Integrating network toxicology and Mendelian randomization to uncover the role of AHR in linking air pollution to male reproductive health

Background

With the rapid advancement of global industrialization and urbanization, air pollution has emerged as a major public health concern. This study investigates the molecular mechanisms linking air pollutants (APs) to male reproductive health (MRH), providing a scientific foundation for disease prevention and treatment.

Methods

APs-disease-related genes were retrieved from multiple network databases, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. A protein-protein interaction (PPI) network was constructed to elucidate potential molecular interactions. Differentially expressed genes from two external Gene Expression Omnibus (GEO) sequencing datasets were selected for validation, and intersection analysis was performed to identify key genes. Mendelian randomization (MR）was then applied to assess the causal relationships between key genes and male infertility (MIF), erectile dysfunction (ED), total testosterone levels, and testicular dysfunction. Additionally, molecular docking analysis was conducted to evaluate the binding affinity between key genes and APs.

Results

This study focused on seven common APs (Benzene, SO₂, NO, CO, NO₂, Toluene, and O₃) and two MRH conditions (ED and MIF). Through intersection analyses and external validation, Aryl Hydrocarbon Receptor (AHR) was identified as a key regulator. MR analysis suggested that AHR may contribute to MIF and ED by suppressing testosterone levels and impairing testicular function.

Conclusion

By integrating network toxicology, MR, and molecular docking analysis, this study highlights the critical role of AHR as a molecular bridge between air pollution and MRH. These findings provide novel molecular insights into the impact of Aps on MRH.