Frontiers in immunology · 2026
Effective analysis of testicular seminoma toxicity and mechanisms of acetyl tributyl citrate using network toxicology, bulk RNA sequencing data, single-cell RNA sequencing data, and clinical data.
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Yi Haisheng, Gong Yibo, Yang Wenjie, Jia Yinzhao, Chen Jintao, Zhang Chao, Lin Xueming, Tian Hua, Wu Bo, Cao Xiaoming, Liang Gang, Yuan Xiaobin
Аннотация
INTRODUCTION: Acetyl tributyl citrate (ATBC) is a widely used plasticizer ubiquitously present in the environment. Long-term high-dose ATBC exposure has been associated with reproductive system damage, yet its toxic effects and underlying mechanisms in testicular seminoma remain unclear. This study aimed to investigate the impact of ATBC on the prognosis of testicular seminoma.
METHODS: We integrated network toxicology analysis, single-cell RNA sequencing (scRNA-seq), bulk RNA-seq data, and clinical datasets to explore the prognostic role of ATBC-related genes in testicular seminoma. Bulk RNA-seq profiles, scRNA-seq data of testicular seminoma, and predicted ATBC target genes were obtained from public databases. Prognostic candidate genes were screened through differential expression analysis in seminoma datasets. Cox regression and machine learning algorithms were applied to the large TCGA-TGCT cohort to construct a robust prognostic risk model for patient stratification. Additional analyses included functional pathway enrichment, immune microenvironment assessment, single-cell gene expression profiling, key cell subtype identification, and clinical validation via immunohistochemistry and real-world clinical data.
RESULTS: PDK1 and OARD1 were confirmed as ATBC-associated prognostic genes for testicular seminoma. The established risk model showed moderate discriminatory capacity, with area under the curve (AUC) values for 1-, 2-, and 3-year survival all exceeding 0.6. Enriched pathways were mainly related to immunity and metabolism, and the high-risk group exhibited more active cell-mediated immune responses. Five cell subtypes were identified by scRNA-seq, among which B cells were recognized as the key cell population; dynamic expression changes of prognostic genes were observed during the differentiation of these key cells. Furthermore, protein levels of PDK1 and OARD1 were significantly higher in normal testicular tissues than in testicular seminoma tissues.
DISCUSSION: In conclusion, PDK1 and OARD1 are reliable prognostic biomarkers for testicular seminoma. This study provides an important theoretical basis for developing strategies to alleviate the adverse effects of ATBC on the male reproductive system.
METHODS: We integrated network toxicology analysis, single-cell RNA sequencing (scRNA-seq), bulk RNA-seq data, and clinical datasets to explore the prognostic role of ATBC-related genes in testicular seminoma. Bulk RNA-seq profiles, scRNA-seq data of testicular seminoma, and predicted ATBC target genes were obtained from public databases. Prognostic candidate genes were screened through differential expression analysis in seminoma datasets. Cox regression and machine learning algorithms were applied to the large TCGA-TGCT cohort to construct a robust prognostic risk model for patient stratification. Additional analyses included functional pathway enrichment, immune microenvironment assessment, single-cell gene expression profiling, key cell subtype identification, and clinical validation via immunohistochemistry and real-world clinical data.
RESULTS: PDK1 and OARD1 were confirmed as ATBC-associated prognostic genes for testicular seminoma. The established risk model showed moderate discriminatory capacity, with area under the curve (AUC) values for 1-, 2-, and 3-year survival all exceeding 0.6. Enriched pathways were mainly related to immunity and metabolism, and the high-risk group exhibited more active cell-mediated immune responses. Five cell subtypes were identified by scRNA-seq, among which B cells were recognized as the key cell population; dynamic expression changes of prognostic genes were observed during the differentiation of these key cells. Furthermore, protein levels of PDK1 and OARD1 were significantly higher in normal testicular tissues than in testicular seminoma tissues.
DISCUSSION: In conclusion, PDK1 and OARD1 are reliable prognostic biomarkers for testicular seminoma. This study provides an important theoretical basis for developing strategies to alleviate the adverse effects of ATBC on the male reproductive system.