Abstract Despite the widespread use of natural remedies, supplements and nutraceuticals fueled by their reputation for promoting wellness, their potential for toxicity remains a significant public health issue. A common misconception is that “natural” equates to “safe,” leading many to prefer herbal options over conventional medicine. However, these substances often harbor potent bioactive elements capable of triggering severe complications, ranging from organ toxicity and allergic responses to dangerous interactions with pharmaceutical drugs. The safety profile of dietary supplements and nutraceuticals is further obscured by a lack of standardization. Issues regarding ingredient purity and inconsistent concentrations mean that consumers often ingest these products without a clear understanding of the risks, particularly in high doses. This review investigates the toxicological properties of these substances, advocating for more rigorous safety testing and transparent consumer education. By deepening the collective understanding of these risks, medical professionals, regulators and the public can work together to establish safer consumption habits and mitigate the hidden dangers of these popular products.
Abstract Per- and polyfluoroalkyl substances (PFAS) have been recognized as environmental contaminants that may be potentially associated with colorectal cancer (CRC). However, the underlying molecular mechanisms remain elusive. In this study, network toxicology and bioinformatics approaches are utilized to decipher the molecular mechanisms responsible for PFAS-induced CRC. The potential targets of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) were retrieved from three databases, namely ChEMBL, STITCH, and Swiss Target Prediction. Three transcriptomic datasets, designated as GSE87211, GSE44076, and GSE106582, were sourced from the Gene Expression Omnibus (GEO) database. The core pathogenic targets of PFAS were finally determined using two machine learning algorithms: LASSO regression and SVM-RFE. Further validation of the core targets was carried out through Mendelian randomization, molecular docking and molecular dynamics simulation. A total of 15 potential pathogenic targets for PFOA and 14 for PFOS were successfully identified. The intersection analysis of key targets for PFOA and PFOS yielded ten core targets implicated in PFAS-induced CRC. Subsequently, Mendelian randomization analysis was conducted, revealing a causal relationship between the plasma protein SMPD1 and CRC. Molecular docking and molecular dynamics simulations had further demonstrated the potential for spontaneous binding affinity between SMPD1 and PFAS. This computational study predicted potential core pathogenic targets that may mediate PFAS-associated colorectal cancer. These in silico results advance our preliminary understanding of the putative pathogenic mechanisms behind PFAS-related colorectal malignancy and supply candidate molecules worthy of subsequent experimental verification to discover preventive and therapeutic biomarkers for vulnerable high-risk groups.
In recent years, air pollutants have emerged as a major global contributor to chronic diseases and cancer. This study reveals the potential mechanisms by which air pollutants influence TNBC and identifies key genes. We first screened air pollutant-related target genes through data collection, simultaneously obtaining TNBC-related target genes from Genecards and OMIM databases. The intersection of these sets yielded potential targets. Protein-protein interaction (PPI) analysis and visualization were performed on the intersecting genes, followed by GO and KEGG enrichment analysis to identify core genes influencing potential TNBC pathways. We then selected the optimal predictive model through combination of 101 machine learning algorithms. A prognostic model was constructed using a Random Survival Forest (RSF) combined with a StepCox [forward] model, validated across two external datasets. Finally, molecular docking was performed between the selected target genes and air pollutants to assess interactions. Analysis yielded 27 air pollutant-TCGA target genes. Enrichment analysis indicated these targets primarily regulate cell biology processes including proliferation, metabolism, and gene expression. Machine learning algorithm analysis confirmed the RSF-StepCox [forward] model as the optimal predictor. The RSF combined with the StepCox [forward] model emerged as the optimal predictive model, identifying five core genes. Conclusions indicate that long-term exposure to air pollutants primarily influences TNBC prognosis through five key genes-PIM1, GSK3B, CA12, CA9, and IDO1-providing new insights into the molecular mechanisms by which air pollutants affect TNBC.
Atopic dermatitis (ad) is a chronic inflammatory skin disease characterized by xerosis, eczematous lesions, and intense pruritus. Bisphenol A (BPA), a ubiquitous endocrine disruptor, impairs immune function and promotes cutaneous inflammation, yet its precise role in ad pathogenesis remains unclear. This study integrated network toxicology, molecular docking, HaCaT cell experiments, and a DNCB-induced mouse model with oral BPA exposure to systematically investigate BPA-induced ad mechanisms. Venn analysis identified 94 shared BPA-ad targets, and PPI network analysis selected five core targets (TNF, CXCL8, MMP9, TP53, PTGS2). Functional enrichment highlighted inflammatory/immune processes and the NF-kappa B pathway. Molecular docking confirmed stable BPA binding to all five targets, with PTGS2 showing the strongest affinity. In HaCaT cells, BPA dose-dependently reduced viability, increased TNF-alpha and CXCL8 secretion, and upregulated MMP9, PTGS2, and phosphorylated NF-kappa B. In vivo, BPA exposure exacerbated DNCB-induced ear lesions, epidermal hyperplasia, and serum TNF-alpha and IL-6 levels. GEO clinical dataset analysis further supported translational relevance. These findings provide a theoretical basis for understanding BPA-induced ad mechanisms and identify candidate targets for environmental risk management and targeted intervention in ad.
Abstract Cadmium, a heavy metal, is also a well-established environmental pollutant, mainly known for its neurotoxic and behavioural effects on organisms in aquatic environments, particularly during early developmental stages. The effects of ionic Cadmium have been widely studied in zebrafish (Danio rerio), a well-accepted model organism for neurodevelopmental toxicology, whereas only a limited number of studies have focused on the risk factors associated with Cadmium sulphide nanoparticles. These nanoparticles are entering the aquatic environments rapidly, but their toxicological effects remain poorly defined. This review focuses on and explores the behavioural and neurodevelopmental effects of ionic Cd in zebrafish, primarily on well-documented findings related to Cd2+ and on the less-studied impacts of CdS NPs. This limited evidence indicates that CdS nanoparticles induce oxidative stress, proteotoxic damage, and alterations in neurodevelopmental gene expression, although the data are fragmentary. By emphasising these gaps in studies on CdS toxicity and placing them within the broader research domain of Cadmium and nanoparticles toxicity studies. This review aims to provide useful information and investigations to promote a more advanced understanding of risks posed by nanoparticles in aquatic ecosystems and food webs.
Copper, an essential yet toxic trace element in humans, is implicated in diverse health risks. Its established pro-inflammatory and neurotoxic properties may contribute to the pathogenesis of overactive bladder (OAB). Although cross-sectional research indicates a role for copper in urge urinary incontinence, its association with OAB and the underlying mechanisms remain to be elucidated. Using data from 2011-2016 National Health and Nutrition Examination Survey (NHANES), 3,039 participants were enrolled. Through multivariable logistic regression, restricted cubic splines, and subgroup analyses, we observed a statistically significant, positive, and consistent association between serum copper concentrations and OAB prevalence. We identified 111 target genes linked to both copper exposure and OAB using GeneCards, OMIM, TTD, PharmGKB, DrugBank and CTD databases. Leveraging STRING database alongside Cytoscape, we constructed the PPI networks and extracted the key genes. Enrichment analysis revealed a significant association between copper and pathways pivotal to OAB pathogenesis. Furthermore, we utilized Discovery Studio to perform molecular docking analyses, indicating strong interactions between copper and key gene proteins. Collectively, our findings suggest a significant correlation between copper exposure and OAB, while also elucidating its potential toxicological mechanism. This study provides a theoretical foundation for the development of preventive and therapeutic strategies for OAB patients.
Microplastics (MPs), ubiquitous environmental pollutants, enter the human body via dietary and respiratory pathways and impair bone and joint tissues, but their toxicological mechanisms in the onset and progression of osteoarthritis (OA) remain elusive. Herein, four common MPs-polyethylene (PE), polyethylene terephthalate (PET), polypropylene (PP), and polystyrene (PS)-were selected as research subjects. Core OA-related targets responsive to MPs exposure were screened using the Gene Expression Omnibus (GEO), SwissTargetPrediction, and Comparative Toxicogenomics Database (CTD), followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Weighted gene co-expression network analysis (WGCNA) combined with three machine learning algorithms (random forest, SVM-RFE, LASSO) was employed for cross-validation to identify key targets, whose diagnostic efficacy was validated via nomograms and receiver operating characteristic (ROC) curves. Molecular docking assays assessed the binding affinity between quercetin and the identified targets, while in vitro experiments preliminarily verified the chondrocyte toxicity of PS-MPs and the protective effects of quercetin. A total of 95 core targets were identified, primarily involved in oxidative stress, inflammatory responses, cartilage matrix metabolism, and cell proliferation/apoptosis. DDIT4 and CDKN1A (area under the curve [AUC] > 0.7) were identified as key diagnostic targets for OA. Quercetin stably bound to DDIT4 (binding energy: -7.8 kcal/mol) and CDKN1A (binding energy: -6.1 kcal/mol), preliminarily mitigating PS-MPs-induced chondrocyte damage. This study clarifies the role of MPs in OA progression, identifies DDIT4 and CDKN1A as core regulatory targets, and provides preliminary evidence that quercetin is a potential natural agent against MPs-induced OA.
Insects have played crucial beneficial roles in promoting the health of both humans and livestock. Additionally, they are vital for agriculture and the maintenance of ecosystems. Some insect species, however, transmit diseases and damage crops. Hence, insecticides are widely deployed to manage their adverse impacts. Insecticides, especially the synthetic forms, harm non-target organisms and the environment. Hence, more research should be directed at the discovery of biotic and ecologically friendly insecticides. Nauphoeta cinerea is increasingly recognized as a useful model organism for evaluating the lethality and toxicological impact of insecticides. This review examines recent studies on the toxicity and molecular mechanisms of both synthetic and biotic insecticides in the Nauphoeta cinerea model. We examined a wide range of insecticidal agents, including plant extracts like jack bean urease, Araucaria angustifolia methanolic extract, microbial extract like anatoxin-a, which elicit significant neurotoxicological consequences marked by acetylcholinesterase inhibition, disruption of ion channels, and modulation of neurotransmitters. Animal-derived secretions from Rhinella species induce potent cardiac and synaptic toxicity due to bufadienolides. Similarly, synthetic insecticides like fipronil and chlorpyrifos induce acetylcholinesterase inhibition, neuromuscular dysfunction, and oxidative stress in the N. cinerea model. Overall, this review highlights the value of N. cinerea as a toxicological model for evaluating lethality, ecological safety, and the mechanisms of action of different insecticidal compounds. It also demonstrates its significance in the discovery and assessment of new insecticidal agents.
Acetyl tributyl citrate (ATBC) is widely used as an alternative plasticizer to phthalates. However, findings regarding the mechanism of action exhibit dose-dependent inconsistencies. Low doses inhibit follicular development in females, whereas normal and high doses appear to lack reproductive toxicity. The underlying mechanism remains unclear. This study utilized a multi-method approach to thoroughly investigate the molecular mechanisms and potential dose-contradictory of ATBC. A total of 106 cross-target points linked to ovarian toxicity were identified, with 10 key targets enriched in pathways related to epigenetic regulation, hormone signaling transduction, and metabolism. Clinical validation demonstrated that HDAC2 and SMARCA4 expression was significantly decreased, whereas SIRT1 and EP300 expression was significantly increased in individuals with diminished ovarian reserve (adjusted P-value <0.05). Molecular docking further demonstrated that ATBC is predicted to have moderate-to-strong binding affinity for epigenetic targets like SIRT1 and TP53, but lower affinity for compensatory targets such as SMARCA4. These computational findings support the hypothesis that low-dose ATBC may preferentially bind to high-affinity epigenetic targets, potentially disrupting chromatin remodeling and hormonal signaling, thereby silencing genes involved in follicle development. In contrast, normal and high doses might engage low-affinity targets, triggering hepatic and renal compensatory pathways that accelerate ATBC excretion and induce epigenetic compensatory effects, ultimately preventing the onset of toxic symptoms. This provides a putative mechanistic explanation for the reported dose-dependent paradoxical effect of ATBC. In summary, this study provides a theoretical foundation for evaluating reproductive risks associated with low-dose ATBC exposure and for safeguarding women's reproductive health.
Abstract Polystyrene microplastics (PS-MPs) are widely distributed in the environment and may have lasting effects on the reproductive health of multiple species. Existing studies suggest that PS-MPs can affect the reproductive system through pathways such as oxidative stress, leading to DNA damage, hormonal imbalances, and inflammatory responses. Because standardized experimental exposure protocols are lacking, there are significant differences in the study results. In addition, there are significant differences between acute exposure in laboratory conditions and long-term low-dose exposure in real-world settings. Studies have confirmed that certain natural substances, such as Kelulut honey, probiotics, and pinostrobin, can play a potential mitigating role through antioxidant activity. But these findings are still in the preclinical stage and have not yet been translated into clinical applications. Future research should focus on the development of environment-related exposure models, strategies to clearly distinguish between particle-specific effects and environmentally relevant exposure models, and the establishment of biomarker systems for human threat and risk assessment.
Artificial sweeteners (AS) are widely used as sugar substitutes in obese and diabetic populations to control sugar intake and blood glucose levels. However, recent studies indicate that their consumption may not only fail to alleviate obesity but also increase the incidence and mortality of age-related cardiovascular diseases and cancers. Currently, research on their direct association with aging remains very limited. Toxicity analysis of seven common artificial sweeteners (aspartame, Acesulfame-K, sucralose, saccharin, neotame, sodium cyclamate, and NHDC) was conducted using ADMETlab 3.0. Their targets (from CTD, SwissTargetPrediction, and SEA databases) were intersected with aging-related targets (from GeneCards, OMIM, and Aging Atlas databases) to identify common targets. Finally, enrichment analysis was performed through the Metascape platform. The PPI network constructed by STRING was analyzed using Cytoscape, and molecular docking and dynamics simulations were employed to validate the interactions of key targets. The results demonstrated that these AS exhibited genotoxicity and shared 139 targets with aging processes. GO analysis associated them with oxygen response and extracellular matrix, while KEGG enrichment analysis highlighted the significance of cancer and PI3K-Akt pathways. INS and AKT1 were identified as key targets, with molecular docking confirming stable binding characteristics of AS-AKT1. SA-beta-gal and WB showed NHDC, Neotame promote senescence with P21 and P53 upregulation. This study demonstrated that AS may influence the human aging process by binding to AKT1 and interfering with pathways such as PI3K-Akt, which provides further research directions for elucidating their functional relationship and strengthening the application foundation of AS.
Fluoride, a non-metallic, negatively charged halogen poses serious health risks to different organisms. Animal experiments and epidemiological studies indicate that excess fluoride damage an array of organs and systems, including male reproductive system. Different antioxidants can be used to lessen the adverse impacts of fluoride. This study was aimed to find out the detrimental consequences of fluoride and subsequent mitigation by vitamin C and E in the male reproductive system. Animals were randomly divided into four groups, group I- control; group II- treated with sodium fluoride (NaF) at a dose of 15 mg/kg/day; group III- supplemented with vitamin C (200 mg/kg/day) and vitamin E (400 mg/kg/day) along with NaF; group IV- only vitamin C and E for 30 consecutive days. Fluoride treatment compromised structural integrity of testis and epididymis, as evidenced by histomorphometry and scanning electron microscopy. Enhanced testicular and epididymal oxidative stress was also noted in treated group as evidenced by altered Nrf2 expression. Decreased expression of StAR and reduced levels of 3 beta-HSD and 17 beta-HSD, FSH, LH and testosterone in treated group indicate altered testicular steroidogenesis. Fluoride treatment also led to occurrence of apoptosis in testis and epididymis which was assessed by the genomic and proteomic level of Bax, Bcl2, Caspase 3 and Caspase 9. Overexpression of TNF-alpha and NF-kappa beta designate the manifestation of testicular inflammation upon fluoride exposure. Structural anomaly, altered redox status and augmented apoptotic event in spermatozoa were also the destructive consequence in fluoride treated group. However, supplementation revealed considerable recovery from these adverse consequences.
Kidney is the primary target organ for Ochratoxin A (OTA)-induced carcinogenesis, yet the underlying mechanism(s) are unknown. Cancer cells undergo various metabolic reprogramming. Hence, we assessed the effect of low-dose OTA on pre-neoplastic changes and metabolic perturbations in NRK52E cells. Cells were exposed to OTA for 2 months (sub-chronic) and 4 months (chronic), and various pre-neoplastic properties were evaluated using different cell-based assays, such as soft agar, clonogenic, wound healing, and ATP determination assay. Additionally, NMR-based metabolomic profiling was performed to assess OTA-induced metabolic perturbations in NRK52E cells and the involvement of key metabolites in OTA-induced cellular transformation. OTA exposure resulted in pronounced induction of cell survival, proliferation, and migration at both exposure durations in NRK52E cells, with more significant effects observed after 4 months of chronic exposure. Further, metabolomics study showed significant metabolic perturbations in NRK52E cells following chronic exposure to OTA. Notably, lactate emerged as the most important altered metabolite among those identified. Furthermore, exogenous lactate exposure to NRK52E cells induced pronounced pre-neoplastic changes similar to those observed in OTA-transformed cells. Collectively, this study showed that chronic OTA exposure caused pre-neoplastic transformations in NRK52E cells and suggests that lactate may play a crucial role in OTA-induced cellular transformation. [GRAPHICS]
Air pollution is a major environmental health risk and has been classified as a Group 1 carcinogen. While its link to lung cancer is well established, the molecular mechanisms connecting air pollution to breast cancer are not fully understood. In this study, we used a network toxicology approach to investigate the relationship between seven common air pollutants and breast cancer. Target genes associated with these pollutants were identified from public databases and compared with genes linked to breast cancer. Forty-eight core genes were found as potential mediators. Functional enrichment analyses revealed that these genes were involved in xenobiotic metabolism, DNA damage response, cell cycle regulation, and inflammatory pathways such as PI3K-Akt and TNF signaling. Protein-protein interaction networks highlighted CCNE2 as a central hub gene, and high expression of CCNE2 was associated with poorer overall survival in breast cancer patients. Molecular docking suggested that CCNE2 can stably bind to aromatic pollutants, especially toluene. Single-cell RNA sequencing and immunohistochemistry analyses showed that CCNE2 expression is mainly localized in breast cancer epithelial cells. These findings provide insight into the potential molecular mechanisms by which air pollution may contribute to breast cancer development and highlight CCNE2 as a possible biomarker for prognosis and environmental risk assessment.
This study employed a combined network toxicology and pharmacology research strategy to investigate the molecular mechanisms of perfluorooctane sulfonate (PFOS)-induced hepatic fibrosis (HF) and evaluate the intervention effects of Andrographis paniculata (AP). Potential targets of PFOS and HF were retrieved from the CTD and GEO databases, while active components and targets of AP were screened using the TCMSP platform. Protein-protein interaction (PPI) network, enrichment analysis, and molecular docking were then applied to identify key targets and pathways. The results identified 249 shared targets between PFOS and HF, significantly enriched in inflammatory response, oxidative stress, and the TNF/NF-kappa B signaling pathway. Core targets such as IL1B, CXCL8, EGFR, and PTGS2 were identified by PPI analysis, and molecular docking confirmed strong binding affinity between PFOS and these proteins. Additionally, 49 common targets were found between AP and HF, mainly involved in PPAR and MAPK signaling pathways and arachidonic acid metabolism, with high binding activity to AP's active components. In summary, PFOS may be involved in hepatic fibrosis by regulating inflammation- and oxidative stress-related pathways via targets such as EGFR and PTGS2, whereas AP may counteract this effect through multi-target mechanisms that suppress inflammation, alleviate oxidative stress, and inhibit abnormal extracellular matrix deposition. These findings offer a theoretical foundation for understanding PFOS hepatotoxicity and supporting the clinical application of AP.
This study aimed to elucidate mechanisms linking exposure to microplastic-associated phthalates-Di(2-ethylhexyl) phthalate (DEHP) and Dibutyl phthalate (DBP)-with colorectal cancer (CRC) pathogenesis. We integrated network toxicology and molecular docking to identify core molecular targets and pathways. Hub genes were identified through Protein-Protein Interaction (PPI) network analysis, their differential expression validated using TCGA data, and functional pathways explored via GO/KEGG enrichment. Binding affinities were assessed by molecular docking, and a cross-validation analysis against reference carcinogens was performed to validate the model. We identified 324 common targets, screening 13 differentially expressed hub genes in CRC. Functional enrichment linked these genes to oncogenic processes like PI3K-Akt signaling. Docking simulations revealed favorable binding affinities of DEHP and DBP with 8 key targets, including TP53, EGFR, and MAPK3. The strongest interactions were observed for DEHP with MMP9 (-7.8 kcal/moL) and DBP with both ESR1 and MMP9 (-7.0 kcal/moL). Cross-validation confirmed a core network of 6 hub genes shared with carcinogens Benzo[a]pyrene (BaP) and Bisphenol A (BPA), validating the commonality of downstream pathways. This study proposes a validated molecular framework for phthalate-induced colorectal carcinogenesis, demonstrating that DEHP and DBP may promote CRC progression by targeting key proteins like MMP9 and ESR1. Crucially, our analysis reveals a novel "specificity + commonality" mechanism, identifying a common downstream oncogenic network while pinpointing a unique, ESR1-mediated pathway as a specific upstream trigger for phthalates. These findings offer novel mechanistic insights into the health risks of microplastic-associated pollutants.
Benzo[a]pyrene diol epoxide (BPDE), a key carcinogenic metabolite of benzo[a]pyrene, has been linked to respiratory damage, yet its role in interstitial lung disease (ILD) remains elusive. This study systematically investigated the mechanisms of BPDE-induced ILD by integrating network toxicology, machine learning, and molecular docking. Potential targets of BPDE were retrieved from ChEMBL, STITCH, and SwissTargetPrediction, while ILD-related genes were identified by differential expression analysis and weighted gene co-expression network analysis (WGCNA) from public transcriptomic datasets. We identified 79 shared targets between BPDE and ILD, with enrichment analyses revealing significant involvement in xenobiotic response, ion channel activity, and pathways such as PI3K-Akt, IL-17, and TNF signaling. Machine learning (SVM-RFE, LASSO, and Random Forest) pinpointed five core genes (EPHB3, GRIA1, NR4A2, RAF1, VEGFA) with high diagnostic accuracy. Single-gene GSEA revealed their collective roles in disrupting DNA repair, metabolism, and immune regulation. Immune infiltration analysis linked these core genes to distinct alterations in both innate and adaptive immunity. Molecular docking predicted strong BPDE-core protein binding. Finally, we proposed an adverse outcome pathway (AOP), from BPDE-induced core gene dysregulation, through activation of key signaling and immune dysregulation, to persistent lung injury and fibrosis. These findings reveal a multi-mechanistic framework for BPDE-induced ILD, and highlight novel core genes with diagnostic and therapeutic potential, laying the groundwork for further investigation into environmental pollutant-driven lung fibrosis.
Short-chain chlorinated paraffins (SCCPs) are prevalent persistent organic pollutants (POPs) that were officially listed under the Stockholm Convention in 2017. Due to their widespread environmental distribution, human exposure to SCCPs is inevitable, particularly in occupational settings where elevated concentrations pose significant health risks, including hepatic toxicity, endocrine disruption, and occupational diseases. Although early SCCPs exposure has been linked to parental toxicity and related diseases, potential cross-generational neurotoxic effects remain unexplored. This study investigated whether prenatal exposure to different doses of SCCPs induces Alzheimer's disease (ad)-like neuropathology in adult mouse offspring and provides the first evidence of cross-generational neurotoxicity. Compared with the control group, adult offspring exposed to SCCPs exhibited significant alterations in body weight, and the brain organ coefficient of female offspring in the medium-dose group was significantly increased. Histopathological examinations revealed substantial neuronal loss, disruption of Nissl body structure, nuclear dissolution, and enhanced formation of neurofibrillary tangles (NFTs) in the brains of SCCP-exposed offspring. Additionally, phosphorylation levels of Tau protein at Ser396 and Ser199 were significantly elevated, accompanied by increased expression of amyloid beta (A beta), which is consistent with hallmark pathological features of ad. These effects were more pronounced in male offspring, indicating sex-dependent susceptibility. Mechanistically, SCCP-induced neurotoxicity may involve upregulation of Tau kinases CDK5 and GSK-3 beta and downregulation of the Tau phosphatase PP2A, promoting Tau hyperphosphorylation. Overall, prenatal SCCPs exposure induces persistent ad-like neuropathological changes in adult offspring, suggesting that early-life SCCPs exposure may increase the risk of neurodegenerative diseases later in life.
Nanoplastics (NPs) can accumulate in the testis, inducing male reproductive toxicity. However, their effects on steroidogenesis remain controversial, and the underlying mechanisms are not fully elucidated. This study explored the impact of gut microbiota dysbiosis on steroid hormone levels in mice exposed to low-level of polystyrene (PS) NPs of two sizes: 500 nm (PS500) and 100 nm (PS100). The results demonstrated that PS500 enhanced steroid hormone synthesis, with greater increases than PS100. Metabolome analysis confirmed that, in the most significantly enriched pathway of unsaturated fatty acid synthesis, PS500 elevated the levels of arachidonic acid, palmitic acid, oleic acid and stearic acid, while PS100 only increased arachidonic acid and palmitic acid. More importantly, in PS500-exposed group, the gut microbes Desulfovibrio and Allobaculum were linked to unsaturated fatty acid biosynthesis, which was correlated with testicular steroidogenesis; whereas these correlations were absent in PS100-exposed group. It was thus proposed that larger-sized PS500 reduced Desulfovibrio abundance, which may promote oleic acid synthesis, being associated with the enhanced synthesis of steroid hormones in mouse testis. Collectively, these findings shed new light on the role of gut microbiota-metabolism-testis axis in NPs-triggered male reproductive damage, suggesting potential implications for the evaluation and intervention of human health risks from environmental exposure to NPs.
The aim of this study is to explore the molecular mechanisms underlying nicotine-derived nitrosamine ketone (NNK)-induced gastric cancer. The potential targets of NNK were retrieved from the ChEMBL, STITCH, and Swiss Target Prediction databases. Five transcriptomic datasets (GSE66229, GSE184336, GSE27342, GSE122401, and GSE54129) were obtained from the GEO database. Gastric cancer-associated genes were identified through differential expression analysis and weighted gene co-expression network analysis (WGCNA) of the sample data. By integrating gastric cancer-associated genes and NNK-related target genes, this study utilized machine learning, network toxicology, SHAP interpretability analysis, molecular docking and molecular dynamics simulations to investigate the target genes involved in NNK-induced gastric cancer. A total of 27 genes were identified as potential molecular targets associated with NNK-induced gastric cancer. Through machine learning and SHAP interpretability analysis, five genes (TEAD4, GPER1, LY6E, SULT2A1, and EEF1A2) were pinpointed as key targets in NNK-induced gastric cancer. In subsequent molecular docking and molecular dynamics simulations, NNK demonstrated a strong spontaneous binding affinity with the target protein. This investigation pinpointed five crucial pathogenic targets elicited by NNK in gastric cancer. These results offer in-depth understandings of the pathogenic mechanisms underlying NNK-induced gastric cancer and are conducive to the identification of novel therapeutic targets for the prevention and treatment in high-risk populations.
