Multi-Organ Toxicity of Combined PFOS/PS Exposure and Its Application in Network Toxicology

Exposure to polystyrene microplastics and perfluorooctane sulfonate disrupt the homeostasis of intact planarians and the growth of regenerating planarians

Network toxicology of perfluorooctanoic acid-induced hepatointestinal injury and the protective effect of Lycium barbarum polysaccharides against perfluorooctanoic acid in broilers.

Polystyrene modulation of perfluorooctanoic acid toxicity in zebrafish: Transcriptomic and toxicological insights.

Glioblastoma (GBM) is the most lethal primary brain tumor with limited treatment options. Perfluorooctanoic acid (PFOA), a ubiquitous "forever chemical" classified as a group 1 carcinogen by the IARC, can cross the blood-brain barrier and accumulate in neural tissue. This study aimed to determine the causal relationship between genetically predicted higher circulating PFOA levels and GBM risk, elucidate underlying molecular mechanisms, and identify potential therapeutic targets using an integrated multi-omics framework. Two-sample Mendelian randomization (MR) analysis was conducted using 23 single-nucleotide polymorphisms as instrumental variables. The outcome data were derived from the FinnGen consortium (endpoint C3_GBM, defined by ICD-O-3 morphology code 9440/3 with topography C71), with statistical analysis performed using SAIGE with saddlepoint approximation to address case-control imbalance. Network toxicology was applied to identify shared targets between PFOA and GBM, followed by protein-protein interaction network analysis and hub gene screening. The significance of gene set overlap was assessed using hypergeometric testing. Gene Ontology and KEGG enrichment analyses were performed on the full set of 86 overlapping genes to clarify biological pathways. Molecular docking assessed potential binding interactions between PFOA and hub proteins, and drug-target interaction analysis was conducted using the DGIdb database. MR analysis demonstrated a significant causal association between genetically predicted higher circulating PFOA levels and increased GBM risk (IVW OR = 2.64, 95% CI 1.13-6.20, p = 0.017), with no evidence of pleiotropy or heterogeneity. Network toxicology identified 86 overlapping targets (hypergeometric test p = 2.31 × 10⁻1⁸, OR = 3.12) and 9 hub genes (IL1B, MYC, BCL2, ALB, EGFR, ESR1, IL6, TNF, CASP3). Enrichment analyses of all 86 overlapping genes highlighted the AGE-RAGE signaling pathway, response to xenobiotic stimulus, chemical carcinogenesis-receptor activation, and positive regulation of glial cell proliferation. Molecular docking predicted potential PFOA binding to all hub proteins (binding energy < - 6.0kcal/mol), with strongest affinities for MYC and TNF. Cisplatin emerged as the top drug repositioning candidate. This study provides the first genetic evidence supporting genetically predicted higher circulating PFOA levels as a causal risk factor for glioblastoma, potentially mediated by AGE-RAGE-driven neuroinflammation and oncogenic pathway activation, highlighting both environmental risk implications and therapeutic opportunities.

PFOS promotes Alzheimer's disease through aggravating the cell apoptosis and AKT/GSK3β/NF-κB/NLRP3 pathway mediated inflammation.

As Perfluorooctanoic Acid (PFOA) has been extensively utilized as a processing aid in the manufacture of non-stick coatings, waterproof materials, and other products, concerns regarding its adverse health effects have emerged. Epidemiological data revealed a strong correlation between renal cell carcinoma (RCC) and PFOA concentration, while animal experimental results also demonstrate the association between PFOA and RCC. However, the key targets and mechanisms underlying PFOA-induced RCC remain elusive. This study utilized network toxicology to elucidate the critical target genes and mechanisms of PFOA-induced clear cell RCC (ccRCC), the most prevalent RCC subtype. We retrieved potential PFOA targets from the Swiss Target Prediction database, ChEMBL, and STITCH, and identified RCC-related targets from GeneCards and OMIM. Transcriptomic data for ccRCC patients were obtained from The Cancer Genome Atlas Program (TCGA) to identify differentially expressed genes. We intersected genes from these datasets for constructing a protein-protein interaction (PPI) network. Hub genes were identified from the network using MCODE and cytoHubba plugins in Cytoscape. A risk score based on these hub genes was developed for prognostic analysis, and molecular docking was applied to validate the interactions between PFOA and hub targets. Intersection genes from these datasets, yielding 70 potential PFOA-induced ccRCC targets. Network analysis identified 7 hub genes- CYP2C9, CYP3A4, CYP1A1, CYP1A2, CYP2B6, CYP2C8 , and ABCB1 , and molecular docking confirmed PFOA's binding affinity to their corresponding proteins. Enrichment analysis using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome databases on the 70 potential targets and 7 hub genes revealed four potential mechanisms of PFOA-induced ccRCC: abnormal xenobiotic metabolism and accumulation of toxic intermediates, disrupted lipid homeostasis, oxidative stress and reactive oxygen species (ROS) generation, and disrupted steroid hormone signaling. Our findings provide novel insights into PFOA-induced ccRCC mechanisms, with implications for risk assessment and environmental health.

MPs and PFOS single and combined exposure significantly alter genetic expressions of growth hormone and insulin growth factor-related biomarkers during zebrafish embryonic development

Polystyrene micro and nanoplastics attenuated the bioavailability and toxic effects of Perfluorooctane sulfonate (PFOS) on soybean (Glycine max) sprouts

SummaryThis study elucidates the pathogenic mechanisms of perfluorooctane sulfonate (PFOS) in chronic obstructive pulmonary disease (COPD) through network toxicology and molecular docking. By integrating multiple databases, we identified 158 PFOS-related targets in COPD, with five key proteins (epidermal growth factor receptor [EGFR], ESR1, GRB2, HSP90AA1, and SRC) showing central roles in protein interaction networks. Functional enrichment analysis revealed their involvement in key pathophysiological processes, including airway inflammatory responses, oxidative stress, and immune regulation, primarily through modulation of cell survival and proliferation pathways and immune and hormonal regulation pathways. Gene set enrichment analysis (GSEA) further validated these findings by confirming the significant enrichment of five key KEGG pathways identified in our analysis. Molecular docking studies confirmed high-affinity binding between PFOS and these core targets, indicating PFOS may dysregulate inflammatory responses, oxidative balance, and cellular proliferation in COPD pathogenesis. These findings provide critical molecular insights into environmental pollutant-aggravated respiratory disorders and highlight potential intervention targets for COPD management.

Perfluorooctane sulfonate (PFOS), a widely used persistent organic pollutant, has been implicated in multiple toxicities. However, its nephrotoxic mechanisms remain unclear. Chronic kidney disease (CKD) is a growing global health concern. We adopted a multidisciplinary approach combining epidemiological analysis, network toxicology, molecular docking, and animal experiments to investigate PFOS-induced kidney injury using CKD as a model. NHANES data (n = 9119) were analyzed to examine the association between serum PFOS levels and CKD prevalence. Network toxicology identified PFOS-related target genes, which were further refined through protein-protein interaction (PPI) analysis and validated using the GSE32591 dataset. A diagnostic model was constructed, and molecular docking and in vivo studies were performed to verify gene-compound interactions and biological effects. Coremine Medical was used to identify traditional Chinese medicine (TCM) candidates targeting key genes. Serum PFOS levels were significantly associated with CKD, showing a U-shaped dose-response. Four hub genes-ALB, PTGS2, AKT1, and IGF1-were identified and used to develop a diagnostic model with excellent accuracy (AUC = 0.96). Molecular docking confirmed stable PFOS-protein interactions. PFOS exposure in mice led to dose-dependent renal tubular injury, elevated NGAL and KIM-1 levels, and PI3K-AKT pathway activation. Astragalus membranaceus, identified through TCM screening, exhibited strong binding to the target proteins and may have therapeutic potential. This study reveals key molecular targets and pathways involved in PFOS-induced nephrotoxicity and proposes a TCM-based therapeutic strategy. Our findings offer new perspectives for risk assessment and intervention in PFOS-related kidney disease.

Environmental pollution was a global problem that caused great damage to human health. Perfluorodecanoic acid (PFDA) and perfluorooctane sulfonic acid (PFOS), as members of perfluoroalkyl and polyfluoroalkyl substances (PFASs), were considered as "permanent environmental pollutants," and have been reported to be risk factors in cancer. Research has reported that the exposure to PFASs increased the risk of developing glioma, and PFDA and PFOS promoted glioblastoma (GBM) cells proliferation. However, research linking PFASs exposure to GBM prognosis is lacking. This study utilized network toxicology and bioinformatics analysis to elucidate the potential mechanism of PFDA and PFOS on GBM. Functional experiments were conducted to verify the biological function of PFDA/PFOS target genes on GBM. Seven target genes of PFDA/PFOS were identified as being specifically and abnormally expressed in GBM, with AUC values reaching 0.95 for CTSB, 0.95 for CHI3L1, 0.84 for VEGFA, 0.95 for MMP2, 0.96 for FAM83D, 0.98 for MMP9, and 0.97 for HOXD10 in TCGA cohort. PFDA/PFOS exposure related GBM prognosis model based on XGBoost algorithm, with the highest C-index reaching 0.84, uncovering that PFDA/PFOS may affect the prognosis via FN1, CHI3L1 and HOXD10. Molecular docking results verified the interactions between PFDA/PFOS and the identified genes. The VinaScore was -7.4kcal/mol between FN1 and PFOS,-8.1kcal/mol between CHI3L1 and PFOS, and -6.2kcal/mol between HOXD10 and PFDA. In vitro experiments proved the roles that the prognostic genes contributed to the maligant behaviors of GBM. This study combined bioinformatics and network toxicology analysis strategies to identified hub genes potentially mediating the effects of PFDA/PFOS, providing evidences that PFDA/PFOS exposure have a potential association with GBM prognosis. Our study emphasized the need for further epidemiological and clinical studies.

Observational studies have shown that exposure to per- and polyfluoroalkyl substances can lead to neurotoxicity. We focus on whether perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) affect brain morphology and the potential molecular mechanisms of toxicity. Causal relationship between exposure to both PFOA and PFOS and brain morphology was explored based on Mendelian randomization (MR), and the toxic molecular mechanism was investigated using network toxicology. MR analysis indicated PFOA exposure reduced brain volume in left parahippocampal (p = 0.018) and right rostral anterior cingulate (p = 0.007), while PFOS exposure decreased volume in left middle temporal (p = 0.036), paracentral (p = 0.022), postcentral (p = 0.014), posterior cingulate (p = 0.002), rostral middle frontal (p = 0.040), superior frontal (p = 0.027), superior parietal (p = 0.033), and in the right hemisphere: inferior parietal (p = 0.017), superior frontal (p = 0.030), superior parietal (p = 0.025), and caudal middle frontal (p = 0.041). GO/KEGG analyses revealed 161 targets linked to the neurotoxicity of PFOA and PFOS, primarily associated with fatty acid metabolism, GABA signaling, neurotransmitter receptor activity, ferroptosis, and PPAR pathways. Molecular docking verified key targets (PPARG, FASN, SCD, CD36, GOT2) underlying the toxicity mechanism. Exposure to PFOA and PFOS leads to reduced brain volume - neurotoxicity at the macroscopic level. At the molecular level, we identified PPARG, FASN, SCD, CD36, and GOT2 as key targets implicated in the pathology of brain damage induced by PFOA and PFOS.

This study combined network toxicology, molecular docking, and animal experiments to systematically investigate the reproductive toxicity and potential mechanisms of perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA). A total of 173 and 151 male infertility-related targets were identified for PFOA and PFNA, respectively, with key targets including AKT1, ESR1, EGFR, and HSP90AA1. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed significant involvement of pathways such as phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT), mitogen-activated protein kinase (MAPK), and Forkhead box O (FoxO). Molecular docking predicted favorable binding affinities (all binding energies < -7 kcal/mol) between both compounds and the core targets, suggesting potential biological relevance. Due to their structural similarity and overlapping target profiles, PFOA was selected as the representative compound for experimental exposure. In vivo studies showed that PFOA exposure led to significant downregulation of PI3K, AKT, and mammalian target of rapamycin (mTOR) expression in mouse testes at both mRNA and phosphorylation levels. Additionally, PFOA exposure caused disruptions in serum testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels, increased oxidative stress markers (elevated malondialdehyde (MDA), reduced superoxide dismutase (SOD) and glutathione (GSH)), and induced sperm DNA fragmentation and morphological abnormalities. Histological analysis revealed testicular structural damage, germ cell disorganization, and increased apoptosis. These findings demonstrate that PFOA and PFNA likely exert reproductive toxicity through interference with the PI3K-AKT-mTOR signaling pathway, leading to oxidative stress, endocrine disruption, and reduced spermatogenesis.

Perfluorooctane sulfonate (PFOS) enhanced polystyrene particles uptake by human colon adenocarcinoma Caco-2 cells

Objectives Perfluorooctanoic acid (PFOA), widely used in food-contact materials, industrial coatings, and other applications, enters the food chain via air, soil, and water, posing a potential public health risk. Methods This study employs network toxicology, Mendelian randomization, molecular docking and molecular dynamics simulation to preliminarily elucidate the mechanisms by which PFOA’s toxic targets contribute to renal impairment. Through integrated analysis of multi-database bioinformatics, we identified 85 cross-targets associated with PFOA-induced renal toxicity. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed significant enrichment of these targets in pathways related to ribosomes, lysosomes, complement and coagulation cascades, steroid hormone metabolism, immune-inflammatory diseases, and drug metabolism. STRING and Cytoscape tools identified five core targets (CYP3A4, CASP3, REN, PPARG, and IL-10). Mendelian randomization confirmed IL-10 as a central mediator of PFOA’s nephrotoxicity. Molecular docking and molecular dynamics simulation demonstrated a high binding affinity between PFOA and IL-10. Results Our findings suggest that PFOA likely exacerbates renal injury by suppressing IL-10 expression, thereby amplifying inflammatory responses, accelerating renal cell damage and fibrosis, and ultimately impairing kidney function. Conclusion This study elucidates the molecular mechanisms underlying PFOA-induced nephrotoxicity, offering novel insights for environmental health research.