This study investigated blood levels of phthalates, non-phthalate plasticizers (NPPs), and bisphenols in 39 Sicilian women and evaluated how food-contact practices contribute to multivariate exposure profiles. A total of...This study investigated blood levels of phthalates, non-phthalate plasticizers (NPPs), and bisphenols in 39 Sicilian women and evaluated how food-contact practices contribute to multivariate exposure profiles. A total of 23 plasticizers and 9 bisphenols were analyzed in whole blood using validated GC-MS and LC-MS/MS methods. At least one plasticizer was detected in every participant, whereas bisphenols were rarely quantified. Five phthalates (DMP, DEP, DBP, DiBP, DEHP) and two NPPs (DiBA, DEHT) showed the highest occurrence, with broad concentration ranges indicating marked inter-individual variability. Correlation analysis revealed coherent PAE co-exposure patterns, mixed PAE-DiBA associations, and a distinct DEHT-driven profile. Participants were classified into four chemically defined exposure clusters based on total plasticizer burden and relative PAE/NPP dominance: C1 (Low-PAE), C2 (High-PAE), C3 (Low-NPP), and C4 (High-NPP). PCA and CDA confirmed that these profiles represent distinct multivariate exposure patterns, supported by significant differences in individual compounds and derived indices. Food-contact behaviors differed significantly across clusters. High-NPP profiles (C4) reported the most frequent use of PET bottles, PET container reuse, rigid trays, and plastic-based storage or heating practices, whereas C1 showed consistently lower frequencies. These findings highlight substantial heterogeneity in exposure patterns and demonstrate that everyday food-contact habits play a measurable role in shaping blood levels of plasticizers in Mediterranean women.
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
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
Hexadecane was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, photoirritation/photoallergenicity, skin sensitization, and environmental safety. Data show that hexad...Hexadecane was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, photoirritation/photoallergenicity, skin sensitization, and environmental safety. Data show that hexadecane is not genotoxic and provide a calculated Margin of Exposure (MOE) > 100 for the repeated dose toxicity endpoint. Data from read-across analog undecane (CAS # 1120-21-4) provide a calculated MOE >100 for the reproductive toxicity endpoint. Data show that there are no safety concerns for hexadecane for skin sensitization under the current declared levels of use. The photoirritation/photoallergenicity endpoints were evaluated based on ultraviolet/visible (UV/Vis) spectra; hexadecane is not expected to be photoirritating/photoallergenic. The local respiratory toxicity endpoint was evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material, and the exposure to hexadecane is below the TTC (1.4 mg/day). The environmental endpoints were evaluated; hexadecane was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients (RQs), based on its current volume of use (VoU) in Europe (EU), North America (NA), Asia-Pacific (AP), and South America (SA) (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.
Elevated levels of lead and copper dyshomeostasis are significant risk factors for cognitive dysfunction in older adults. During brain aging, microglia transition to a senescence-associated secretory phenotype (SASP), th...Elevated levels of lead and copper dyshomeostasis are significant risk factors for cognitive dysfunction in older adults. During brain aging, microglia transition to a senescence-associated secretory phenotype (SASP), thereby contributing to cognitive decline. However, whether lead affects cognitive function by promoting microglial SASP transition remains unclear. In this study, we exposed BV2 microglial cells to lead or co-exposure to lead and copper to simulate severe copper dyshomeostasis. Lead exposure promoted the transition of BV2 cells to a SASP, characterized by enlarged cell bodies, increased M1 activation, and enhanced release of inflammatory cytokines. This promotion was more enhanced in the presence of copper and was attributed to intracellular copper overload. Mechanistically, copper overload triggered reactive oxygen species (ROS) production and mitochondrial DNA (mtDNA) release, activating the cGAS-STING-NLRP3 axis, driving M1 microglial activation, and sustaining neuroinflammation. Copper chelation following lead or lead and copper co-exposure reduced ROS, mtDNA release, and neuroinflammatory cytokine production. Our findings suggest that cellular copper overload, responsible for activating mtDNA-cGAS-STING-NLRP3 axis, plays a significant role in microglial transition following lead exposure.
Bisphenol analogues such as BPA, BPS, BPF, and BPAF are widely used in consumer products, raising concern over their combined health risks. This study conducted a probabilistic population-level assessment of cumulative e...Bisphenol analogues such as BPA, BPS, BPF, and BPAF are widely used in consumer products, raising concern over their combined health risks. This study conducted a probabilistic population-level assessment of cumulative estrogenic exposure to these compounds from personal care products among Korean adults. Using data from a nationwide survey (n = 3000), product concentration records, and 100,000-iteration Monte Carlo simulations stratified by sex, daily external doses were estimated. Cumulative estrogenic exposure was expressed as BPA equivalents based on relative potency factors, and risks were evaluated through margin of exposure (MOE) and hazard quotient (HQ) analyses. BPF dominated mass-based exposure (∼82%), while BPAF contributed most after potency adjustment. The median cumulative exposure was 4.1 × 10 μg/kg bw/day, with MOEs above 10 and HQs well below 1. Scenario-based uncertainty evaluation (clearance, absorption, and toothpaste ingestion retention) indicated that conclusions remained robust under plausible parameter ranges. Overall, current exposure levels suggest minimal estrogenic risk, yet high-potency analogues such as BPAF warrant continued monitoring. The RPF-MOE framework provides a practical tool for evaluating and managing bisphenol substitutes in consumer products.
Snortable energy powders have recently emerged, under brands such as Sniffy, raising public health and regulatory concerns because of largely unknown nasal toxicity. This study aimed to assess the cytotoxic potential of...Snortable energy powders have recently emerged, under brands such as Sniffy, raising public health and regulatory concerns because of largely unknown nasal toxicity. This study aimed to assess the cytotoxic potential of Sniffy powders on human nasal epithelial cells and identify the constituents driving the observed toxicity. RPMI 2650 nasal epithelial cells were cultured at the air-liquid interface and exposed for 24 h to graded doses of Sniffy powders (from 0.6 to 30 mg/cm). Cell viability and membrane integrity were assessed by resazurin reduction and LDH release. To investigate the contribution of specific constituents (caffeine, creatine, and flavourings), comparative assays were conducted using individual ingredients and combinations. Sniffy induced a strong, dose-dependent cytotoxic response, with a 50% reduction in cell viability and a twofold increase in LDH at 6 mg/cm, corresponding to localized "hotspot" deposition in the nasal cavity. Caffeine alone reproduced the cytotoxicity of the full commercial formulation, whereas creatine and flavourings showed negligible effects. These results demonstrate that intranasal exposure to snortable caffeine-based powders can cause substantial epithelial injury in vitro, primarily driven by caffeine. The findings underscore the importance of route-specific toxicological assessment and support the maintenance of regulatory restrictions on the nasal use of such products.
Although food additives play important technological roles in food processing and undergo rigorous safety evaluations before approval, concerns about human exposure persist, particularly for children. Due to limited info...Although food additives play important technological roles in food processing and undergo rigorous safety evaluations before approval, concerns about human exposure persist, particularly for children. Due to limited information in Brazil, this study estimated the intake of food additives in a sample of children aged 1-3 years in Campinas-SP under conservative assumptions (Tier 2b) in order to screen and prioritize substances for refined exposure assessment. Data from a 24-h dietary recall and a database of 3300 commercial products were used to select 77 food additives. Estimated daily intakes were calculated using maximum permitted levels established by Brazilian legislation and compared to the Health-Based Guidance Values (HBGV). Fifty-one food additives did not exceed the HBGV and were considered low priority; 14 exceeded only at the 95th percentile of exposure (P95) and were classified as medium priority; and 12 exceeded the HBGV for both mean and P95 intake, being considered high priority. Among the high priority substances, sodium aluminum phosphate (acidic), sodium nitrite, annatto extracts (norbixin-based), and polyglycerol esters of interesterified ricinoleic acid stood out, along with phosphates as group. Given the conservative assumptions, these findings indicate priorities for further studies and regulatory evaluation rather than evidence of actual health risk.
Total parenteral nutrition (TPN) for preterm infants includes essential trace elements (TEs)-manganese (Mn), zinc (Zn), copper (Cu), chromium (Cr), and selenium (Se)-that are critical for early development and later heal...Total parenteral nutrition (TPN) for preterm infants includes essential trace elements (TEs)-manganese (Mn), zinc (Zn), copper (Cu), chromium (Cr), and selenium (Se)-that are critical for early development and later health. However, supplemented levels have at times exceeded regulatory recommendations and have been linked to adverse effects on the brain, prompting discontinuation of several TPN products. These concerns warrant systematic evaluation of the effects of developmental TEs exposure on growth and neurobehavior, particularly in light of increasing concern over early-life disruption of stress-regulatory and neurodevelopmental pathways. Using the zebrafish embryo model, we investigated how individual and combined developmental exposures to Mn, Zn, Cu, Cr, and Se-spanning 25-fold below to 25-fold above recommendations-affect development and stress response behaviors. Embryos were enzymatically dechorionated and exposed from 6 to 120 h post-fertilization. Individual TEs exposures induced concentration-dependent increases in mortality and developmental defects, while their mixture caused less pronounced yet significant effects. All TE exposures significantly reduced larval length, and higher concentrations altered acute stress-response behaviors. Collectively, our findings highlight adverse effects on larval development and stress-related neurobehaviors in response to clinical recommended levels and elevated multiples thereof, highlighting the importance of evaluating developmental sensitivity to clinically relevant TE exposure ranges and element-element interactions.
The "forever chemicals" per- and polyfluoroalkyl substances (PFAS) have been measured in wild caught fish, but few studies have examined PFAS in aquaculture. This study aims to quantify PFAS in commercial aquaculture fee...The "forever chemicals" per- and polyfluoroalkyl substances (PFAS) have been measured in wild caught fish, but few studies have examined PFAS in aquaculture. This study aims to quantify PFAS in commercial aquaculture feeds, quantify PFAS in fillets and livers of aquaculture fish fed commercial diets, and estimate human dietary exposure of PFAS through consumption of aquaculture fish. Thirteen commercial feeds were analyzed for 29 PFAS. Fifteen PFAS were detected with perfluorooctanesulfonic acid (PFOS) detected in all feeds. A 63-day feeding trial on juvenile red drum (Sciaenops ocellatus) fed two different feeds at three ration levels was conducted. Only PFOS was detected in the fillets and livers, and fish given the higher PFOS diet exhibited a higher percentage of detection in their fillets (70.8 %; mean = 0.09 ng/g) compared to fish given the lower PFOS diet (0 %). There was a significant difference in size between the feed groups (p-value < 0.0001), suggesting a possible growth dilution effect. PFOS did not differ among rations, and levels in the fillets did not exceed EFSA guidelines. This study provides baseline data on dietary contribution of PFAS to and from aquaculture fish and allows for informed safe consumption recommendations to safeguard human health.
OBJECTIVE: To determine whether very high-dose maternal omega-3 fish oil supplementation induces sex-dependent autism-related behavioral and neurobiological changes in rat offspring. METHODS: Pregnant Sprague-Dawley rats...OBJECTIVE: To determine whether very high-dose maternal omega-3 fish oil supplementation induces sex-dependent autism-related behavioral and neurobiological changes in rat offspring. METHODS: Pregnant Sprague-Dawley rats received tap water or fish oil (60% EPA, 40% DHA; 5000 mg/kg/day) throughout gestation. Litters were standardized at birth and offspring weaned on P21. At P50, sociability (three-chamber test) and locomotion (open field) were assessed. Brain IGF-1, plasma biochemical markers, and serum testosterone were measured. Hippocampal CA1/CA3 neurons and GFAP immunoreactivity were analyzed. RESULTS: Omega-3-exposed males showed a profound sociability deficit (15.4 ± 4.8% vs. 78.3 ± 6.1%; p < 0.001), while females were unaffected. Locomotor activity was unchanged. IGF-1 increased in both sexes, with a greater rise in males. Prenatal omega-3 elevated triglycerides, uric acid, and ALT in both sexes and selectively increased cholesterol and testosterone in males. Histology revealed CA1 neuronal alterations and marked astrogliosis in exposed males. CONCLUSION: Very high-dose prenatal omega-3 intake produces a male-specific autism-like phenotype associated with IGF-1 upregulation, hippocampal glial activation, and metabolic changes, underscoring the importance of defining upper safety thresholds for prenatal omega-3 intake during pregnancy.
Amiodarone (AMD) is a potent antiarrhythmic drug, although reports indicate its neurotoxic and endocrine-disrupting properties. This study evaluated AMD toxicity in a hippocampal neuron model (differentiated HT-22 cells)...Amiodarone (AMD) is a potent antiarrhythmic drug, although reports indicate its neurotoxic and endocrine-disrupting properties. This study evaluated AMD toxicity in a hippocampal neuron model (differentiated HT-22 cells) and its effects on neurosteroid secretion. AMD exhibited neurotoxicity only at high concentrations (10-50 μM). At a non-toxic concentration (1 μM), AMD decreased mRNA expression of CYP19A1, CYP17A1, CYP1A1, CYP1B1, PPARγ, AR, and ER1, while increasing AhR, NF-κB, ER2, and 17β-HSD expression. AMD also reduced AhR and PPARγ protein levels and altered AhR/PPARγ-regulated transcripts, suggesting involvement of both signaling pathways. Furthermore, AMD decreased estradiol secretion and aromatase protein levels without significantly affecting progesterone or testosterone. Co-treatment with the PPARγ antagonist GW9662 and AMD reduced the secretion of all three hormones. Experiments using the AhR antagonist CAY10464 and GW9662 indicated that AMD regulates hormone production through the PPARγ-AhR axis. The inhibitory effect of AhR blockade appeared to be functionally compensated by PPARγ activity, whereas inhibition of PPARγ abolished this protective effect and revealed stronger AhR-mediated regulation of steroidogenesis. Protein analysis further supported a complex mechanism involving AhR-PPARγ crosstalk. Additionally, ER signaling may contribute to the reduction of aromatase expression.
NDMA is a nitrosamine recognized as an environmental contaminant of water and food, unintentionally formed during industrial processes and water treatment. Due to its mobility in aquatic environments, persistence, and ca...NDMA is a nitrosamine recognized as an environmental contaminant of water and food, unintentionally formed during industrial processes and water treatment. Due to its mobility in aquatic environments, persistence, and carcinogenic potential, NDMA has emerged as a toxicological and public health concern. This study evaluated the effects of low-dose exposure (7.2 ng/kg/day) on the prostate of male Wistar rats across two generations within the Paternal Origins of Health and Disease (POHaD) framework. F0 males were exposed via gavage from postnatal day (PND) 60 to 104. In F1, offspring were evaluated at PND70 (paternal exposure) and PND120 (direct exposure PND22-70). Exposed F0 males showed increased prostate weight. Stereology revealed epithelial expansion and luminal reduction in F0 and F1 (PND120), increased interstitial area in paternally exposed offspring, and reduced interstitium in F1 (PND70). Collagen analyses showed reduced type III in F0 and reduced types I and III in F1 (PND70), while type I increased in F1 (PND120) with exposure. All groups exhibited inflammatory infiltrate and mast cell degranulation. RT-qPCR indicated decreased androgen receptor (Ar) expression in F1 (PND120) with exposure, reduced Tnf-α in exposed F1, and increased Il-6 only in exposure. NDMA induced direct and intergenerational prostatic toxicity, reinforcing the POHaD concept.
Lacticaseibacillus rhamnosus NCDC 610, isolated from the cereal-based fermented milk product Rabdi, has previously demonstrated antimicrobial, immunomodulatory, hypocholesterolemic, and antidiabetic properties. To ensure...Lacticaseibacillus rhamnosus NCDC 610, isolated from the cereal-based fermented milk product Rabdi, has previously demonstrated antimicrobial, immunomodulatory, hypocholesterolemic, and antidiabetic properties. To ensure its safe application in foods and probiotic formulations, a comprehensive preclinical safety assessment was performed in accordance with ICMR and OECD guidelines. A battery of in vitro and in vivo assays was conducted to evaluate virulence factors, mucin degradation, biogenic amine production, antibiotic susceptibility, cytotoxicity in HT-29 cells, and adhesion ability. Additionally, acute and sub-acute oral toxicity studies were performed in C57BL/6 mice, including haematological, biochemical, histopathological, and immunological parameters. Lcb. rhamnosus NCDC 610 lacked virulence-associated attributes and did not exhibit haemolytic, gelatinase, coagulase, DNase, β-glucosidase, or β-glucuronidase activities. It neither utilized mucin nor produced biogenic amines, as confirmed by colourimetric and HPLC analyses. Further, Lcb. rhamnosus NCDC 610 was susceptible to clinically relevant antibiotics, maintained >95% cell viability in HT-29 cells, and showed moderate adhesion to intestinal epithelial cells. In vivo studies revealed no treatment-related toxicity, behavioural abnormalities, organ damage, bacterial translocation, or adverse immune responses. Collectively, these findings demonstrate the in vitro and in vivo safety of Lcb. rhamnosus NCDC 610 and support its potential for further evaluation as a functional probiotic candidate.
Per- and polyfluoroalkyl substances (PFASs) are environmentally persistent industrial substances with potential health impacts during pregnancy. However, evidence linking PFASs exposure to gestational diabetes mellitus (...Per- and polyfluoroalkyl substances (PFASs) are environmentally persistent industrial substances with potential health impacts during pregnancy. However, evidence linking PFASs exposure to gestational diabetes mellitus (GDM) remains inconclusive. This study systematically evaluated the PFASs-GDM association using the Toxicological Risk Assessment for Environmental Chemicals (TRAEC) strategy. A systematic literature search was conducted using PubMed and Web of Science to identify epidemiological studies, animal models, and cell-based experiments. To validate the evidence, we performed targeted mouse experiments on gestational exposure to typical PFASs. The TRAEC strategy assessed the reliability, correlation, and risk intensity of the evidence sources. The evaluation integrated findings from 36 studies on nine PFASs subtypes and GDM risk. Our mouse experiments showed that prenatal perfluorononanoic acid (PFNA) exposure increased baseline blood glucose levels, impaired glucose tolerance, and reduced insulin sensitivity, confirming epidemiological observations. The TRAEC evaluation revealed a significant correlation between PFASs exposure and GDM risk, with moderate-strength evidence across study designs. Perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and PFNA exhibited the strongest associations. By integrating epidemiological, animal, and mechanistic evidence via a standardized framework, this study robustly confirms PFASs exposure elevates GDM risk, highlighting the need for public health interventions to protect maternal-fetal metabolic health.
INTRODUCTION: Pyriproxyfen (PPF) and diflubenzuron (DFB) are widely used pesticides with metabolic toxicity in humans underexplored. White adipose tissue (WAT) is a potential target for endocrine-disrupting chemicals. AI...INTRODUCTION: Pyriproxyfen (PPF) and diflubenzuron (DFB) are widely used pesticides with metabolic toxicity in humans underexplored. White adipose tissue (WAT) is a potential target for endocrine-disrupting chemicals. AIM: We investigated the effects of PPF and DFB on human adipose-derived stem cells (hASCs) redox balance, epigenetic regulation, and adipogenic differentiation. METHOD: Visceral WAT hASCs were exposed to PPF or DFB (0.01-2 mg/L). Cytotoxicity was observed at ≥1.5 mg/L, with 1 mg/L selected for further experiments. RESULTS: 8-day exposure to PPF or DFB reduced catalase and superoxide dismutase activities while increasing glutathione peroxidase. This was accompanied by 74% increase in mRNA expression of H3K27 demethylase KDM6B and elevated secretion of CCL2 in PPF-exposed cells. During adipogenic differentiation, PPF and DFB upregulated early transcription factors and enhanced lipid accumulation. Differentiated adipocytes exhibited higher proportion of saturated fatty acids and increased leptin secretion, while adiponectin levels remained unchanged. In mature primary adipocytes, PPF suppressed the secretion of leptin and adiponectin, and significantly increased basal lipolysis. DISCUSSION: our results show endocrine and metabolic disruption induced by non-cytotoxic concentrations of PPF and DFB. PPF upregulated the epigenetic modulator KDM6B and promoted dysregulated adipogenic programming in hASCs, favouring lipid accumulation and a pro-inflammatory, metabolically compromised phenotype.
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
6PPD-quinone (6PPD-Q), a toxic tire-derived antioxidant transformation product, is a pervasive environmental contaminant linked to reproductive toxicity. However, its role in ovarian cancer (OC) remains elusive. We integ...6PPD-quinone (6PPD-Q), a toxic tire-derived antioxidant transformation product, is a pervasive environmental contaminant linked to reproductive toxicity. However, its role in ovarian cancer (OC) remains elusive. We integrated network toxicology with transcriptomic analysis to elucidate the oncogenic mechanisms of 6PPD-Q. By screening the GEO, SwissTargetPrediction, and SEA databases, we identified 26 intersection targets. Utilizing machine learning and SHAP analysis, five core biomarkers-DDR1, ABL1, PDE2A, FRK, and F10-were prioritized. Molecular docking demonstrated high binding affinities between 6PPD-Q and these core proteins. In vitro validation, including CCK-8, plate colony formation, and qRT-PCR assays, confirmed that 6PPD-Q exposure significantly promotes OC cell proliferation. Mechanistically, 6PPD-Q may regulate the expression of hub targets to affect OC progression. This study establishes a definitive "exposure-target-phenotype" chain, characterizing 6PPD-Q as a potential environmental promoter of OC and suggest potential intervention targets.
Food-grade titanium dioxide (TiO2) and tris (1, 3-dichloro-2-propyl) phosphate (TDCPP) are environmental pollutants with high exposure among children, which pose potential risks to neurodevelopment. However, the neurotox...Food-grade titanium dioxide (TiO2) and tris (1, 3-dichloro-2-propyl) phosphate (TDCPP) are environmental pollutants with high exposure among children, which pose potential risks to neurodevelopment. However, the neurotoxicity of their co-exposure remains poorly understood. In this study, we employed C8-D1A astrocytes, BV2 microglia, and Neuro-2a neuroblastoma cells to investigate the neurotoxicity of food-grade TiO and TDCPP co-exposure. Toxicity experiments revealed that combined exposure to food-grade TiO2 and TDCPP elicited the most pronounced toxic effects on BV2 cells. Further co-culture experiments confirmed that this co-exposure primarily exacerbated apoptosis in Neuro-2a neurons indirectly through the activation of BV2 cells. Transcriptomic and RT-qPCR analysis revealed downregulated the expression of the aconitate decarboxylase 1 (Acod1) gene, while upregulating pro-inflammatory cytokines (Il-6, Il-1β and Tnf-α) and the DNA demethylase Tet2 in BV2 cells. Validation via Acod1 gene knockdown, exogenous itaconate intervention and co-culture experiments confirmed that co-exposure to food-grade TiO2 and TDCPP suppressed the Acod1/itaconate axis and was associated with elevated TET2 activity and NF-κB activation. These changes correlated with microglial inflammatory responses and neuronal apoptosis, suggesting potential epigenetic involvement. Our results elucidate a novel mechanism for food-grade TiO and TDCPP combined neurotoxicity and suggest the therapeutic potential of itaconate in mitigating neuroinflammation.
Herbal medicines are widely used, yet their hepatotoxic potential remains underexplored in predictive toxicology. UHPLC-based compound profiling was combined with a Random Walk with Restart (RWR) network approach using h...Herbal medicines are widely used, yet their hepatotoxic potential remains underexplored in predictive toxicology. UHPLC-based compound profiling was combined with a Random Walk with Restart (RWR) network approach using herb compound target associations filtered by P-value and Z-score thresholds. Predictions were evaluated in HepG2 cells using microscopy-based phenotypic assessment, mitochondrial membrane potential measurement, ALT and AST activities in culture supernatants, transcriptomic profiling by RNA sequencing with enrichment analysis, and qRT-PCR as supportive validation. RWR prioritized apoptosis, oxidative stress, and inflammatory pathways for Camellia sinensis, Piper longum, Atractylodes lancea, Angelica gigas, Xanthium sibiricum, and Cynanchum wilfordii, whereas Astragalus membranaceus showed limited enrichment. Consistent with these predictions, the six prioritized extracts induced injury-associated morphological changes, loss of mitochondrial membrane potential, and increased ALT and AST release, while A. membranaceus showed minimal changes. RNA sequencing showed broad transcriptomic perturbations and clustering of the predicted hepatotoxic extracts with coordinated changes across hepatotoxicity-relevant gene categories. Overall, this framework supports scalable preclinical screening of herbal products by linking computational pathway prioritization with experimental validation, and broader herb-compound-target coverage with expanded toxicological datasets may further improve predictive performance for safety assessment.