Jiaxin Zheng , Na Zhu , Chang Liu , Xiang Li , Keming Zhang , Zhuo Yang , Danbo Wang , Bo Liu
{"title":"PD-1抑制剂对卵巢功能的影响——基于两样本孟德尔随机化和可视化实验验证。","authors":"Jiaxin Zheng , Na Zhu , Chang Liu , Xiang Li , Keming Zhang , Zhuo Yang , Danbo Wang , Bo Liu","doi":"10.1016/j.reprotox.2025.109057","DOIUrl":null,"url":null,"abstract":"<div><div>Although immune checkpoint inhibitors (ICIs) have transformed cancer treatment by improving survival, their ovarian safety remains uncertain. This study combined Mendelian randomization (MR) and experimental validation to assess the impact of PD-1 inhibitors on ovarian function. MR analysis used summary statistics from large European-ancestry genome-wide association studies (GWAS), applying the inverse-variance weighted (IVW) method, supported by sensitivity analyses. For in vitro experiments, mouse follicles were cultured with 10 µg/ml PD-1 inhibitor ch15mt (clinically relevant concentration), 200 nM doxorubicin (DOX), or PBS control. Follicular morphology was evaluated via diameter measurements; endocrine function by estradiol (E2) quantification using ELISA. Real-time cytoplasmic Ca²⁺ dynamics were monitored using FRET-based Cyto-Ca2 + probes for high-resolution stress assessment. MR results showed no significant association between genetically predicted PD-1 levels and risks of premature ovarian insufficiency, infertility, or alterations in ovarian hormones including AMH and E2. Sensitivity analyses confirmed MR robustness. In vitro, PD-1 inhibition did not affect follicular size or E2 secretion. Notably, DOX induced rapid Ca²⁺ elevation, while PD-1 inhibitor treatment had no detectable effect on Ca²⁺ fluctuations. This first integrative MR and experimental study demonstrates that PD-1 inhibitors at clinically relevant concentrations lack acute ovarian toxicity. While further work is needed to assess long-term effects, these findings demonstrate that standard anti-PD-1 immunotherapy regimens do not compromise follicular viability or endocrine function, strongly supporting their safety in fertility-sparing oncology protocols.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"138 ","pages":"Article 109057"},"PeriodicalIF":2.8000,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Effects of PD-1 inhibitors on ovarian function-based on two-sample mendelian randomization and visualization experimental validation\",\"authors\":\"Jiaxin Zheng , Na Zhu , Chang Liu , Xiang Li , Keming Zhang , Zhuo Yang , Danbo Wang , Bo Liu\",\"doi\":\"10.1016/j.reprotox.2025.109057\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Although immune checkpoint inhibitors (ICIs) have transformed cancer treatment by improving survival, their ovarian safety remains uncertain. This study combined Mendelian randomization (MR) and experimental validation to assess the impact of PD-1 inhibitors on ovarian function. MR analysis used summary statistics from large European-ancestry genome-wide association studies (GWAS), applying the inverse-variance weighted (IVW) method, supported by sensitivity analyses. For in vitro experiments, mouse follicles were cultured with 10 µg/ml PD-1 inhibitor ch15mt (clinically relevant concentration), 200 nM doxorubicin (DOX), or PBS control. Follicular morphology was evaluated via diameter measurements; endocrine function by estradiol (E2) quantification using ELISA. Real-time cytoplasmic Ca²⁺ dynamics were monitored using FRET-based Cyto-Ca2 + probes for high-resolution stress assessment. MR results showed no significant association between genetically predicted PD-1 levels and risks of premature ovarian insufficiency, infertility, or alterations in ovarian hormones including AMH and E2. Sensitivity analyses confirmed MR robustness. In vitro, PD-1 inhibition did not affect follicular size or E2 secretion. Notably, DOX induced rapid Ca²⁺ elevation, while PD-1 inhibitor treatment had no detectable effect on Ca²⁺ fluctuations. This first integrative MR and experimental study demonstrates that PD-1 inhibitors at clinically relevant concentrations lack acute ovarian toxicity. While further work is needed to assess long-term effects, these findings demonstrate that standard anti-PD-1 immunotherapy regimens do not compromise follicular viability or endocrine function, strongly supporting their safety in fertility-sparing oncology protocols.</div></div>\",\"PeriodicalId\":21137,\"journal\":{\"name\":\"Reproductive toxicology\",\"volume\":\"138 \",\"pages\":\"Article 109057\"},\"PeriodicalIF\":2.8000,\"publicationDate\":\"2025-09-11\",\"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/S089062382500228X\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"REPRODUCTIVE BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Reproductive toxicology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S089062382500228X","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"REPRODUCTIVE BIOLOGY","Score":null,"Total":0}
Effects of PD-1 inhibitors on ovarian function-based on two-sample mendelian randomization and visualization experimental validation
Although immune checkpoint inhibitors (ICIs) have transformed cancer treatment by improving survival, their ovarian safety remains uncertain. This study combined Mendelian randomization (MR) and experimental validation to assess the impact of PD-1 inhibitors on ovarian function. MR analysis used summary statistics from large European-ancestry genome-wide association studies (GWAS), applying the inverse-variance weighted (IVW) method, supported by sensitivity analyses. For in vitro experiments, mouse follicles were cultured with 10 µg/ml PD-1 inhibitor ch15mt (clinically relevant concentration), 200 nM doxorubicin (DOX), or PBS control. Follicular morphology was evaluated via diameter measurements; endocrine function by estradiol (E2) quantification using ELISA. Real-time cytoplasmic Ca²⁺ dynamics were monitored using FRET-based Cyto-Ca2 + probes for high-resolution stress assessment. MR results showed no significant association between genetically predicted PD-1 levels and risks of premature ovarian insufficiency, infertility, or alterations in ovarian hormones including AMH and E2. Sensitivity analyses confirmed MR robustness. In vitro, PD-1 inhibition did not affect follicular size or E2 secretion. Notably, DOX induced rapid Ca²⁺ elevation, while PD-1 inhibitor treatment had no detectable effect on Ca²⁺ fluctuations. This first integrative MR and experimental study demonstrates that PD-1 inhibitors at clinically relevant concentrations lack acute ovarian toxicity. While further work is needed to assess long-term effects, these findings demonstrate that standard anti-PD-1 immunotherapy regimens do not compromise follicular viability or endocrine function, strongly supporting their safety in fertility-sparing oncology protocols.
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.