Integrative causal and single-cell analyses reveal genes responsive to endocrine disruptors driving human male infertility

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Male infertility is a growing global health concern increasingly linked to environmental exposure to endocrine-disrupting chemicals (EDCs). However, the specific molecular mechanisms by which EDCs contribute to impaired reproductive function remain unclear. In this study, we systematically identified EDC-related genes using curated chemical-gene interaction databases and assessed their causal roles in male infertility through Mendelian randomization (MR) and colocalization analyses, utilizing large-scale cis-eQTL and GWAS datasets. A total of six genes, RHEB, PARP1, SLTM, PLIN1, PEX11A, and SDCBP, showed strong evidence of causal relationships and shared genetic variants associated with both gene expression and infertility traits. Single-cell RNA sequencing of human testicular tissue revealed that these genes are predominantly expressed in germ cells and are significantly dysregulated in non-obstructive azoospermia (NOA) samples, supporting their functional relevance. Additionally, environmental mapping indicated that several widely encountered EDCs, including bisphenol A (BPA) and its analogs, triphenyl phosphate (TPP), and sodium arsenite, interact with multiple candidate genes. These findings provide mechanistic insight into how chemical exposures can dysregulate gene expression in testicular cells and contribute to male infertility, highlighting the need for targeted environmental risk assessments and regulatory strategies.