6PPD-quinone exposure impairs erectile function through dysregulation of the HIF-1α/eNOS/NO axis: multi-omics and in vivo evidence
Year: 2026
Type: article
Abstract: Background 6PPD-quinone (6PPD-Q), a transformation product of the tire antioxidant 6PPD, has emerged as an environmental contaminant with potential reproductive toxicity. However, its role in erectile dysfunction (ED) and the underlying mechanisms remain unclear. Methods This study integrated network toxicology, transcriptomics, single-cell RNA sequencing, machine learning, Mendelian randomization, molecular docking, molecular dynamics simulation, and animal experiments to investigate the potential mechanisms linking 6PPD-Q exposure to ED. Results A total of 134 genes were identified at the intersection of the 6PPD-Q- and ED-related gene sets. Integration of bulk and single-cell transcriptomic data, followed by LASSO and SVM-RFE analyses, prioritized ACO1, HIF1A, PDK4, and PTPN11. Among these genes, only HIF1A showed a significant association with ED risk in the Mendelian randomization analysis. Molecular docking and a 100-ns molecular dynamics simulation supported the structural plausibility of an interaction between 6PPD-Q and HIF-1α. In rats, 6PPD-Q exposure reduced the ICPmax/MAP ratio and cavernosal NO levels without affecting testosterone. These changes were accompanied by increased HIF-1α and decreased p-eNOS, eNOS, and p-eNOS/eNOS levels in the corpus cavernosum. PX-478 partially restored eNOS/NO signaling and erectile function. Conclusion These findings suggest that 6PPD-Q may contribute to ED by activating HIF1A-related stress responses and impairing eNOS/NO-mediated endothelial relaxation.
Source: Frontiers in Endocrinology
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7222419740