Hong Yanggang, Wang Yirong, Li Jiajun, Shu Wanyi, Chen Haolin, Chen Congde
Key Laboratory of Structural Malformations in Children of Zhejiang Province, Department of Pediatric Urology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Key Laboratory of Children Genitourinary Diseases of Wenzhou City, Department of Pediatric Urology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
J Assist Reprod Genet. 2025 Sep 16. doi: 10.1007/s10815-025-03664-6.
Environmental endocrine-disrupting chemicals (EDCs) are increasingly implicated in male infertility, yet the gene-level mechanisms by which EDCs contribute to non-obstructive azoospermia (NOA) remain unclear. This study aimed to identify EDC-related genes that are causally linked to NOA and uncover their potential roles in reproductive dysfunction.
We integrated transcriptomic analysis of GEO datasets, EDC-associated gene data from the Comparative Toxicogenomics Database (CTD), and Mendelian randomization (MR) to prioritize candidate genes with causal relevance to male infertility. Phenome-wide association study (PheWAS) was conducted to assess systemic effects. EDC-gene interactions were visualized, and single-cell RNA sequencing (scRNA-seq) was used to validate cell-type-specific gene expression in the testis.
A total of 136 genes were identified at the intersection of differentially expressed genes in NOA and EDC-related genes. MR analysis highlighted PPP6R1 and AP1M2 as causally linked to male infertility. PheWAS revealed a significant association between PPP6R1 and cardiovascular traits (p < 1 × 10), suggesting pleiotropic effects. Interaction analysis identified 26 EDCs targeting these genes, including thiram, bisphenol A, and sodium arsenite. The scRNA-seq confirmed downregulation of both genes in germ cells of NOA patients.
Our multi-omics approach suggests a potential EDC-gene-NOA axis, identifying PPP6R1 and AP1M2 as candidate genes whose expression may be influenced by environmental exposure in the context of male infertility. These findings deepen mechanistic understanding of NOA pathogenesis and support future research into environmental and molecular targets for diagnosis and prevention.
环境内分泌干扰化学物质（EDCs）与男性不育的关联日益增加，然而EDCs导致非梗阻性无精子症（NOA）的基因水平机制仍不清楚。本研究旨在鉴定与NOA有因果关系的EDC相关基因，并揭示它们在生殖功能障碍中的潜在作用。
我们整合了GEO数据集的转录组分析、来自比较毒理基因组学数据库（CTD）的EDC相关基因数据以及孟德尔随机化（MR），以确定与男性不育有因果相关性的候选基因。进行全表型关联研究（PheWAS）以评估全身效应。对EDC-基因相互作用进行可视化，并用单细胞RNA测序（scRNA-seq）验证睾丸中细胞类型特异性基因表达。
在NOA差异表达基因与EDC相关基因的交叉点共鉴定出136个基因。MR分析突出显示PPP6R1和AP1M2与男性不育有因果关系。PheWAS揭示PPP6R1与心血管特征之间存在显著关联（p < 1 × 10），表明存在多效性效应。相互作用分析确定了靶向这些基因的26种EDC，包括福美双、双酚A和亚砷酸钠。scRNA-seq证实NOA患者生殖细胞中这两个基因均下调。
我们的多组学方法提示了一个潜在的EDC-基因-NOA轴，确定PPP6R1和AP1M2为候选基因，其表达可能在男性不育背景下受环境暴露影响。这些发现加深了对NOA发病机制的机制理解，并支持未来对诊断和预防的环境及分子靶点的研究。
