicide on the developing immune system. We have previously described that oral exposure of rats to a GlyBH during pregnancy and lactation induces neurobehavioral alterations, brain oxidative stress imbalance, and impairment in the activity of enzymes involved in the glutamatergic and cholinergic systems in adulthood. The purpose of this study was to investigate further the mechanisms of neurotoxicity exerted by GlyBHs and to explore a possible link between their effects on the CNS and the immune system. For this purpose, pregnant Wistar rats were orally exposed to 0.4 % GlyBH from gestational day 0 until weaning (postnatal day (PND) 21), and a series of behavioural and biochemical analyses were conducted in PND90 female pups. Haematological and serological parameters were affected by exposure to the herbicide. In addition, GlyBH altered lactate dehydrogenase (LDH) activity and the redox status in specific brain areas, and decreased the number of astrocytes in the hippocampus of perinatally exposed rats. Finally, GlyBH-treatment induced a depressive-like behaviour evaluated by the forced swim test. Taken together, the findings of the present study demonstrate that exposure to a Gly-containing herbicide during pregnancy and lactation induced long-lasting changes in the immune system of 90-day-old female offspring, which in turn could affect their CNS.
Long-term oral exposure to finasteride and different doses of minoxidil induces testicular and epididymal alterations in adult Balb/c mice.
Santana FFV, Ferreira JVS, Araujo DC … +8 more , Rafael APS, Freitas CFA, Guimarães-Ervilha LO, Coimbra JLP, Machado-Neves M, Costa GMJ, da Silva J, da Matta SLP
Toxicology · 2025 Dec · PMID 40945818 · Publisher ↗
Oral finasteride and topical minoxidil are approved treatments for androgenetic alopecia, while low-dose oral minoxidil has emerged as a promising off-label alternative. Despite its vasodilatory and androgen-modulating p...
Oral finasteride and topical minoxidil are approved treatments for androgenetic alopecia, while low-dose oral minoxidil has emerged as a promising off-label alternative. Despite its vasodilatory and androgen-modulating properties, the minoxidil effects on male reproductive health remain poorly understood. Given its growing off-label use and potential reproductive impact, this study aimed to evaluate the histopathological, hormonal, and oxidative stress effects of oral minoxidil on the testes and epididymides of adult Balb/c mice. A total of 120 animals were divided into six groups (n = 20) receiving daily oral doses of water, vehicle, finasteride (5 mg/kg), or minoxidil (2.5, 5, or 7.5 mg/kg). Half were euthanized after 42 days and the remainder after 84 days of treatment. On the 42nd day, both minoxidil and finasteride induced testicular structural alterations, including vacuolization of the seminiferous epithelium, reduction in seminiferous epithelium height, and increase in the proportion of Leydig cells. In the minoxidil-treated groups, these alterations were accompanied by decreased serum estradiol levels and oxidative imbalance, suggesting these might be underlying mechanisms of minoxidil-induced reproductive toxicity. After 84 days, although no significant changes were observed in the estradiol levels and oxidative status, testicular structural alterations persisted, characterized by continued vacuolization of the seminiferous epithelium and decreased seminiferous epithelium proportion after finasteride and minoxidil treatments. Although no dose-dependent minoxidil effect was observed, the dose of 5 mg/kg more frequently induced alterations. Histological epididymal changes were identified with both drugs at both time points. However, only finasteride significantly reduced sperm transit time (at 42 and 84 days) and cauda sperm count (at 84 days). These results suggest that while both minoxidil and finasteride induce broader testicular alterations, finasteride significantly affects epididymal function. This study highlights potential reproductive risks associated with long-term oral minoxidil use and emphasizes the importance of clinical studies assessing its safety in male reproductive health, particularly in individuals of reproductive age.
Differential effects of mercury compounds on mutagenicity, genotoxicity and repair of UV-DNA damage.
Cyran A, Ursu GM, Krawic C … +1 more , Zhitkovich A
Toxicology · 2025 Dec · PMID 40930455 · Full text
Mercury (Hg) is a global contaminant that is present in human diet as methylmercury (MeHg). Recent studies linked MeHg exposure with high risks of skin cancers. It is unknown whether MeHg is directly genotoxic in skin ce...
Mercury (Hg) is a global contaminant that is present in human diet as methylmercury (MeHg). Recent studies linked MeHg exposure with high risks of skin cancers. It is unknown whether MeHg is directly genotoxic in skin cells or able to enhance mutagenic effects of UV radiation. We examined mutagenicity and genotoxicity of MeHg and its metabolite inorganic Hg (iHg) and their impact on processing of carcinogenic UV-DNA damage. We found that iHg and MeHg were both nonmutagenic in the Hprt assay in rodent CHO cells. iHg but not MeHg strongly enhanced mutagenicity of UV-B without changes in repair of mutagenic cyclobutane pyrimidine dimers (CPDs). In human keratinocytes, iHg increased genotoxic stress and formation of micronuclei by UV-B which occurred in cells with both normal and inactive nucleotide excision repair of UV-DNA damage. Repair of UVB-induced CPDs and 6-4 photoproducts in keratinocytes was unaffected by iHg or MeHg. Formation of micronuclei in human keratinocytes by MeHg and UV-B was additive, indicating their independence. Thus, iHg(II) was not directly mutagenic/genotoxic but it enhanced mutagenicity and clastogenicity of UV-DNA damage without interference with its repair. MeHg did not alter DNA repair or mutagenicity/genotoxicity of UV-B but it acted as a clastogen in human keratinocytes.
Corrigendum to 'β-Estradiol antagonizes the inhibitory effects of caffeine in BMMSCs via the ERβ-mediated cAMP-dependent PKA pathway' [Toxicology 394 (2018) 1-10].
Wang C, Zhou Y, Guan X … +2 more , Yu M, Wang H
Toxicology · 2025 Dec · PMID 40903329 · Publisher ↗
Abstract loading — click title to view on PubMed.
Characterization and comparison of respiratory toxicity induced by sublethal poisoning to two organophosphorus compounds: A pesticide and a sarin structural analog in mice.
Hanak AS, Fémy F, Berriche A … +7 more , Reymond C, Rotiel T, Madi M, Jaffré N, Calas AG, Dal Bo G, Thibault K
Toxicology · 2025 Dec · PMID 40902968 · Publisher ↗
The chemical risk associated with the use of organophosphorus nerve agents remains a major concern, as highlighted by recent international events (e.g., Syrian conflict, Novichok poisoning incidents) and the tense geopol...
The chemical risk associated with the use of organophosphorus nerve agents remains a major concern, as highlighted by recent international events (e.g., Syrian conflict, Novichok poisoning incidents) and the tense geopolitical climate. Concurrently, the use of organophosphorus pesticides continues to represent a major global public health challenge, resulting in numerous poisonings and fatalities each year. Organophosphorus compounds exert their toxic effects by irreversibly inhibiting cholinesterase enzymes, disrupting cholinergic signaling within the affected organism. This disruption impairs vital functions and, without appropriate medical intervention, can result in respiratory failure and death. However, whether differences in the molecular and physiological mechanisms underlying organophosphorus compound-induced respiratory failure between pesticides and nerve agents exist remains poorly defined. This study aimed to characterize and compare respiratory toxicity in mice exposed to two sublethal organophosphorus compounds: a pesticide (paraoxon) and a sarin structural analog (NIMP). Respiratory ventilation in mice was monitored using double-chamber plethysmography. Cholinesterase activity and inflammatory biomarkers were quantified in blood and tissues involved in respiration. Both compounds dose-dependently affected ventilatory function of the mice, reducing respiratory rate and minute volume and increasing specific airway resistance. No significant differences were observed between the two organophosphorus compounds in these effects. However, lungs and diaphragm triggered a rapid inflammatory response, depending on the specific organophosphorus compound tested. While NIMP exposure increased IL-6 expression, potentially involving the NF-κB pathway, POX exposure upregulated IL-1ß expression without activating NF-κB. Thus, exposure to POX or NIMP similarly impaired ventilatory function in mice, but distinct signaling pathways appear to be involved.
Mechanisms of podophyllotoxin-induced enterotoxicity: A multi-omics integration of gut microbiota, short-chain fatty acids, and inflammatory mediators.
Lu Y, Liu Y, Bai X … +7 more , Jiang T, Chen X, Wang Y, Du P, Sun Y, Liu C, Duan J
Toxicology · 2025 Dec · PMID 40902967 · Publisher ↗
Podophyllotoxin (PPT), a lignan extracted from the roots and stems of Podophyllum species, exhibits significant enterotoxicity that limits its clinical application. However, its underlying mechanisms remain unclear. This...
Podophyllotoxin (PPT), a lignan extracted from the roots and stems of Podophyllum species, exhibits significant enterotoxicity that limits its clinical application. However, its underlying mechanisms remain unclear. This study aimed to elucidate the mechanisms underlying PPT-induced enterotoxicity. Changes in body weight, fecal morphology, toxic phenotypes, and histopathological features were evaluated. 3D reconstruction, 16S rRNA sequencing, targeted short-chain fatty acids (SCFAs) analysis, and inflammatory cytokine assays were performed. The findings demonstrated that PPT induced pathological changes in rats, including weight loss, diarrhea, and colonic damage. PPT administration significantly reduced beneficial bacteria such as Lactobacillus, while increasing harmful bacteria such as Escherichia-Shigella. The predicted pathways of bacterial invasion of epithelial cells and lipopolysaccharide biosynthesis were significantly upregulated. Levels of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), were also increased. Additionally, the expression of undecaprenyl-diphosphate synthase (UPPS) and SCFAs production was reduced. These findings indicate that PPT may alter gut microbial composition, increase Escherichia-Shigella invasion in the intestinal epithelial cells, promote lipopolysaccharide production, enhance the release of pro-inflammatory cytokines, including TNF-α and IL-6, and inhibit UPPS expression and SCFAs generation, collectively contributing to enterotoxicity. This study provides novel insights into the mechanisms behind PPT-induced enterotoxicity, which is essential for preventing and treating PPT toxicity.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe