Ecotoxicology and Environmental Safety

Identifying prognostic biomarkers and immune interactions in ovarian cancer associated with perfluorooctanoic acid exposure: Insights from comparative toxicogenomics and molecular docking studies

Perfluorooctanoic acid (PFOA) exposure has been implicated in various health issues. This study aims to identify common genes associated with PFOA exposure and ovarian cancer, elucidate their biological functions, and explore their prognostic significance. We identified common genes linked to PFOA exposure and ovarian cancer using the Comparative Toxicogenomics Database. Protein-protein interaction and functional enrichment analyses were performed via Metascape. A PFOA-related risk model was developed using TCGA data and LASSO regression. Survival and expression analyses were conducted, and a prognostic nomogram was created. Tumor immune microenvironment interactions were investigated using ESTIMATE and ssGSEA methods. Molecular docking studies assessed the binding affinities between PFOA and target proteins. Utilizing the Comparative Toxicogenomics Database, we identified 229 common genes linked to both PFOA exposure and ovarian cancer. A comprehensive protein-protein interaction (PPI) network analysis revealed distinct functional modules. Enrichment analysis indicated significant involvement of these genes in pathways like the PI3K-Akt signaling pathway and focal adhesion. Lasso regression identified seven key prognostic genes (ERBB2, CCNH, PDE2A, CXCL11, TIAM1, SLC9A1, and EPHA2), with survival analysis demonstrating that PFOA-related high risk group exhibited significantly worse overall survival. Expression analysis showed the dysregulation of key prognostic genes in tumor tissues, while immune correlation analysis indicated significant associations with the tumor microenvironment. Molecular docking and molecular dynamics simulations revealed strong binding affinities between PFOA and the PDE2A. Overall, this research contributes to a deeper understanding of the health risks associated with PFOA exposure and highlights the importance of continued monitoring and regulation of environmental pollutants to safeguard public health.

Elevated urinary phthalate levels in endometrial cancer patients: Evidence from a comparative study

Phthalates are common plasticizers with endocrine-disrupting properties. Although laboratory studies suggest links to estrogen-dependent cancers, their association with endometrial cancer (EC) in humans remains unclear. This study investigated urinary phthalate metabolite levels in relation to EC and explored potential lifestyle and dietary contributors to phthalate exposure. A total of 232 women, including 116 EC patients and 116 healthy controls, were enrolled. Urine samples were analyzed by UPLC-MS/MS to measure eight phthalate metabolites, adjusted for creatinine. Lifestyle and dietary information were collected via questionnaires. Logistic regression assessed associations between phthalate levels and EC, while Spearman's correlation examined inter-metabolite relationships. All eight metabolites were detected in over 90 % of participants, with significantly higher concentrations in the EC group. Among them, mono-benzyl phthalate (MBzP) was the only metabolite independently associated with EC (OR 3.712, 95 % CI 1.464-9.414, p = 0.006). Using a cutoff value of 0.145 µg/g Cr, EC remained the only independent predictor of elevated MBzP levels (OR 5.696, 95 % CI 2.572-12.615, p < 0.001). No significant associations were found between MBzP levels and lifestyle or dietary habits. Correlations among phthalate metabolites were generally consistent across groups, though MBzP showed weaker correlations, indicating potentially distinct exposure pathways. This study is the first to demonstrate an independent link between urinary MBzP levels and EC in humans. The lack of lifestyle or dietary influence highlights the complexity of exposure sources, emphasizing the need for further research to understand underlying mechanisms and environmental factors contributing to phthalate exposure.

Particulate matter and their interaction of physical activity on ovarian cancer survival: A prospective cohort study

Insufficient data exists regarding the trade-off between the survival benefits of exercise in patients with ovarian cancer (OC) and the potential risks associated with increased particulate matter (PM) exposure during physical activity (PA). This study included 822 individuals newly diagnosed with OC. The total PA and subtypes (occupational [OPA], traffic [TPA], household [HPA], leisure-time [LTPA]) were assessed for the year preceding diagnosis using the Physical Activity Questionnaire of the China Kadoorie Biobank. The residential average PM concentrations 1-year before the date of OC diagnosis were assessed by random forest models at a 1 km × 1 km resolution. The comprehensive exposure to three types of PM was evaluated using a PM score (PMS). In addition, we further examined interaction of PMS with different types of PA on OC survival. Cox proportional hazard models were employed to determine hazard ratios (HRs) and their corresponding 95 % confidence intervals (CIs). Through a median follow-up of 44.95 months, 373 deaths were documented. The highest tertile of the total PA (HR = 0.68, 95 %CI = 0.53, 0.87), TPA (HR = 0.66, 95 %CI = 0.47, 0.95), HPA (HR = 0.41, 95 %CI = 0.25, 0.67), and LTPA (HR = 0.02, 95 %CI = 0.01, 0.05) showed improved overall survival (OS) compared with the lowest tertile, OPA decreased OS (HR = 1.50, 95 %CI = 1.17, 1.92). Additionally, a 34 % reduction in OC survival was observed with each standard deviation rise in PMS (95 %CI = 1.10, 1.63). Notably, OPA intensified PMS-related OS reductions, while total PA, HPA, and LTPA attenuated this association. We revealed that joint exposure to comprehensive PM was significantly linked to decreased OS of patients with OC, particularly for those primarily engaged in OPA. However, the long-term benefits of total PA, HPA, and LTPA may ameliorate the adverse effects of comprehensive PM exposure during PA.

Dietary protein intake and PM2.5 on ovarian cancer survival: A prospective cohort study

Evolving evidence suggests both protein consumption and particulate matter less than 2.5 micrometers (PM The objective of this study was to explore the association of dietary protein, PM A prospective cohort study was carried out, which encompassed 658 newly diagnosed OC patients (18-79 years) residing in China. Dietary protein intakes were collected through a food frequency questionnaire examination, including total protein and protein from diverse sources. Average residential PM During a median follow-up of 37.60 months, 123 deaths were documented. As for all-cause mortality, the multivariate-adjusted HRs (95 % CIs) in the highest vs. the lowest tertile were 0.57 (0.35-0.93), 0.60 (0.36-0.99), and 0.58 (0.37-0.90) for intakes of fish, egg, as well as fruit/vegetable protein, respectively (all P for trend < 0.05). A positive association between PM This study provides evidence linking the potential interactions between dietary fish, egg, and fruit/vegetable protein intake and PM

Development of a multi-indicator risk prediction model for cervical cancer associated with benzo[a]pyrene and nicotine exposure: A multi-omics study integrating toxicological analyses and molecular docking

Exposure to the tobacco-related compounds Benzo[a]pyrene and Nicotine has been associated with the development of several diseases. The aim of this study was to investigate the common genes associated with cervical cancer, construct a risk prediction model to reveal their biological functions, and evaluate the prognostic significance of the model to identify its potential value in the treatment of cervical cancer. In this study, genes associated with Benzo[a]pyrene and Nicotine and cervical cancer-related genes were screened by multiple databases. Target genes were analysed using a multi-omics machine learning algorithm to construct a risk-prognostic model, and nine key target genes were identified. The risk prediction models were evaluated by univariate and multivariate Cox regression analyses, and model validation was performed using the TCGA and GSE44001 datasets. In addition, clinical relevance, biofunctional enrichment, immune infiltration, and drug sensitivity analyses were performed, and the binding affinities of the two compounds to the target genes were investigated by combining molecular docking and kinetic analyses, and the Mendelian randomisation method was applied to analyse the causal association between the target genes and cervical cancer. A total of 682 genes associated with the two compounds were screened by ChEMBL, STITCH and SwissTargetPrediction databases, while 1451 genes associated with cervical cancer were identified by using GeneCards and OMIM databases, among which 109 genes were associated with both the two compounds and cervical cancer. The degree of interaction between different genes was determined by protein interaction network analysis. Based on various machine learning algorithms, a risk prediction model associated with Benzo[a]pyrene and Nicotine exposure and cervical cancer was constructed, and the good prediction performance of the model was verified in TCGA and GSE44001 datasets. In addition, a column-line diagram associated with the risk prediction model was constructed to provide a clinical tool for predicting prognosis. Further analyses revealed significant differences in the enrichment of biological processes, immune-infiltrating cells and immunomodulatory factors between the high-risk and low-risk groups, and the risk prediction model was strongly correlated with drug susceptibility, showing significant associations especially in tipifarnib-P1, AZD3463, docetaxel and AT-7519. Molecular docking and molecular dynamics simulations revealed a strong binding affinity between Benzo[a]pyrene and SLAMF6. Furthermore, Mendelian randomisation analysis revealed a significant causal relationship between SLAMF6 and AIG1. Risk prediction models based on multi-omics data and machine learning algorithms provide potential reference targets for prognosis prediction and personalised treatment of cervical cancer patients. The results of this study provide important insights into the understanding of the health risks of cervical cancer associated with Benzo[a]pyrene and Nicotine exposures and the development of preventive and therapeutic strategies for cervical cancer, which may contribute to the development of precision medicine for cervical cancer.

Multi-omics network toxicology reveals the role of benzo[a]pyrene in ovarian cancer: Integrating gut microbiota dynamics and Mendelian randomization

This study elucidates the role and molecular mechanisms of the environmental carcinogen benzo[a]pyrene (BaP) in the pathogenesis of ovarian cancer by employing an integrative approach that combines multi-omics networks, gut microbiota analysis, and Mendelian randomization. Target genes associated with BaP were identified using ChEMBL, PharmMapper, and GeneCards. Protein-protein interaction networks and functional enrichment analyses were conducted utilizing Cytoscape, while molecular docking (CB-Dock 2) confirmed a strong binding affinity between BaP and core targets (e.g., HSP90AA1: -11.7; AHR: -10.0). Analysis of TCGA data revealed significant dysregulation of 11 core genes in ovarian tumors (e.g., upregulated BCL2L1/CASP3; downregulated ALB/MTOR; all p < 0.001), with prognostic implications (AHR HR = 1.17, p = 0.028; CYCS HR = 1.18, p = 3.5E-05). Single-cell transcriptomic data analysis (via scCancerExplorer) uncovered cell-type-specific enrichment patterns (e.g., AHR/EGF in endothelial/proliferative T cells). Mendelian randomization demonstrated an inverse correlation between serum albumin levels and ovarian cancer risk (HR = 0.43, 95 % CI: 0.27 - 0.70; p = 0.002). Gut microbiota analysis (using gutMGene/SEA databases) identified specific bacteria (Faecalibacterium prausnitzii, Lacticaseibacillus rhamnosus, Fusobacterium nucleatum) that contribute to BaP-induced carcinogenesis via metabolites targeting human genes enriched in cancer pathways. This study establishes a multi-omics network linking BaP exposure to ovarian cancer, emphasizing the interplay between host molecular targets, gut microbiota, and systemic biomarkers (e.g., serum albumin), thereby providing novel insights into the mechanisms of environmental carcinogenesis and potential therapeutic strategies.

Association between plasma perfluoroalkyl substances and high-grade serous ovarian cancer overall survival: A nested case-control study

Although evidence suggests that perfluoroalkyl and polyfluoroalkyl substances (PFASs) are positively correlated to several disease risks, no studies have proven if plasma PFASs are related to ovarian cancer survival. To explore the association between plasma PFASs and high-grade serous ovarian cancer (HGSOC) overall survival (OS) in the population who did not smoke. We conducted a nested case-control study within the Ovarian Cancer Follow-Up Study, matching 159 dead patients and 159 survival ones based on body mass index, sample date, and age at diagnosis. Nine plasma PFASs were extracted by solid phase extraction and measured using a liquid chromatography system coupled with tandem mass spectrometry. Baseline plasma concentrations of perfluorinated carboxylic acids (PFCAs) [perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroheptanoic acid (PFHpA)] and perfluorinated sulfonic acids (PFSAs) [perfluorooctane sulfonic acid (PFOS) and perfluorohexane sulfonic acid (PFHxS)] were calculated. Odds ratios (ORs) and corresponding 95 % confidence intervals (CIs) were calculated via conditional logistic regression models. To elucidate the combined effects, Bayesian kernel machine (BKMR), and regression quantile g-computation (QGC) models were utilized. In full-adjusted model, significant differences were observed between HGSOC survival and perfluorobutane sulfonic acid, PFHpA, PFHxS, PFOS, PFCA, and PFSA. ORs and 95 %CIs were 2.74 (1.41-5.31), 1.97 (1.03-3.76), 2.13 (1.15-3.95), 2.28 (1.16-4.47), 3.74 (1.78-7.85), and 2.56 (1.31-5.01), respectively for the highest tertile compared with the lowest tertile. The QGC and BKMR models indicated that elevated concentrations of PFAS mixtures were associated with poor OS in HGSOC. Both individual and mixed plasma PFASs may relate to poor OS of HGSOC. Further research is necessary to establish causality, and it is recommended to reinforce environmental risk mitigation strategies to minimize PFAS exposure.

PM2.5 exposure and its interaction of oxidative balance score on ovarian cancer survival: A prospective cohort study

Recent evidence advises particles with a diameter of 2.5 µm or less (PM

Plant-based diet indices and their interaction with ambient air pollution on the ovarian cancer survival: A prospective cohort study

Ambient air pollution might serve as a prognostic factor for ovarian cancer (OC) survival, yet the relationships between plant-based diet indices (PDIs) and OC survival remain unclear. We aimed to investigate the associations of comprehensive air pollution and PDIs with OC survival and explored the effects of air pollution-diet interactions. The present study encompassed 658 patients diagnosed with OC. The overall plant-based diet index (PDI), the healthful PDI (hPDI), and the unhealthful PDI (uPDI) were evaluated by a self-reported validated food frequency questionnaire. In addition, an air pollution score (APS) was formulated by summing the concentrations of particulate matter with a diameter of 2.5 microns or less, ozone, and nitrogen dioxide. Cox proportional hazard models were applied to calculate hazard ratios (HRs) and 95 % confidence intervals (CIs). The potential interactions of APS with PDIs in relation to overall survival (OS) were assessed on both multiplicative and additive scales. Throughout a median follow-up of 37.60 (interquartile: 24.77-50.70) months, 123 deaths were confirmed. Comparing to the lowest tertiles, highest uPDI was associated with lower OS of OC (HR = 2.06, 95 % CI = 1.30, 3.28; P-trend < 0.01), whereas no significant associations were found between either overall PDI or hPDI and OC survival. Higher APS (HR Joint exposure to various ambient air pollutants was significantly associated with lower survival among patients with OC, particularly for those who predominantly consumed unhealthy plant-based foods.

Urinary heavy metals and overall survival of advanced high-grade serous ovarian cancer: A nested case-control study in China

Environmental pollution has emerged as a significant determinant in ovarian cancer prognosis. However, limited evidence exists regarding the correlations between heavy metals and ovarian cancer prognosis. To elucidate the relationship between urinary heavy metals and their mixtures with overall survival (OS) of advanced high-grade serous ovarian cancer (HGSOC). Within the Ovarian Cancer Follow-Up Study, we conducted a nested case-control study. A sum of 159 deceased patients and an equal number of alive patients were included, matched by sample date, body mass index, and age at diagnosis. Urinary concentrations of five heavy metals were quantified: arsenic (As), cadmium (Cd), chromium (Cr), mercury (Hg), and lead (Pb). Conditional logistic regression models were employed to calculate odds ratios (ORs) and their 95 % confidence intervals (CIs). To elucidate joint effects, we utilized quantile g-computation and Bayesian kernel machine regression models. For the multivariable adjusted conditional logistic regression model, significant associations were found between high urinary levels of As (OR=1.99, 95 %CI: 1.05-3.79), Cd (OR=2.56, 95 %CI: 1.29-5.05), Hg (OR=2.24, 95 %CI: 1.09-4.62), and Pb (OR=3.80, 95 %CI: 1.75-8.27) and worse OS of HGSOC, comparing the highest tertile to the lowest. Analysis of joint effects showed that elevated concentrations of heavy metal mixtures were related to poor OS of HGSOC. Pb exhibited the highest contribution to the overall association within the metal mixtures. High urinary heavy metal concentrations were linked to worse OS of HGSOC. Future research is necessary to validate our findings.

Exploring the impact of estrogenic endocrine disruptors on cervical cancer progression: A transcriptome analysis and prognostic model development

Cervical cancer is the fourth most common cancer among women globally. The detrimental health effects of estrogenic endocrine disruptors (EED), such as bisphenol A (BPA) and phthalates, are recognized, but their role in cervical cancer progression remains unclear. To investigate this, a transcriptome analysis using bioinformatics was conducted. The Comparative Toxicogenomics Database (CTD) identified estrogen-responsive genes (ERGs) associated with EED. Cervical cancer expression and clinical data were sourced from The Cancer Genome Atlas (TCGA). The limma package identified differentially expressed ERGs (DERGs), which were further analyzed for molecular mechanisms through enrichment analysis. LASSO regression developed a prognostic risk score model, and COX analysis identified prognostic biomarkers. ssGSEA assessed immune tumor infiltration, and Autodock performed molecular docking. A total of 217 DERGs were linked to endocrine resistance, estrogen signaling, and the cell cycle. The prognostic risk score and nomogram based on DERGs were highly predictive of cervical cancer prognosis and could serve as independent risk factors. The risk score influenced the tumor immune microenvironment by affecting immune cell presence. SCARA3 and FASN emerged as independent prognostic factors, with molecular docking confirming strong binding between EED and FASN. DERGs can aid in creating a reliable prognostic model and predicting overall survival in cervical cancer patients, offering new insights into the impact of EED on cancer progression and highlighting environmental factors related to cancer risks and development.

Phthalate exposure as a hidden risk factor for uterine leiomyoma in adult women: Accumulated evidence from observational studies

There is evidence that exposure to phthalate in women may increase the risk of uterine leiomyomas. Whereas, the association between exposure to phthalate and the incidence of uterine leiomyoma remained inconclusive. A meta-analysis was performed to evaluate their relationship. Literature eligible for inclusion was found in PubMed, EMBASE, Web of Science, and WanFang Medical Database. Pooled odds ratio (OR) with 95 % confidence interval (CI) was calculated to assess the risk for effect estimate for each phthalate. A total of fourteen observational studies with 5777 subjects of adult women were included in this study. In the pooled analysis, we found an elevated risk of uterine leiomyoma among women who were exposed to higher levels of di-2-ethylhexyl phthalate (DEHP) (OR 1.61, 95 % CI: 1.18-2.20), as estimated indirectly from the molar summation of its urinary metabolite concentrations. In addition, a positive association was observed between the occurrence of uterine leiomyoma and exposure to low molecular weight phthalate mixture (OR 1.08, 95 % CI: 1.00-1.15), as well as high molecular weight phthalate mixture (OR 1.08, 95 % CI: 1.01-1.15), as quantified by integrating the effect estimates of individual metabolite from each study. Urinary levels of DEHP metabolites, monobenzyl phthalate, mono-(3-carboxypropyl) phthalate, mono-isobutyl phthalate, mono-n-butyl phthalate, monoethyl phthalate, and monomethyl phthalate were not appreciably correlated with the risk of uterine leiomyoma. Our results indicated that exposure to DEHP, and co-exposure to high or low molecular weight phthalate mixture might be potential risk factors for uterine leiomyoma in adult women. Owing to the indirect estimation of association, when interpreting these findings, cautions should be taken.

Does outdoor light contribute to ovarian cancer mortality? Insights from a case-control study

Unfavorable light environments, including artificial light at night (ALAN) and ultraviolet B (UVB) radiation, may be linked to ovarian cancer, but this association remains uncertain. A multicenter case-control study in Northeastern China was performed. Using propensity score matching, we matched individuals who died from other cancers with controls in a 1:1 ratio. Exposure levels were determined by monthly average outdoor ALAN exposure (0.5 ×0.5 km), UVB radiation (0.25°×0.25°), and PM

Prognostic associations of PFAS in ovarian cancer: Insights from exploratory analysis

Ovarian cancer (OC), a deadliest gynecological malignancy, lacks reliable predictive biomarkers for its heterogeneous clinical outcomes. Per- and polyfluoroalkyl substances (PFAS) are persisting endocrine disruptors potentially affecting female reproductive health, but their roles in OC remain unclear. We aimed to investigate the possible associations between PFAS and OC prognosis. PFAS-related mRNAs were acquired from the Comparative Toxicogenomics resource, mRNAs expression and clinicopathological information of OC were extracted from The Cancer Genome Atlas and Gene Expression Omnibus databases. Prognostic factors were selected using Cox proportional hazards regression (cox), random survival forest, and lasso regression methods. The prediction models for overall survival (OS) and progression free survival (PFS) were further constructed by cox regression. Molecular docking was performed to assess the binding capacity of PFAS to certain mRNAs. The effects of PFAS on the phenotype of OC cells were analyzed by quantitative real-time PCR, CCK8, migration, and invasion detection. PFAS-derived risk scores were constructed based on prognosis-related mRNAs, which were independent predictors for prognosis of OC. PFAS-derived risk scores showed 1-year time-dependent AUC values 0.71/0.67/0.66 (OS) and 0.70/0.65/0.61 (PFS) in training/testing/external validation sets, respectively. Drug sensitivity analysis indicated that patients with lower risk score may derive greater benefit from chemotherapy drugs. Molecular docking analysis suggested a high affinity between PFAS and the targeted proteins of prognosis-related mRNAs. In vitro experiments further substantiated that perfluorooctanoic acid exposure promoted the malignant phenotypes of OC cells and the changes of SLC22A2, SPOCK3, and APOD expressions. In this exploratory study, PFAS-derived risk scores showed potential for predicting OC prognosis and might offer insights relevant to clinical treatment strategies, pointing to the potential prognostic role of PFAS in OC.

Environmentally relevant concentration PFNA promotes degradation of SMAD7 to drive progression of ovarian cancer via TGF-β/SMADs signaling pathway

Perfluorononanoic acid (PFNA), an acknowledged environmental endocrine disruptor, is increasingly utilized as a substitute for perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). Despite its growing use, limited research has been conducted to investigate its potential impact on tumorigenesis and progression, and the potential molecular mechanisms. Earlier studies linked perfluoroalkyl and polyfluoroalkyl substances (PFAS) exposure to breast and gynecological cancer progression in humans, lacking a clear understanding of the underlying mechanisms, notably in ovarian cancer. Our investigation into PFNA's effects at environmental concentrations (0.25-2 mM) showed no significant impact on cell proliferation but a notable increase in invasion and migration of ovarian cancer cells. This led to alterations in epithelial-mesenchymal transition (EMT) markers, including Claudin1, Vimentin, and Snail. Notably, PFNA exposure activated the TGF-β/SMADs signaling pathway. Crucially, SMAD7 degradation through the ubiquitin-proteasome system emerged as PFNA's pivotal molecular target for inducing EMT, corroborated in mouse models. In summary, this study presented evidence that environmentally relevant concentrations of PFNA could induce SMAD7 degradation via the proteasome pathway, subsequently activating the TGF-β/SMADs signaling pathway, and promoting EMT in ovarian cancer. These results illuminated the association between PFNA exposure and metastasis of ovarian cancer.

Benzo[a]pyrene reduces cellular senescence in ovarian cancer by stabilizing c-Myc independently of DNA damage

Benzo[a]pyrene (BaP), a widespread environmental pollutant produced by the incomplete combustion of organic materials and cigarette smoke, has been linked to the promotion of cancer progression. In this study, we demonstrated that BaP not only enhances cisplatin resistance but also suppresses cellular senescence. Importantly, these effects occur independently of DNA damage. Mechanistically, BaP binds to the Thr58 site of c-Myc, preventing its phosphorylation at this residue. This interaction reduces c-Myc ubiquitination, resulting in its stabilization and increased oncogenic activity. The accumulation of c-Myc subsequently drives the expression of genes associated with tumor growth, metastasis, and drug resistance. Our findings uncover a novel mechanism through which environmental pollutants like BaP influence cancer biology, offering a theoretical basis for the prevention and management of such exposures. This research highlights the critical role of environmental factors in cancer development and identifies potential therapeutic targets to counteract the effects of these harmful compounds.