Potential disease-related risk of saccharin in ovarian cancer: An integrative multi-evidence analysis

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology Pub Date : 2025-09-09 DOI:10.1016/j.reprotox.2025.109044

Yang Song , Hao Yang , Yanchun Wang , Chenchen Lin , Xuemei Wang

{"title":"Potential disease-related risk of saccharin in ovarian cancer: An integrative multi-evidence analysis","authors":"Yang Song , Hao Yang , Yanchun Wang , Chenchen Lin , Xuemei Wang","doi":"10.1016/j.reprotox.2025.109044","DOIUrl":null,"url":null,"abstract":"<div><div>Saccharin is a widely used artificial sweetener with controversial safety concerns, particularly regarding reproductive health. Using a network-toxicology framework, we integrated compound- and disease-target databases and intersected them with differentially expressed genes and WGCNA co-expression modules from GEO datasets, yielding 49 candidate targets. Protein–protein interaction analysis and functional prioritization identified five hubs: TNF, MMP2, ERBB2, BCL2L1, and NFE2L2. GO/KEGG enrichment indicated over-representation of biological processes related to inflammatory response, apoptosis, and oxidative stress, alongside multiple cancer-associated pathways. Molecular docking against representative target structures indicated favorable binding of saccharin across hubs, with binding energies ≤ −5.0 kcal/mol. Mendelian randomization then tested the causal effects of gene expression on ovarian cancer risk and suggested a protective signal for TNF (odds ratio [OR] 0.99886, P = 0.0448) and increased risk for BCL2L1 (OR 1.00128, P = 0.0188). In two independent GEO datasets (GSE26712 and GSE14407), TNF and BCL2L1 were identified as differentially expressed genes between tumor and normal tissues. Molecular dynamics simulations further supported binding stability, with backbone RMSD stabilizing at 0.16–0.19 nm. These findings offer mechanistic insights into saccharin-induced ovarian toxicity and support further evaluation of artificial sweeteners' reproductive risks.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"138 ","pages":"Article 109044"},"PeriodicalIF":2.8000,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Reproductive toxicology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0890623825002151","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"REPRODUCTIVE BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Saccharin is a widely used artificial sweetener with controversial safety concerns, particularly regarding reproductive health. Using a network-toxicology framework, we integrated compound- and disease-target databases and intersected them with differentially expressed genes and WGCNA co-expression modules from GEO datasets, yielding 49 candidate targets. Protein–protein interaction analysis and functional prioritization identified five hubs: TNF, MMP2, ERBB2, BCL2L1, and NFE2L2. GO/KEGG enrichment indicated over-representation of biological processes related to inflammatory response, apoptosis, and oxidative stress, alongside multiple cancer-associated pathways. Molecular docking against representative target structures indicated favorable binding of saccharin across hubs, with binding energies ≤ −5.0 kcal/mol. Mendelian randomization then tested the causal effects of gene expression on ovarian cancer risk and suggested a protective signal for TNF (odds ratio [OR] 0.99886, P = 0.0448) and increased risk for BCL2L1 (OR 1.00128, P = 0.0188). In two independent GEO datasets (GSE26712 and GSE14407), TNF and BCL2L1 were identified as differentially expressed genes between tumor and normal tissues. Molecular dynamics simulations further supported binding stability, with backbone RMSD stabilizing at 0.16–0.19 nm. These findings offer mechanistic insights into saccharin-induced ovarian toxicity and support further evaluation of artificial sweeteners' reproductive risks.

查看原文本刊更多论文

卵巢癌中糖精的潜在疾病相关风险：一项综合多证据分析

糖精是一种广泛使用的人工甜味剂，其安全性存在争议，尤其是在生殖健康方面。利用网络毒理学框架，我们整合了化合物和疾病靶点数据库，并将它们与GEO数据集中的差异表达基因和WGCNA共表达模块交叉，得到49个候选靶点。蛋白质相互作用分析和功能优先级确定了五个中心：TNF， MMP2, ERBB2， BCL2L1和NFE2L2。GO/KEGG富集表明炎症反应、细胞凋亡和氧化应激相关的生物过程以及多种癌症相关途径的过度表达。与代表性靶结构的分子对接表明糖精在枢纽间结合良好，结合能≤-5.0kcal/mol。孟德尔随机化测试了基因表达对卵巢癌风险的因果影响，发现TNF（比值比[OR] 0.99886， P=0.0448）和BCL2L1风险增加（比值比[OR] 1.00128， P=0.0188）具有保护作用。在两个独立的GEO数据集（GSE26712和GSE14407）中，TNF和BCL2L1被鉴定为肿瘤和正常组织之间的差异表达基因。分子动力学模拟进一步支持了结合稳定性，主链RMSD稳定在0.16-0.19nm。这些发现为糖精诱导的卵巢毒性提供了机制见解，并支持进一步评估人工甜味剂的生殖风险。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Reproductive toxicology 生物-毒理学

CiteScore

6.50

自引率

3.00%

发文量

131

审稿时长

45 days

期刊介绍： Drawing from a large number of disciplines, Reproductive Toxicology publishes timely, original research on the influence of chemical and physical agents on reproduction. Written by and for obstetricians, pediatricians, embryologists, teratologists, geneticists, toxicologists, andrologists, and others interested in detecting potential reproductive hazards, the journal is a forum for communication among researchers and practitioners. Articles focus on the application of in vitro, animal and clinical research to the practice of clinical medicine. All aspects of reproduction are within the scope of Reproductive Toxicology, including the formation and maturation of male and female gametes, sexual function, the events surrounding the fusion of gametes and the development of the fertilized ovum, nourishment and transport of the conceptus within the genital tract, implantation, embryogenesis, intrauterine growth, placentation and placental function, parturition, lactation and neonatal survival. Adverse reproductive effects in males will be considered as significant as adverse effects occurring in females. To provide a balanced presentation of approaches, equal emphasis will be given to clinical and animal or in vitro work. Typical end points that will be studied by contributors include infertility, sexual dysfunction, spontaneous abortion, malformations, abnormal histogenesis, stillbirth, intrauterine growth retardation, prematurity, behavioral abnormalities, and perinatal mortality.