Food And Chemical Toxicology[JOURNAL]
Sun
200 papers
Cajaninstilbene acid induced apoptosis and cell cycle arrest in glioblastoma multiforme through mitochondrial ROS-mediated MAPK pathways.
Li YA, Bian TZ, Li H … +9 more , Li JW, Ma LT, Wu HD, Chen S, Chen JY, Zeng H, Mao YB, Wang P, Qiao Q
Food Chem Toxicol · 2026 Jul · PMID 42000067 · Publisher ↗
Glioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis and high mortality rate. Cajaninstilbene acid (CSA), a bioactive compound derived from pigeon pea leaves, has been reported to exhibit d...
Glioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis and high mortality rate. Cajaninstilbene acid (CSA), a bioactive compound derived from pigeon pea leaves, has been reported to exhibit diverse biological activities, including potential anticancer properties. Given its dietary origin, understanding the cytotoxic effects and mechanisms of CSA is essential for food safety assessment. In this study, we investigated the cytotoxic mechanisms of CSA in GBM cell lines (LN229 and U87) and a xenograft mouse model. Our results showed that CSA significantly suppressed GBM cell proliferation, induced G2/M phase arrest, and activated caspase-dependent apoptosis. Network pharmacology analysis identified the MAPK signaling pathway as a key mediator of CSA-induced cytotoxicity. Importantly, CSA-induced effects on apoptosis, cell cycle arrest, and cell migration were markedly attenuated by the p38-specific inhibitor SB203580. Further mechanistic studies revealed that CSA-induced p38 phosphorylation dependent on mitochondrial reactive oxygen species (mtROS) production, which was completely reversed by the antioxidant N-acetyl-l-cysteine (NAC). Finally, CSA effectively suppressed tumor growth in a mouse xenograft model without causing significant body weight loss or histopathological toxicity in major organs. Collectively, these findings highlight the cytotoxic mechanism of CSA in GBM cells and provide a basis for its safety evaluation.
Evaluation of oxidant stress markers in a population involved in a health care program.
Poblete-Naredo I, Gutierrez MI, Bravo-Prado A … +2 more , López-Gámez IDR, Albores A
Food Chem Toxicol · 2026 Jul · PMID 42000066 · Publisher ↗
Unhealthy lifestyles lead to obesity, hypertension and diabetes that may contribute to oxidative stress; the latter can be evaluated through biomarkers reflecting total oxidant status (TOS), total antioxidant capacity (T...
Unhealthy lifestyles lead to obesity, hypertension and diabetes that may contribute to oxidative stress; the latter can be evaluated through biomarkers reflecting total oxidant status (TOS), total antioxidant capacity (TAC), and oxidative damage to lipids and proteins, measured by thiobarbituric acid-reactive substances (TBARS) and advanced oxidation protein products (AOPP). Lifestyle modification through healthy nutrition and regular exercise may improve these alterations. This study evaluated the effectiveness of a short-term Health Care Program (HCP) in improving anthropometric, biochemical, and oxidative stress parameters in adults from Mexico City. Outcomes were assessed at the first clinical evaluation during the program (week 8) and nine weeks later (week 16). Significant reductions were observed in body weight, body mass index (BMI), waist circumference, fasting blood glucose, and total cholesterol. In participants with abnormal baseline values (HR), systolic and diastolic blood pressure, and glycated hemoglobin also decreased. TAC and TOS levels significantly declined post-intervention. TBARS and AOPP remained unchanged, although AOPP decreased in HR-BMI participants. No significant changes in TAC, TOS, or AOPP over time were detected according to the number of metabolic risk factors; however, some descriptive patterns were observed. Overall, the HCP improved metabolic and redox parameters, highlighting its potential to reduce oxidative stress.
Bisphenol A exposure disrupts the circadian clock system and impairs glycolipid metabolic function in mice liver.
Dong H, Ding W, Xiao B … +10 more , Li C, Jiang H, Yang W, Li D, Li C, Zhang H, Gao D, Wang A, Jin Y, Chen H
Food Chem Toxicol · 2026 Jul · PMID 42000065 · Publisher ↗
Bisphenol A (BPA) is a widely existing endocrine-disrupting chemical that poses potential threats to human and animal health, including inducing metabolic disorders. Although previous studies have reported the adverse ef...
Bisphenol A (BPA) is a widely existing endocrine-disrupting chemical that poses potential threats to human and animal health, including inducing metabolic disorders. Although previous studies have reported the adverse effects of BPA on liver glucose and lipid metabolism, the underlying molecular mechanisms remain incompletely elucidated. This study systematically evaluated the effects of BPA exposure on liver glucose and lipid metabolism in mouse hepatocytes (AML12) and mouse models, and detected its association with circadian clock disruption. In vitro models, BPA exposure for 24 h significantly decreased the mRNA and protein expression levels of BMAL1 in AML12 cells, while significantly up-regulating the mRNA expression of Nr1d1 and Dbp. On the contrary, the expression of Nr1d1 and Dbp decreased significantly after 48 h of BPA exposure. It is worthy to note that both mRNA and protein levels of BMAL1 were significantly increased in forskolin synchronized AML12 cells. In addition, the genes related to glucose and lipid metabolism were also detected after BPA exposure. The results showed that BPA exposure significantly increased the expression of Cd36 and Glut2 in non-synchronized AML12 cells. Meanwhile, the elevation of Hmgcr expression and the reduction of Pparα were detected in forskolin synchronized AML12 cells. In vivo models, the results showed that ICR mice exposed to BPA (50 μg kg) for 42 consecutive days exhibited impaired glucose tolerance, decreased insulin sensitivity, increased liver glycogen storage, and decreased liver triglyceride (TG) levels. Meanwhile, the mRNA expression of Nr1d1 was significantly increased in mouse liver after BPA exposure. In addition, the mRNA expression of two lipid metabolism-related genes (Srebp1c and Elovl6) was significantly decreased in mouse liver after BPA treatment, but the expression level of Cd36 was significantly increased. In conclusion, this study demonstrates that BPA exposure impairs the circadian clock system and glucose and lipid metabolism in AML12 cells and mouse liver, providing important evidence that BPA overload in the environment can lead to the incidence of metabolic disorders in mammals. This study highlights the potential regulatory role of circadian clock system in BPA induced mammalian liver metabolic disorders and suggests that BPA may pose more profound potential risks to human and animal health.
Role of ferroptosis in liver diseases and its implications for therapeutic strategies.
Zhang E
Food Chem Toxicol · 2026 Jul · PMID 42000064 · Publisher ↗
Ferroptosis, a novel form of regulated cell death (RCD) characterized by iron-dependent accumulation of lipid peroxides and subsequent plasma membrane rupture, is fundamentally distinct from traditional cell death modali...
Ferroptosis, a novel form of regulated cell death (RCD) characterized by iron-dependent accumulation of lipid peroxides and subsequent plasma membrane rupture, is fundamentally distinct from traditional cell death modalities such as apoptosis, necrosis, and autophagy. Accumulating preclinical and clinical evidence indicates that ferroptosis is intricately intertwined with the pathogenesis and progression of a broad spectrum of acute and chronic liver diseases, including acute liver injury (ALI), metabolic dysfunction-associated steatotic liver disease (MASLD), alcoholic liver disease (ALD), viral hepatitis (HBV/HCV infection), liver fibrosis, and hepatocellular carcinoma (HCC). Notably, the role of ferroptosis in liver diseases is pleiotropic: it accelerates disease progression in most acute and early-stage chronic liver diseases by exacerbating hepatocellular damage and inflammatory responses, while exerting a tumor-suppressive effect in advanced liver fibrosis and HCC by selectively eliminating malignant or activated pathogenic cells (e.g., hepatic stellate cells). This review systematically elaborates on the core molecular mechanisms of ferroptosis, with a focus on the regulatory networks of iron metabolism, lipid peroxidation cascades, and endogenous antioxidant defense systems. Subsequently, it systematically summarizes the context-dependent regulatory role of ferroptosis in different types of liver diseases, integrating the latest preclinical findings and clinical correlative evidence, aiming to provide new theoretical insights and translational therapeutic strategies for the clinical management of liver diseases.
Effect of monosodium glutamate and butylated hydroxyanisole on inflammatory responses, oxidative stress, and Cytochrome P450 epoxygenases regulation in rat liver and cerebral cortex.
Torres-Zárate C, Navarro-Mabarak C, Hernández-Ojeda S … +4 more , Santes-Palacios R, Camacho-Carranza R, Morán J, Espinosa-Aguirre JJ
Food Chem Toxicol · 2026 Jul · PMID 41985577 · Publisher ↗
Monosodium glutamate (MSG), a flavor enhancer, and butylated hydroxyanisole (BHA), an antioxidant, are among the most widely used additives worldwide. The present study aims to investigate the inflammatory effect of oral...
Monosodium glutamate (MSG), a flavor enhancer, and butylated hydroxyanisole (BHA), an antioxidant, are among the most widely used additives worldwide. The present study aims to investigate the inflammatory effect of oral administration of MSG (40 mg/kg body weight) and BHA (0.5 mg/kg body weight) for 28 days, by evaluating proinflammatory cytokines in serum and NF-κB, Nrf2, CYP2C11, and CYP2J3 gene and protein expression in liver and cerebral cortex in male Wistar rats. Additionally, one group of rats was intraperitoneally injected with lipopolysaccharide (LPS) to induce systemic inflammation. The administration of MSG significantly increased serum levels of proinflammatory cytokines (TNF-α, IL-6, and IL-1β) and NF-κB gene expression in the liver and cortex. Also, the protein levels of the p65-NFkb subunit increased in cytosolic fraction in liver and Nrf2 transcription factor increased in the nuclear fraction in both the liver and cortex. Although we found that CYP2C11 and CYP2J3 mRNA levels were increased by MSG in the liver and cortex, no differences in protein levels were observed compared to controls. In contrast, BHA consumption did not cause inflammation or oxidative stress. Taken together, our findings suggest that MSG consumption induces systemic inflammation and oxidative stress under the evaluated conditions.
A systematic literature inventory on the interaction between dietary factors and environmental chemical exposures for nervous system health outcomes.
Weitekamp CA, Watson C, Hata E … +9 more , Hester K, Kodavanti UP, Lau C, Lehmann DM, Miller CN, Shaffer RM, Soliman F, Powers M, Branch FM
Food Chem Toxicol · 2026 Jul · PMID 41985576 · Publisher ↗
Environmental health research from the last seven decades suggests that dietary factors can modify adverse health outcomes associated with chemical exposures. However, the interplay between diet, chemical exposures, and...
Environmental health research from the last seven decades suggests that dietary factors can modify adverse health outcomes associated with chemical exposures. However, the interplay between diet, chemical exposures, and health is complex and remains poorly understood. Here, to survey the existing evidence and stimulate future research, we systematically identified and cataloged available literature on the interactions between chemical exposures and dietary factors for one health outcome category, neurotoxicity. The goal of this systematic literature inventory was to identify the relationship of dietary factors on chemical exposure mediated health outcomes related to central nervous system toxicity, given the importance of the microbiome-gut-brain axis in mediating these interactions. From an initial set of 32,529 references, we identified 80 epidemiological studies, 707 toxicological studies, and 175 in vitro studies that met inclusion criteria. Study design information was captured for the 80 epidemiological studies and for 113 toxicological studies that met additional scoping criteria. The most frequently studied chemical-diet interactions across the human and animal evidence streams were metals/metalloids and micronutrients. Knowledge gaps included dietary components known to be central to microbiome function, as well as adverse dietary modifiers compared to protective dietary factors. This systematic literature inventory is intended to support future research.
Time-resolved lipidomic profiling reveals alterations following 3-MCPDEs exposure in Sprague-Dawley rats.
Zheng W
Food Chem Toxicol · 2026 Jul · PMID 41974321 · Publisher ↗
Lipidomic alterations were investigated in the plasma, liver, kidneys, and testes of Sprague-Dawley (SD) rats at 2, 6, 12, 24, and 48 h after oral administration of 3-MCPDEs (500 mg/kg BW). PLS-DA revealed a clear distin...
Lipidomic alterations were investigated in the plasma, liver, kidneys, and testes of Sprague-Dawley (SD) rats at 2, 6, 12, 24, and 48 h after oral administration of 3-MCPDEs (500 mg/kg BW). PLS-DA revealed a clear distinction between the 2 h plasma samples and controls, whereas the largest deviations in organs were observed at 12 h and 24 h post-exposure. Differential lipid analysis in plasma identified 62 putative discriminant lipids, including 34 glycerophospholipids, 13 glycerides, 5 sphingolipids, and 10 other lipid species. Pathway analysis further indicated that glycerophospholipid and sphingolipid metabolic pathways were significantly perturbed following 3-MCPDE exposure. In plasma, glycerophospholipid metabolism was predominantly affected, characterized by marked elevations of lysophospholipids and disrupted homeostasis of PC, PS, and PE species. In contrast, organs exhibited organ-dependent disturbances in sphingolipid metabolism, suggesting tissue-specific vulnerability that may be closely linked to 3-MCPDE-associated toxicity. Overall, these time-resolved lipidomic profiles delineate distinct systemic versus tissue lipid perturbation patterns after 3-MCPDE exposure and provide mechanistic clues for understanding its metabolic toxicity.
Ranking primary food allergens by specific IgE-binding and clinical relevance in Dutch adults to identify reference protein sets for allergenicity assessment.
Yue SR, Chou MCL, Kallen EJJ … +5 more , Knulst AC, Houben GF, Bøgh KL, Le TM, Verhoeckx KCM
Food Chem Toxicol · 2026 Jul · PMID 41966319 · Publisher ↗
The increasing introduction of novel protein sources globally requires more robust allergenicity evaluations to predict their sensitising capacity. This study ranked plant-derived and animal-derived food allergens to est...
The increasing introduction of novel protein sources globally requires more robust allergenicity evaluations to predict their sensitising capacity. This study ranked plant-derived and animal-derived food allergens to establish reference proteins that may support the future development of predictive tools for de novo sensitisation. Sera from 307 Dutch adult patients presenting with suspected food allergy at an allergology outpatient clinic were analysed with Allergy Xplorer multiplex immunoassay. Food components were ranked based on specific IgE-binding frequencies, intensities, and clinical relevance. Plant-derived components demonstrated higher overall positive frequencies (491 vs 122) and median intensities (2.2 vs 1.7 kU/L) than animal-derived components. Within plant protein families, 2S albumins exhibited the highest frequencies (197) and median intensities (4.2 kU/L); with peanut allergens rAra h 2 (10.0%, 4.5 kU/L) and rAra h 6 (9.4%, 7.1 kU/L) most prominent and clinically relevant. Considering overall ranking, a proposed plant-derived reference panel comprises strong (Ara h 2, Jug r 4), intermediate (Ses i 1, Pru p 3), and weak (Gly m 5, Sin a 1) sensitising proteins. Plant-family ranking appears most effective for establishing reference sets, highlighting their potential utility in future allergenicity risk assessment frameworks tailored to clinical relevance of specific food items and novel protein sources.
Development of an in vitro method for simultaneous evaluation of androgenic activity of chemicals and their metabolites using S9: Application in biocides.
Kim NY, Kwon YK, Yang E … +2 more , Lee G, Lee HY
Food Chem Toxicol · 2026 Jul · PMID 41962648 · Publisher ↗
EDCs such as pesticides and biocides may enter the food supply and be ingested by humans. Once absorbed, these substances are metabolized in the liver and subsequently distributed systemically. However, conventional in v...
EDCs such as pesticides and biocides may enter the food supply and be ingested by humans. Once absorbed, these substances are metabolized in the liver and subsequently distributed systemically. However, conventional in vitro assays assess only parent compounds, failing to consider the biological activity of metabolites formed through hepatic metabolism. This study integrated the S9 fraction, an enzyme extract from the liver tissue, into the OECD TG 458 assay to analyze Phases I and II metabolic processes. We introduced the non-metabolizable compound STZ as a new positive control, set a 6 h metabolism based on BPA and bicalutamide metabolism, and established metabolic activity criteria using STZ variability. Using this improved method, we evaluated AR activity and metabolic changes of 57 biocides regulated in Korea. The parent and metabolite forms of all biocides were negative for AR agonist activity. In the AR antagonist assays, 24 parent compounds were positive, 7 lost activity after metabolism, and 17 retained activity. This study demonstrated that incorporating hepatic metabolism into in vitro assays can classify EDCs whose toxicity is reduced through metabolism from those that retain endocrine-disrupting potential. Therefore, this approach may improve the identification of EDCs that pose a greater risk to human health.
Neurotoxicity of copper and copper oxide nanoparticles.
Skalny AV, Santamaria A, Lu R … +6 more , Wang Q, Barbosa F, Kovalenko AA, Ferrer B, Aschner M, Tinkov AA
Food Chem Toxicol · 2026 Jul · PMID 41951029 · Publisher ↗
Overexposure to copper (Cu) nanoparticles (NPs), especially metallic CuNPs and CuONPs, is associated with adverse health effects, with higher susceptibility of the brain cells to their toxic effects. However, the particu...
Overexposure to copper (Cu) nanoparticles (NPs), especially metallic CuNPs and CuONPs, is associated with adverse health effects, with higher susceptibility of the brain cells to their toxic effects. However, the particular mechanisms associated with their neurotoxicity are yet unclear. Therefore, the objective of the present review was to discuss the effects of CuNPs and CuONPs, and the molecular mechanisms underlying their neurotoxicity. In vivo studies with laboratory rodents, fishes, and invertebrate species have shown that both acute and chronic exposure to CuNPs/CuONPs induce neurotoxic effects, resulting in morphological brain alterations and behavioral defects. These findings are in agreement with results from in vitro studies, showing cytotoxic effects of CuNPs and CuONPs in neuronal or neuron-like (primary cultured neurons, SH-SY5Y, N2a, HT22), primary cultured astrocytes, microglial (BV2) cell cultures. Further, it has been demonstrated that both CuNPs and CuONPs induce neurotoxic effects through oxidative stress and apoptosis, impaired neurotransmitter metabolism, neuroinflammation, increased formation and toxicity of Aβ and α-synuclein, and aberrant expression of neurogenesis-related genes. Concomitantly, CuONPs also disrupt mitochondrial dynamics, damage the blood-brain barrier (BBB) and cause cell cycle arrest in neurons. The neurotoxic effects of CuNPs and CuONPs are determined by particle size, shape, solubility, and surface characteristics.
Physiologically based toxicokinetic-toxicodynamic (PBTK-TD) modeling of oral exposure to bongkrekic acid in rats.
Cao X, Xiao J, Lei Y … +6 more , Zhong Y, Hu L, Li X, Liang M, Chen K, Bai W
Food Chem Toxicol · 2026 Jul · PMID 41942060 · Publisher ↗
Bongkrekic acid (BA), a secondary metabolite produced by Burkholderia gladioli pathovar cocovenenans (BGC) in food, represents a major etiological agent of severe foodborne intoxication. The physiologically based toxicok...
Bongkrekic acid (BA), a secondary metabolite produced by Burkholderia gladioli pathovar cocovenenans (BGC) in food, represents a major etiological agent of severe foodborne intoxication. The physiologically based toxicokinetic-toxicodynamic (PBTK-TD) model serves as a valuable tool for dose prediction, enabling the estimation of toxicant exposure in biological systems. This study established a multi-compartment PBTK-TD model based on a time-course dataset obtained following single oral administration of BA in rats. Through optimization of kinetic parameters, the PBTK component effectively characterized the toxicokinetic profiles of BA in blood, liver, and other tissues, integrating newly generated experimental data with existing literature. Regression analysis demonstrated coefficients of determination (R) exceeding 0.93 between model-fitted and observed values. The TD component, by incorporating toxicity-related kinetic parameters in target organs, successfully predicted BA-mediated toxic outcomes. Model validation confirmed that all relative prediction errors fell within the acceptable range (80-125%) as per OECD modeling guidelines. Sensitivity analysis identified parameters with the highest overall sensitivity indices, primarily the liver-to-blood partition coefficient (P) and the metabolic rate constant (k). The multi-compartment model provides refined toxicokinetic data and optimized parameters for BA, establishing a robust framework for acute total exposure assessment.
Synergistic disruption of brain metabolism and inflammatory signaling in adult zebrafish by co-exposure to alternariol monomethyl ether and titanium dioxide nanoparticles at physiologically relevant levels.
Li S, Li F, Zhao W … +3 more , Liu Q, Jing G, Cao Y
Food Chem Toxicol · 2026 Jul · PMID 41936886 · Publisher ↗
The combined health risks of mycotoxins and nanoparticles (NPs) remain poorly understood, particularly at physiologically relevant concentrations. Herein, we investigated the neurotoxic effects of 21-day exposure to alte...
The combined health risks of mycotoxins and nanoparticles (NPs) remain poorly understood, particularly at physiologically relevant concentrations. Herein, we investigated the neurotoxic effects of 21-day exposure to alternariol monomethyl ether (AME, 0.2 nM) and titanium dioxide (TiO) NPs (4.2 μg/mL), alone and in combination, in 5-month-old adult male zebrafish. While individual exposures caused minimal histopathological alterations and modest increase in swimming distance, metabolomic profiling revealed striking synergistic effects, that co-exposure altered 33 brain metabolites (vs. 11 by AME alone), predominantly affecting energy metabolism pathways (purine/pyrimidine metabolism, starch/sucrose conversion) and inflammatory signaling (arachidonic acid cascade). Specifically, combined treatment upregulated key glycolytic intermediates (glucose 1,6-bisphosphate, glucose-6-phosphate), pro-inflammatory PGE2, and nucleotide metabolites (ADP, GMP) while depleting deoxyribonucleotides (dAMP, dCMP). RT-PCR data confirmed pathway-level dysregulation, with co-exposure inducing up-regulation of prostaglandin synthases (ptgs1, ptgs2a), pro-inflammatory cytokines (tnf-α, ilβ), and rate-limiting enzymes in glycolysis (pfk) and pentose phosphate pathway (g6pd). Notably, despite AME alone increasing oxidative stress markers (oxidized glutathione), coordinated antioxidant responses (nrf2, sod2, gpx1a) were only triggered in co-exposed group. Our findings demonstrate that TiO NPs potentiate AME-induced metabolic rewiring and neuroinflammation at physiologically relevant levels, underscoring the necessity to reassess combined toxicities of emerging contaminants through pathway-based approaches.
In vitro and in vivo metabolic activation of diaveridine mediated by CYP3A.
Zhai Y, Dong L, Hao X … +5 more , Li X, Li W, Hu Z, Peng Y, Zheng J
Food Chem Toxicol · 2026 Jul · PMID 41935817 · Publisher ↗
Diaveridine (DVD) is an anticoccidial drug and antibacterial synergist used in the livestock and poultry industries worldwide. DVD residues have been reportedly detected in pork and related meat products. Human exposure...
Diaveridine (DVD) is an anticoccidial drug and antibacterial synergist used in the livestock and poultry industries worldwide. DVD residues have been reportedly detected in pork and related meat products. Human exposure to DVD through the environment and the food chain has attracted wide attention, due to the abuse of DVD. Liver injury of animals administered with DVD has been observed and reported, but the potential mechanisms are unelucidated so far. This study aimed to reveal the metabolic activation pathway of DVD that may be related to its hepatotoxicity. DVD was found to be metabolized to an electrophilic species reactive to nucleophilic sulfhydryl groups of cysteine, glutathione (GSH), and N-acetylcysteine (NAC) to generate the cysteine, GSH, and NAC conjugates correspondingly. The GSH conjugates and NAC conjugate(s) were detected in the bile and urine of mice administered with DVD. Furthermore, cysteine conjugates were observed in proteolytic mixture of hepatic proteins obtained from DVD-administered mice in a dose-dependent pattern. CYP3A4 was found to mediate the metabolism of DVD, and an iminoquinone methide intermediate reactive to sulfhydryl of GSH was observed in vitro and in vivo. The GSH conjugates were also detected in primary mouse hepatocytes after exposure to DVD. Pretreatment with ketoconazole (an inhibitor of CYP3A) decreased the formation of the GSH conjugates, and the cytotoxicity associated with DVD was mitigated. This study suggests that DVD was metabolized to the corresponding iminoquinone methide intermediate possibly associated with the hepatotoxicity induced by DVD. This finding facilitates the risk assessment strategies for DVD in food safety supervision.
RIFM fragrance ingredient safety assessment, cyclohexyl methyl pentanone, CAS Registry Number 4927-39-3.
Api AM, Bartlett A, Belsito D … +31 more , Botelho D, Bruze M, Bryant-Friedrich A, Burton GA, Cancellieri MA, Chon H, Cronin M, Crotty S, Dagli ML, Dekant W, Deodhar C, Farrell K, Fryer AD, Jones L, Joshi K, Lapczynski A, Laskin DL, Lavelle M, Lee I, Moustakas H, Muldoon J, Penning TM, Piersma AH, Ritacco G, Sadekar N, Schember I, Schultz TW, Siddiqi F, Sipes IG, Sullivan G, Thakkar Y
Food Chem Toxicol · 2026 Jul · PMID 41935816 · Publisher ↗
Abstract loading — click title to view on PubMed.
Integrative network toxicology reveals lipoprotein lipase as a key mediator of dibutyl phthalate-associated head and neck squamous cell carcinoma.
Li G, Jin Y, Yuan X … +4 more , Wu X, Li L, Liao J, Cai S
Food Chem Toxicol · 2026 Jul · PMID 41935815 · Publisher ↗
Dibutyl phthalate (DBP) is a widely distributed endocrine-disrupting chemical with potential carcinogenic properties, yet its role in head and neck squamous cell carcinoma (HNSC) remains unclear. Here, we applied an inte...
Dibutyl phthalate (DBP) is a widely distributed endocrine-disrupting chemical with potential carcinogenic properties, yet its role in head and neck squamous cell carcinoma (HNSC) remains unclear. Here, we applied an integrative framework combining network toxicology, Mendelian randomization (MR), multi-omics analyses, molecular docking, molecular dynamics simulations, and in vitro experiments to elucidate the mechanisms underlying DBP-associated HNSC. Lipoprotein lipase (LPL) was identified as the sole overlapping gene between DBP-related targets and HNSC-associated genes. MR analysis supported a potential causal relationship between LPL and HNSC susceptibility. Expression profiling demonstrated tissue- and cell type-specific patterns of LPL and its dysregulation in HNSC, with associations to tumor stage and prognosis. Genomic analyses revealed that LPL alterations were infrequent and mainly driven by copy number loss. LPL expression positively correlated with immune and stromal infiltration. Enrichment analyses implicated immune regulation and PI3K-AKT signaling. Molecular simulations showed stable DBP-LPL binding. Functionally, DBP promoted SCC9 proliferation and reduced LPL expression, and was associated with transcriptional changes in PI3K-AKT-mTOR-related genes, whereas LPL restoration mitigated these effects. These findings reveal a novel DBP-LPL axis in HNSC.
Occurrence of plastic additives in different edible bivalve mollusc species from Galician Rías, NW Spain. Exposure and human health risk estimation.
Carro N, Cobas J, Portela A … +3 more , García I, Ignacio M, Mouteira A
Food Chem Toxicol · 2026 Jul · PMID 41912129 · Publisher ↗
The aim of this paper was to evaluate the levels, geographical and inter-species variability, and the potential implications of plastic additives in bivalve mollusks along the Galician coast (NW, Spain). These compounds,...
The aim of this paper was to evaluate the levels, geographical and inter-species variability, and the potential implications of plastic additives in bivalve mollusks along the Galician coast (NW, Spain). These compounds, included 6 phthalates (PAEs) and 9 bisphenols (BPs). A method based on matrix solid phase dispersion (MSPD) extraction combined with gas chromatography coupled to mass spectrometry (GC-MS, mode SIM) was used. Principal component analysis showed a difference among some of the studied species. Wild mussel samples had higher concentrations of ΣBPs than farmed mussels, and other bivalve mollusks. Cockle had the lowest levels of ΣBPs. Bisphenol A (BPA) was the predominant compound in all samples analyzed. The mean concentration of ΣPAEs in scallops was 198 μg/kg dry weight (dw) versus 165 μg/kg dw in oysters. DEHP was the predominant phthalate. In general samples from the Rías Altas were the most contaminated by PAEs and BPs. In relation to canned bivalve mollusks, it is observed that BPs concentrations were higher than PAEs ones and the BPS levels were higher in canned mussels than in fresh mussels. The human risk assessment showed that phthalate and bisphenol levels found did not pose a risk to human health with Risk Quotient (RQ) < 1.
Integrating network toxicology, machine learning, and experimental evidence reveals candidate targets and pathways in PCDD/F-related colon cancer.
Shen H, Zhu W, Wang D … +5 more , Mou Y, Huang Y, Yang Y, Liu Z, Liu Q
Food Chem Toxicol · 2026 Jul · PMID 41912128 · Publisher ↗
Previous studies have suggested that exposure to carcinogenic polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) pollutants may increase the risk of colon cancer, their underlying molecular mec...
Previous studies have suggested that exposure to carcinogenic polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) pollutants may increase the risk of colon cancer, their underlying molecular mechanisms remain unclear. In this study, we employed a multidisciplinary approach integrating network toxicology, machine learning, molecular docking, molecular dynamics (MD) simulations and in vivo experiments to investigate how PCDD/Fs may promote colon carcinogenesis. Machine learning algorithms converged on MMP7 as a core target, MMP7 expression was upregulated in colon cancer tissues and was associated with immune cell infiltration. Molecular docking and MD simulations further suggested stable interactions between the five representative PCDD/F congeners and the target proteins (MMP7, SRC, and HSP90AA1), supporting their potential involvement in disease progression. Consistent with these in silico findings, exposure of mice to 24 μg/kg TCDF significantly increased the expression of Mmp7 and Hsp90aa1 in murine colonic tissues, increased the levels of proinflammatory cytokines Ifn-γ, Il-1β, and Il-6, and downregulated the expression of Mucin 2 (MUC2). Connectivity Map analysis based on the PCDD/F-related gene signature identified five candidate compounds targeting MMP7 and HSP90AA1, of which four HSP90 inhibitors (tanespimycin, alvespimycin, NVP-AUY922 and AT-13387) showed negative connectivity scores, suggesting potential to reverse the pollutant-induced expression profile.
Curcumin inhibits colorectal cancer progression by regulating MDH2-mediated glycolysis and NAD metabolism.
Zhao Y, Qin H, Sun W … +3 more , Chen Y, Wang R, Li C
Food Chem Toxicol · 2026 Jul · PMID 41903769 · Publisher ↗
INTRODUCTION: Abnormal glycolysis drives colorectal cancer (CRC) progression. Curcumin (Cur) has anti-CRC activity, but its effect on glycolysis remains unclear. This study explores Cur's regulation of glycolysis in CRC...
INTRODUCTION: Abnormal glycolysis drives colorectal cancer (CRC) progression. Curcumin (Cur) has anti-CRC activity, but its effect on glycolysis remains unclear. This study explores Cur's regulation of glycolysis in CRC cells. METHODS: Using SW480 and HCT-116 cells, bioinformatics identified key targets. MDH2 was knocked down via shRNA. Effects of Cur alone or with 2-DG on proliferation were assessed by CCK-8 and Transwell assays. Glycolytic indicators and protein levels were measured using kits and Western blotting. In vivo validation used CRC xenograft mice. RESULTS: Cur dose-dependently inhibited CRC cell glycolysis, reducing metabolic indicators and downregulating key proteins/NAD/NADH ratio. Cur combined with 2-DG synergistically suppressed glycolysis and cell proliferation. Bioinformatics showed higher MDH2 expression in CRC tissues (enriched in glycolysis). MDH2 knockdown enhanced Cur's anti-tumor effects and glycolysis suppression in vitro. In vivo, MDH2 silencing potentiated Cur's tumor-inhibitory efficacy, with reduced tumor size, increased necrosis, and enhanced downregulation of glycolytic/NAD metabolic proteins. CONCLUSIONS: The study systematically demonstrated that curcumin suppresses CRC progression by targeting the MDH2-driven glycolysis and NAD metabolic axis, thereby providing novel theoretical basis for metabolism-targeted CRC therapies.
Unveiling the bioactive potential and chemical profiling of Oenothera glazioviana extracts: chromatographic, spectrophotometric, and in silico approaches.
Terzic M, Ak G, Kochan-Jamrozy K … +12 more , Gucwa M, Stefanowicz-Hajduk J, Turecka K, Hałasa R, Zoltan C, Jeko J, Senkardes I, Yapıcı I, Gulcin I, Cetiz MV, Uba AI, Zengin G
Food Chem Toxicol · 2026 Jul · PMID 41895506 · Publisher ↗
Oenothera glazioviana, a largely uninvestigated member of the Onagraceae family, represents a rich source of bioactive natural compounds. This study provides the first integrated analysis of its aerial parts, combining d...
Oenothera glazioviana, a largely uninvestigated member of the Onagraceae family, represents a rich source of bioactive natural compounds. This study provides the first integrated analysis of its aerial parts, combining detailed phytochemical profiling, in vitro antioxidant, antimicrobial and anticancer evaluation, enzyme inhibitory assessment, and in silico molecular docking. LC-MS profiling identified phenolic acids, flavonoids, ellagitannins, and minor secondary metabolites, with ethanol-water and water extracts exhibiting the highest phenolic content. Antioxidant potential, assessed using multiple in vitro assays, was highest in the ethanol-water extract (ABTS: 1594.85 mg TE/g; CUPRAC: 675.58 mg TE/g), highlighting the preferential extraction of hydrophilic phenolics. Enzyme inhibition studies demonstrated selective modulation of acetylcholinesterase (2.45 mg GALAE/g), tyrosinase (64.72 mg KAE/g), and α-glucosidase (1.13 mmol ACAE/g). The ethanol-water extract also possessed good antimicrobial activity on the tested microbial strains. In anticancer studies, the results showed that the ethyl acetate extract had significant anticancer activity on AGS and HeLa cells with IC values of 12.00 ± 0.15 and 34.27 ± 2.36 μg/mL, respectively, and with low cytotoxicity against a non-cancerous control - HaCaT. Furthermore, molecular docking and molecular dynamics simulations were performed to elucidate the molecular basis of the extracts' anticancer, anti-enzymatic, and antimicrobial activities. These findings highlight O. glazioviana as a versatile source of bioactive compounds with promising pharmacological and nutraceutical potential, paving the way for future studies on their structure-activity relationships, bioavailability, and in vivo efficacy.
Immune gene MMP9 as a potential key mediator in TCDD exposure-associated atherosclerosis: An integrated study based on network toxicology and experimental validation.
Bingqi G, Yingrui W, Yuhuan L … +4 more , Sixiang Z, Zixuan L, Guiping C, Zheng L
Food Chem Toxicol · 2026 Jul · PMID 41895505 · Publisher ↗
BACKGROUND: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic, recalcitrant persistent organic pollutant with ubiquitous environmental distribution. Atherosclerosis (AS) is a systemic vascular disorder charact...
BACKGROUND: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic, recalcitrant persistent organic pollutant with ubiquitous environmental distribution. Atherosclerosis (AS) is a systemic vascular disorder characterized by chronic vascular inflammation, lipid accumulation, and atherosclerotic plaque formation, in which immunometabolic dysregulation serves as one of the central pathogenic mechanisms. Although an association between environmental TCDD exposure and AS has been preliminarily corroborated, the precise molecular mechanisms underlying TCDD exposure-associated initiation and progression of AS remain incompletely elucidated, especially the mediating role of immune genes. OBJECTIVES: This study sought to explore the potential molecular mechanisms linking TCDD exposure and atherosclerosis via an integrated strategy combining network toxicology and experimental validation. We aimed to screen and identify a core immune gene matrix metallopeptidase 9 (MMP9) and its related regulatory pathways potentially involved in this pathological process through systematic bioinformatic analysis, thereby providing novel theoretical insights and candidate targets for risk assessment, early diagnosis, and targeted intervention of environmentally associated atherosclerosis. METHODS: First, publicly available AS-related transcriptomic datasets and TCDD exposure-associated gene expression profiles were retrieved from the GEO database, subjected to batch correction, and analyzed in an integrated manner. Immune-related differentially expressed genes (Immune-DEGs) closely linked to both TCDD exposure and atherosclerosis were screened using network toxicology approaches. A diagnostic model was constructed using a combined machine-learning pipeline incorporating multiple foundational algorithms, and core immune targets were prioritized via SHapley Additive exPlanations (SHAP) analysis and Weighted Gene Co-expression Network Analysis (WGCNA). Functional enrichment and immune infiltration analyses were performed to characterize the biological functions of core immune targets and their associations with the atherosclerotic inflammatory microenvironment. Pseudotime analysis based on publicly available single-cell RNA sequencing data was conducted to delineate the dynamic expression pattern of MMP9 during atherosclerotic plaque evolution, with in silico knockout employed to evaluate its functional contribution. Furthermore, an in vitro cellular model of atherosclerosis was established using oxidized low-density lipoprotein (ox-LDL) to induce human umbilical vein endothelial cell (HUVEC) injury, and MMP9 mRNA and protein expression levels were validated by quantitative real-time polymerase chain reaction (RT-qPCR) and Western blot (WB), respectively. Molecular docking and molecular dynamics simulations were performed to assess the binding affinity between TCDD and MMP9. RESULTS: Integrated bioinformatic analyses and machine learning screening identified MMP9 as a core immune gene potentially mediating TCDD exposure-associated atherosclerosis. Immune infiltration analysis revealed a positive correlation between MMP9 expression and pro-inflammatory cell infiltration within atherosclerotic lesions. Functional enrichment indicated that MMP9 is predominantly involved in inflammatory signaling activation, vascular matrix remodeling, and lipid metabolism regulation. Pseudotime analysis demonstrated that MMP9 was markedly upregulated in advanced atherosclerotic plaques, driving pathological extracellular matrix remodeling and enhanced plaque vulnerability. In silico MMP9 knockout significantly attenuated extracellular matrix degradation, reduced inflammatory infiltration, and preserved the structural stability of the fibrous cap. In the in vitro AS cellular model, MMP9 expression was significantly elevated. Molecular docking and dynamics simulations verified high-affinity binding between TCDD and MMP9, with a binding energy of -9.7 kcal/mol, supporting the formation of a stable complex. CONCLUSIONS: This study identifies the immune gene MMP9 as a potential pivotal molecular mediator in TCDD exposure-associated atherosclerosis. Bioinformatic evidence and molecular simulation results suggest that TCDD may specifically bind to MMP9 to modulate inflammatory responses and vascular matrix remodeling, thereby potentially exacerbating the initiation and progression of atherosclerosis.
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