This narrative review examines lycopene, a natural carotenoid found in tomatoes and other fruits, as a multi-target inhibitor of ferroptosis - an iron-dependent form of regulated cell death driven by lipid peroxidation....This narrative review examines lycopene, a natural carotenoid found in tomatoes and other fruits, as a multi-target inhibitor of ferroptosis - an iron-dependent form of regulated cell death driven by lipid peroxidation. Preclinical evidence indicates that lycopene suppresses ferroptosis through four complementary mechanisms: activation of the Nrf2/GPX4 antioxidant axis, inhibition of ferritinophagy via NCOA4 downregulation, inhibition of CYPOR (reducing hydrogen peroxide production), and direct scavenging of lipid peroxyl radicals. The therapeutic potential of lycopene is evaluated in polycystic ovary syndrome (PCOS), non-alcoholic steatohepatitis (NASH), neurodegenerative disorders, cancer, cardiovascular diseases, and injuries induced by environmental toxicants including atrazine, cadmium, cisplatin, and cyclophosphamide. Despite promising preclinical findings, significant limitations preclude clinical translation: poor oral bioavailability, lack of identified direct molecular targets, absence of large-scale clinical trials, sex bias in animal studies, and publication bias. The proposed dual role of lycopene in cancer (inducing ferroptosis in malignant cells while inhibiting it in normal cells) remains an unproven hypothesis requiring direct experimental testing. Future research priorities include developing bioavailable formulations, conducting target identification studies, and validating ferroptosis-specific biomarkers. Currently, the primary contribution of lycopene research remains in mechanistic preclinical studies, and clinical recommendations are premature.
Animal models have been widely used to explore the pathogenesis of food allergy. However, the influence of sex differences in mice on food allergy is unknown. In this study, recombinant tropomyosin (TM) exhibited IgE-bin...Animal models have been widely used to explore the pathogenesis of food allergy. However, the influence of sex differences in mice on food allergy is unknown. In this study, recombinant tropomyosin (TM) exhibited IgE-binding activity comparable to that of natural TM in Lateolabrax japonicus, and could be used to construct fish-sensitized models. Female and male BALB/c mice were employed to characterize their susceptibility to TM, and the differences in allergic symptoms and immune responses were compared. Results showed that, compared with male mice, female mice had more severe disruptions in the intestinal barrier, as well as both stronger humoral (IgE, IgG2a) and Th2 immune responses (CD19 B cells, IL-4). Furthermore, the disruption of Treg/Th17 balance in female mice was more significant than in male mice. Hence, BALB/c female mice are an ideal choice for establishing an food allergy model, highlights the significant role of genetic variation in the immune response.
Aflatoxin B1 (AFB1) is a prevalent food- and feed-borne mycotoxin, and growing evidence indicates that the renal epithelium is a vulnerable target. However, host determinants that modify epithelial susceptibility remain...Aflatoxin B1 (AFB1) is a prevalent food- and feed-borne mycotoxin, and growing evidence indicates that the renal epithelium is a vulnerable target. However, host determinants that modify epithelial susceptibility remain poorly defined. Here, we investigated AFB1-triggered injury in porcine kidney epithelial PK15 cells and examined the contribution of CXCL8. PK15 cells were exposed to AFB1 (0-32 μM) to define dose-dependent cytotoxicity, and sub-IC50 conditions (4 and 8 μM for 24 h) were used for mechanistic analyses; RNA sequencing at 4 μM for 24 h was used as an exploratory screen to prioritize candidate susceptibility factors. CXCL8 emerged as the most strongly induced transcript and was subsequently evaluated using CRISPR/Cas9-mediated knockout. CXCL8 deficiency attenuated AFB1-induced loss of viability, reduced Annexin V/PI-positive cells, and alleviated mitochondrial ultrastructural injury. In parallel, CXCL8 knockout decreased ROS accumulation, partially restored intracellular GSH and the BCL2/BAX transcriptional ratio, and reduced caspase-3 induction and cleavage. Collectively, these data support CXCL8 as an AFB1-inducible susceptibility factor associated with oxidative stress amplification and caspase-3 activation in PK15 cells, while indicating that the upstream regulatory axis and the precise downstream signaling route require further validation in physiologically relevant renal models.
Prenatal caffeine exposure (PCE) is linked to fetal growth restriction (FGR) and has been associated with bile-acid-related pregnancy complications. Because the fetal-placental-maternal bile-acid (BA) circulation is esse...Prenatal caffeine exposure (PCE) is linked to fetal growth restriction (FGR) and has been associated with bile-acid-related pregnancy complications. Because the fetal-placental-maternal bile-acid (BA) circulation is essential for pregnancy homeostasis and fetal development, we asked whether PCE disrupts BA balance across these compartments and sought the underlying placental mechanism. We established a rat model of PCE and analyzed placental samples from pregnancies complicated by FGR. Targeted BA metabolomics, transporter expression assays, cAMP/PKA signaling measurements, and trophoblast functional assays were performed to delineate the mechanism. PCE increased maternal serum total bile acids but reduced BAs in male fetuses; female fetuses were unchanged. Male placentas exhibited increased OATP2B1 and BCRP and decreased MRP4, consistent with sex-biased remodeling of placental BA transport. In BeWo cells, caffeine altered taurocholic-acid transport, changed transporter expression, and suppressed A2AR-dependent cAMP/PKA/SP1 signaling; pharmacologic activation of A2AR or cAMP partially reversed these effects. In human FGR placentas, OATP2B1 was elevated and SP1 signaling was attenuated. PCE reprograms placental BA transport by inhibiting the A2AR-cAMP/PKA-SP1 axis, potentially enhancing fetal-to-maternal BA efflux, increasing a cholestasis-like maternal BA load, and contributing to male fetal hypo-bileacidemic. Altered placental BA transport may therefore link prenatal caffeine exposure to sex-specific fetal vulnerability.
Zearalenone (ZEA), a mycotoxin produced by Fusarium fungi, has drawn significant attention due to its multi-organ toxicity. To explore the molecular mechanisms of ZEA-induced hepatotoxicity and identify effective interve...Zearalenone (ZEA), a mycotoxin produced by Fusarium fungi, has drawn significant attention due to its multi-organ toxicity. To explore the molecular mechanisms of ZEA-induced hepatotoxicity and identify effective intervention strategies, this study identified key targets associated with ZEA-induced hepatotoxicity by screening public databases. Further construction of a protein interaction network revealed five crucial targets: TP53, STAT3, HSP90AA1, ESR1, and PPARG. Moreover, genistein (GEN) was identified from the TCMSP database as a compound capable of simultaneously targeting these targets. Molecular docking results indicated that GEN exhibits strong binding affinity with the five targets (all binding energies <0 kcal/mol). To validate hepatotoxicity mediated by ZEA and intervention mechanisms of GEN, ZEA exposure and ZEA + GEN treated mouse models were conducted. The results exhibited that exposure to ZEA led to increased liver weight and liver coefficient as well as abnormal changes in typical hepatotoxicity indicators in mice, while GEN can alleviate the aforementioned changes. Furthermore, results from quantitative RT-PCR and Western blot indicated that hepatic Hsp90aa1 and HSP90α (the protein encoded by the Hsp90aa1 gene) expression was significantly upregulated by ZEA but significantly downregulated after GEN supplementation. In conclusion, HSP90α may be a key regulatory node in GEN treatment of hepatotoxicity caused by ZEA.
This study compared the developmental and mechanistic toxicity of Tartrazine (TAZ), a synthetic azo dye in food, pharmaceutical, and cosmetic products with its light- (TAZ-LD) and heat-degraded (TAZ-HD) forms as it under...This study compared the developmental and mechanistic toxicity of Tartrazine (TAZ), a synthetic azo dye in food, pharmaceutical, and cosmetic products with its light- (TAZ-LD) and heat-degraded (TAZ-HD) forms as it undergoes photolytic and thermal degradation that may yield reactive by-products with distinct toxicological profiles, using zebrafish model. Embryos exposed to 5-80 mg/L and evaluated for morphology, hatching, larval locomotion, histopathology, oxidative stress and the expression of inflammation and apoptosis-related genes. Compared with the parent dye, both degraded preparations produced greater developmental impairment, including dose-dependent pericardial and yolk-sac edema, axial malformations, delayed or aberrant hatching, and reduced swimming performance; TAZ-HD consistently elicited the strongest effects. Biochemical assays revealed substantially elevated ROS, MDA, and protein carbonyls alongside reduced levels of SOD, CAT, and GSH in degraded-TAZ exposures. Histology showed progressive tissue degeneration and immune infiltration, and gene expression analyses profile indicating pronounced upregulation of pro-inflammatory and pro-apoptotic genes with suppression of bcl2. Collectively, these results demonstrate that physical degradation markedly amplifies the developmental toxicity of TAZ by driving oxidative stress, inflammation, and apoptosis. The findings underscore the need to consider degraded products of TAZ in risk assessments of food colorants and to re-evaluate exposure scenarios reflecting real-world processing and storage conditions.
Dietary supplements are consumed by over half of US adults, yet post-market safety surveillance remains limited. We applied four disproportionality methods (PRR, ROR, GPS, BCPNN), CUSUM temporal detection, and demographi...Dietary supplements are consumed by over half of US adults, yet post-market safety surveillance remains limited. We applied four disproportionality methods (PRR, ROR, GPS, BCPNN), CUSUM temporal detection, and demographic stratification to 48,840 dietary supplement adverse event reports from the FDA CAERS database (2004-2025). Analysis was conducted at the product-name level, not the ingredient level, and the signals reported below are product-name-level signals to be interpreted as flags for further investigation rather than confirmed ingredient-specific risks. Of 4779 product-adverse event pairs, 3017 (63.1%) were detected by three or more methods. After variant-name consolidation of the most heavily fragmented products (Section 4.4 and Supplementary Material 4), this resolves to an estimated 1800-2200 distinct product-level signals. Kratom dominated the critical risk tier, with Kratom-Death ranked highest (PRR 19.7, N = 178). Hepatotoxicity signals clustered in herbal/botanical and weight loss products. Herbal/botanical supplements carried the highest serious outcome rate among classifiable products (78.0%; adjusted OR 2.08, 95% CI 1.53-2.84); the 54% "Other"-category share, however, limits the generalisability of category-specific estimates to all supplements within each nominal category. CUSUM detected 451 temporally emerging signals including preliminary hepatic enzyme elevations for AG1 and Nutrafol (2023-2025). Of consensus signals, 97.3% survived false discovery rate correction; 81% of established international supplement safety signals were recovered. These findings support regulatory prioritisation of herbal/botanical and weight loss supplement categories and identify emerging signals warranting continued monitoring.
Human biomonitoring of mercury (Hg) exposure commonly relies on blood and hair measurements, often assuming a stable conversion ratio between these matrices. However, this assumption neglects dynamic toxicokinetic proces...Human biomonitoring of mercury (Hg) exposure commonly relies on blood and hair measurements, often assuming a stable conversion ratio between these matrices. However, this assumption neglects dynamic toxicokinetic processes governing Hg distribution and elimination. Here, we characterized the distribution, determinants, and toxicokinetic implications of the hair-to-blood total Hg ratio in 453 individuals from Amazonian riverine communities chronically exposed to methylmercury (MeHg). Total Hg (THg) was determined in blood and hair, Hg speciation in hair by LC-ICP-MS, and selenium (Se) in blood was measured by ICP-MS. Model-based estimates of MeHg intake and Hg excretion were derived, and linear, non-linear, and multivariable analyses were applied. Blood and hair THg were strongly correlated (R = 0.86, p < 0.0001), confirming hair as a robust biomarker of chronic exposure. However, the hair-to-blood ratio showed high inter-individual variability (median 303; range 73.6-2132) and a significant inverse association with blood THg (β = -0.394, p < 0.001), indicating non-linear partitioning. Blood Se levels were elevated and positively associated with the ratio (β = 1.081, p < 0.001). Estimated MeHg intake exceeded the USEPA reference dose by over tenfold. These findings demonstrate that the hair-to-blood Hg ratio is a dynamic biomarker influenced by exposure intensity and potentially by Se status.
Tête A, Arnaud L, Le Mentec H
… +17 more, Poupin N, Gallais I, Tournadre N, Duarte-Hospital C, Lippi Y, Mathevet F, Lefort G, Lavau C, Burel A, Surya R, Shay JW, Pilati C, Coumoul X, Huc L, Vialaneix N, Bortoli S, Lagadic-Gossmann D
Colorectal cancer, the third most common cancer worldwide, represents a major public health challenge. While only 5-10% of cases are linked to inherited genetic mutations, environmental factors play a crucial role. Epide...Colorectal cancer, the third most common cancer worldwide, represents a major public health challenge. While only 5-10% of cases are linked to inherited genetic mutations, environmental factors play a crucial role. Epidemiological evidence suggests that diet alone may account for 30-70% of cases, making it a primary source of exposure to environmental contaminants in the colon. The disease develops progressively through the accumulation of genetic alterations, including loss of tumor suppressor gene function (APC and TP53) and activation of the proto-oncogene K-Ras. Understanding the complex interactions between genetic predisposition and environmental exposures requires advanced experimental models. In this study, we characterized an in vitro model using a non-malignant human colonic epithelial cell line and its isogenic derivatives carrying key mutations associated with colorectal cancer. These cell lines mimic the major stages of carcinogenesis: initiation, promotion, and progression. We conducted a comprehensive analysis of their biological properties, including proliferation, migration, clonogenic capacity, apoptosis resistance, and response to genotoxic stress. Additionally, metabolic profiling and xenobiotic response assessments were performed. Multivariate analysis revealed distinct features among the cell lines, providing a robust framework to investigate how environmental factors interact with genetic susceptibility in the development of colorectal cancer.
BACKGROUND: Brominated flame retardants (BFRs) are persistent pollutants with health concerns, yet their molecular mechanisms in the inflammatory bowel disease (IBD) and colorectal cancer (CRC) are unclear. METHODS: We e...BACKGROUND: Brominated flame retardants (BFRs) are persistent pollutants with health concerns, yet their molecular mechanisms in the inflammatory bowel disease (IBD) and colorectal cancer (CRC) are unclear. METHODS: We employed an integrated approach combining computational toxicology, bioinformatics, and molecular docking to identify core molecular targets linking BFR exposure to IBD/CRC. The prognostic and immunological significance of key genes was validated using TCGA data and functional assays in human CRC (HT29) and normal colon epithelial (NCM460) cells. RESULTS: We identified 12 core targets, notably UQCRC1 and NR3C2, which stably bind BFRs. Low expression of UQCRC1 and NR3C2 predicted poor patient prognosis and exhibited consistent positive correlations with anti-tumor immune cell infiltration. In vitro experiments demonstrated that BFR (TBBPA and HBCD) exposure markedly promoted the proliferation, viability and cell cycle progression of HT29 CRC cells, accompanied by significant downregulation of UQCRC1 and NR3C2 expression. In normal NCM460 colon epithelial cells, BFR treatment induced cytotoxicity, inhibited cell proliferation, triggered the upregulation of pro-inflammatory cytokines, and disrupted intestinal barrier function by suppressing the expression of intestinal tight junction proteins. CONCLUSION: BFR exposure was accompanied by altered expression of UQCRC1/NR3C2 and phenotypic changes in colon cells. Dysregulation of the two genes was significantly correlated with clinical prognosis and tumor immune microenvironment in IBD and CRC patients.
Zearalenone (ZEA) is a non-steroidal estrogenic mycotoxin produced by Fusarium species that commonly contaminates cereal grains and their derived products, thereby posing significant risks to public health. The complexit...Zearalenone (ZEA) is a non-steroidal estrogenic mycotoxin produced by Fusarium species that commonly contaminates cereal grains and their derived products, thereby posing significant risks to public health. The complexity of ZEA contamination is amplified by the presence of modified forms, which may undergo hydrolysis to release the parent compound during digestion. Effective detoxification strategies are therefore urgently needed. This review provides a comprehensive overview of ZEA biosynthesis and its modified forms, the species-specific metabolism of ZEA and its derivatives, and their toxicity mechanisms. We systematically evaluate ZEA biodegradation by microorganisms and enzymes, with emphasis on catalytic mechanisms and molecular modification strategies to enhance efficiency. Practical applications of ZEA-degrading agents in food and feed systems are also discussed. Collectively, these innovations offer promising solutions to reduce the risks associated with ZEA contamination in food production systems.
Bisphenol A (BPA) is a high-production industrial chemical used in polycarbonate plastics and epoxy resins. Dietary intake is a major exposure pathway for the general population due to BPA migration from food-contact mat...Bisphenol A (BPA) is a high-production industrial chemical used in polycarbonate plastics and epoxy resins. Dietary intake is a major exposure pathway for the general population due to BPA migration from food-contact materials. Using nationally representative data from the Korean National Environmental Health Survey (KoNEHS; Cycles 1-4, 2009-2020), we evaluated temporal trends in urinary BPA concentrations among 18,050 adults and assessed associations with processed food consumption. Analyses accounted for the complex survey design, and urinary BPA concentrations were adjusted for creatinine. In pooled analyses adjusting for demographic and lifestyle factors, frequent consumption of processed foods-particularly canned foods (β = 0.134), instant noodles (β = 0.180), and burgers (β = 0.116)-was associated with higher urinary BPA concentrations. Urinary BPA concentrations increased during 2012-2017 and declined from 2018 onward, a temporal pattern consistent with strengthened national regulations related to food-contact materials and plastic waste management in South Korea. These findings identify processed food consumption as an important dietary correlate of BPA exposure and support continued biomonitoring to inform exposure-reduction strategies and risk management for food-contact materials.
Natural toxins represent structurally diverse class of bioactive compounds that pose underrecognized risks extending beyond traditional food safety concerns into chemical security applications. Recent high-profile incide...Natural toxins represent structurally diverse class of bioactive compounds that pose underrecognized risks extending beyond traditional food safety concerns into chemical security applications. Recent high-profile incidents have highlighted critical gaps in detection capabilities, clinical management, and regulatory frameworks governing these substances. This review discusses the diversity, potency profiles and security implications of natural toxins with a focus on compounds with outstanding acute toxicity, such as batrachotoxin from Phyllobates poison dart frogs (LD50 2-3 μg/kg intravenously), amatoxins from Amanita species (LD50 100-300 μg/kg) and conotoxins from cone snails (LD50 10-100 μg/kg), comparable to synthetic chemical warfare agents. Critical vulnerabilities include the absence of specific antidotes, analytical challenges related to structural diversity and incomplete coverage by routine toxicological screens. Historical examples of intentional intoxications (e.g., ricin assassination of Georgi Markov in 1978 and bioterrorism by mail between 2003 and 2013) illustrate the general availability but also the limitations of this modus operandi. Developments in high-resolution mass spectrometry and computational toxicology offer promising improvements in detection. International regulations under the Chemical Weapons Convention need further improvement to address the growing threat posed by these natural but potentially weaponizable compounds.
Johnson VJ, Waidyanatha S, Germolec DR
… +11 more, Cora MC, Cesta MF, Shockley KR, Jeffers A, Cimon K, Mutlu E, Cristy T, Pierfellice J, Luster MI, Burleson GR, Ryan K
Echinacea is commonly used as a dietary supplement owing to its putative anti-inflammatory, antiviral, and antibacterial activities. Unfortunately, determining risk posed to human health is challenging. A novel combinati...Echinacea is commonly used as a dietary supplement owing to its putative anti-inflammatory, antiviral, and antibacterial activities. Unfortunately, determining risk posed to human health is challenging. A novel combination of chemical and biological characterization was employed for selection of a representative extract sample used for in vivo investigation of the immunomodulatory properties of Echinacea (E.) purpurea. In vitro cytokine profiling showed the extract could stimulate pro-inflammatory cytokine production in the absence of detectable endotoxin. An in-depth in vivo evaluation of the immune response following a 28-day oral exposure to the selected E. purpurea extract was conducted in adult Harlan Sprague Dawley (HSD) female rats at doses up to 2000 mg/kg/day. There was no evidence that E. purpurea caused overt toxicity or effects on humoral immunity. However, cell-mediated immunity was increased but only at low doses and with no evidence of a dose-response. In addition, E. purpurea treatment enhanced natural killer cell activity and the relative percentage of macrophages/monocytes in the spleen of rats from the highest treatment group. These results suggest that E. purpurea may have immunomodulatory properties that support antiviral and antibacterial activity but may also foster an immunostimulatory environment that could exacerbate some immune-mediated conditions.
Gastric cancer (GC) is a primary epithelial malignancy originating in the stomach. This research explored the influence and mechanism of Orientin on cellular senescence in GC. Orientin was predicted to regulate multiple...Gastric cancer (GC) is a primary epithelial malignancy originating in the stomach. This research explored the influence and mechanism of Orientin on cellular senescence in GC. Orientin was predicted to regulate multiple cell cycle-related pathways, including cyclin-dependent protein kinase activity. Orientin docked with cyclin dependent kinase 2 (CDK2), cyclin A2 (CCNA2), cyclin E1 (CCNE1), and cyclin E2 (CCNE2) with binding energies of -9.1, -7.5, -7.2, and -8.3 kcal/mol, respectively. The IC values of Orientin for AGS and HGC-27 cells were 24.33 μM and 39.28 μM, respectively. Orientin dose-dependently inhibited GC cell proliferation, promoted G0/G1 phase arrest, as well as downregulated CDK2, CCNA2, CCNE1, and CCNE2 expression. It enhanced senescence-associated β-galactosidase staining intensity, upregulated p16 and p21, and downregulated phosphorylated retinoblastoma (p-Rb). In vivo, Orientin also suppressed tumor progression, promoted p16 and p21 expression, and inhibited CCNE/CCNA-CDK2 signaling. Orientin exerts anti-cancer effects in GC through triggering cellular senescence and cell cycle arrest, likely via activating p16/p21-Rb signaling axis and inhibiting the CCNE/CCNA-CDK2 pathway.
Alcohol Use Disorder (AUD) is a complex condition marked by physical and psychological dependence, often accompanied by lasting changes in brain regions such as the hippocampus that contribute to memory and cognitive imp...Alcohol Use Disorder (AUD) is a complex condition marked by physical and psychological dependence, often accompanied by lasting changes in brain regions such as the hippocampus that contribute to memory and cognitive impairments. Emerging evidence highlights the role of gut microbiota dysbiosis in AUD and suggests a link between the gut-brain axis, neuroinflammation, and behavioral alterations. Probiotics have been proposed as potential modulators of microbial balance and inflammatory responses, with possible benefits for alcohol-related deficits. This study examined the effects of probiotic treatment on alcohol-conditioned behavior, withdrawal symptoms, selected fecal bacterial populations, and hippocampal alterations in a rat model of ethanol withdrawal. Ninety-six male Wistar rats were assigned to different drinking and treatment conditions and divided into groups for behavioral, neuroanatomical, and microbiological assessments. Conditioned place preference (CPP) was used to evaluate alcohol-related learning, while hippocampal volume, cell density, and fecal Lactobacillus and Enterobacteriaceae levels were measured. Ethanol exposure reduced fecal Lactobacillus levels and was associated with decreased hippocampal volume and altered cell density. Probiotic treatment partially restored Lactobacillus levels and reduced withdrawal severity, but did not significantly restore hippocampal structural parameters. Probiotics reduced CPP acquisition in control rats and accelerated CPP extinction in ethanol-exposed rats, suggesting a limited modulatory effect on alcohol-related behaviors.
Bisphenol S (BPS), a common substitute for bisphenol A, has emerged as a widespread environmental contaminant, yet its metabolic effects remain poorly understood. Increasing evidence links BPS exposure to metabolic dysfu...Bisphenol S (BPS), a common substitute for bisphenol A, has emerged as a widespread environmental contaminant, yet its metabolic effects remain poorly understood. Increasing evidence links BPS exposure to metabolic dysfunction-associated steatotic liver disease (MASLD), although the underlying mechanisms are unclear. Here, we investigated the metabolic effects of chronic BPS exposure (4, 25, and 50 μg/kg/day for 12 weeks) in C57BL/6 mice and evaluated its impact on human Huh-7 hepatocytes. In vivo, exposure to 25 μg/kg/day exhibited obesogenic potential, while all doses induced insulin resistance and promoted hepatic micro- and macrovesicular steatosis. BPS triggered endoplasmic reticulum (ER) stress and suppressed AMP-activated protein kinase (AMPK) phosphorylation, disrupting hepatic lipid and glucose metabolism. Consistently, BPS exposure in Huh-7 cells induced ER stress, reduced AMPK activity, and impaired insulin-stimulated Akt phosphorylation, indicating decreased insulin sensitivity. Notably, pharmacological activation of AMPK attenuated BPS-induced inhibition of insulin signaling, identifying AMPK as a key mediator of BPS-driven metabolic dysfunction in hepatocytes. Collectively, these findings demonstrate that BPS promotes hepatic steatosis and insulin resistance by activating ER stress and inhibiting AMPK, highlighting BPS as a potential environmental contributor to MASLD and related metabolic disorders.
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
The widespread presence of nano- and microplastics (NMPs) in the environment and their detection in human tissues raise concerns about their potential metabolic impacts. While previous studies have focused on NMPs toxici...The widespread presence of nano- and microplastics (NMPs) in the environment and their detection in human tissues raise concerns about their potential metabolic impacts. While previous studies have focused on NMPs toxicity, the size-dependent effects of NMPs on adipogenesis remain poorly understood. Adipocyte differentiation in 3T3-L1 cells was investigated using environmentally relevant NMPs sizes (200 nm, 2 μm and 20 μm), representing 10-fold size increments under non-cytotoxic conditions (50 μg/mL). Smaller NMPs (200 nm and 2 μm) were associated with uptake-related pathways linked to caveolin-mediated endocytosis and macropinocytosis, respectively, and were accompanied by increased lipid accumulation, glucose uptake, adiponectin expression, and adipogenic marker activation. Internalized NMPs induced mitochondrial overload, characterized by elevated ROS, altered respiratory activity, proton leak, membrane depolarization, and impaired mitochondrial dynamics. Molecular docking revealed that styrene monomers and dimers, bind PPARγ and CD36, supporting their role as functional mimetics in adipogenic signaling. In contrast, larger particles (20 μm), which remain extracellular, trigger only modest lipid accumulation and mild pro-inflammatory responses via NFκB1 signaling. Our findings highlight particle size as a determinant of NMP-induced metabolic disruption in adipocytes, linking internalization to metabolic dysfunction and identifying PPARγ signaling and mitochondrial pathways as possible therapeutic targets for NMP-induced adipose dysfunction.
2,4-Dichlorophenoxyacetic acid (2,4-D) is a widely used herbicide, yet its immunomodulatory properties remain insufficiently characterized, raising concerns about potential adverse outcomes. This study examined whether 2...2,4-Dichlorophenoxyacetic acid (2,4-D) is a widely used herbicide, yet its immunomodulatory properties remain insufficiently characterized, raising concerns about potential adverse outcomes. This study examined whether 2,4-D, at environmentally and biologically relevant concentrations, influences inflammatory responses in RAW 264.7 macrophages under basal and lipopolysaccharide (LPS)-stimulated conditions. Under basal conditions, 2,4-D had no effect on inflammatory mediator production or activation of nuclear factor-kappa B (NF-κB) p65, extracellular signal-regulated kinase (ERK1/2), or p38 signaling pathways. However, 2,4-D markedly potentiated LPS-induced responses, increasing pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β), COX-2 expression, nitric oxide production, and CD80 surface expression without cytotoxicity. Consistently, 2,4-D enhanced LPS-induced activation of NF-κB p65, ERK1/2, and p38 pathways. Comparative Toxicogenomics Database analysis revealed 167 overlapping genes associated with both 2,4-D and LPS exposure. Integrative pathway, PPI, and Metascape analyses identified RELA (NF-κB p65) and MAPK1 (ERK2) as key mediators. Pharmacological inhibition confirmed that IL-6 and COX-2 responses depended mainly on NF-κB p65 and ERK1/2, whereas CD80 up-regulation was predominantly NF-κB p65 dependent. Collectively, these findings provide new mechanistic insight into the amplification of macrophage inflammatory responses by 2,4-D under immune-challenged conditions via NF-κB p65 and ERK1/2 signaling pathways.