Molecular mechanisms of p-phenylenediaminequinone toxicity in male infertility: a network toxicology and docking study

p-Phenylenediaminequinones (PPD-Qs) are oxidized derivatives of common p-phenylenediamine (PPD) Antioxidants. These compounds have emerged as persistent environmental toxicants detected across diverse ecological matrices and human samples. Despite their widespread presence, the mechanistic links between PPD-Qs and male reproductive dysfunction remain largely unexplored. In this study, we employed an integrated approach combining network toxicology and molecular docking to systematically investigate the molecular mechanisms underlying the association of five PPD-Qs with male infertility and its principal subtypes: hypogonadotropic hypogonadism (HH), hyperprolactinemia (HPL), and immunological infertility (IMI). Our analysis identified 479 PPD-Q-related targets and 3142 male infertility-related targets, with 230 overlapping targets indicating potential interactions. Protein-protein interaction network analysis revealed 15 core targets associated with male infertility, while subtype-specific analyses identified 22, 13, and 66 core targets for HH, HPL, and IMI, respectively. GO and KEGG enrichment analyses delineated three primary mechanistic pathways: (1) disruption of reproductive endocrine homeostasis through estrogen, GnRH, and Prolactin signaling; (2) dysregulation of cellular signaling cascades, including the MAPK and PI3K-AKT pathways; and (3) modulation of immune function and oxidative stress responses. Notably, Akt1 and ESR1 emerged as conserved targets across all conditions. Molecular docking studies demonstrated strong binding affinity (-6.6 to -9.8 kcal/mol) between PPD-Qs and core targets, with DTPD-Q exhibiting the highest affinity. Our findings establish Akt1 and ESR1 as conserved molecular targets across male infertility and its subtypes, supported by the strong computational binding affinities. By integrating network toxicology, this study extends previous research on individual PPD-Qs, demonstrating their capacity to disrupt multiple pathways involving endocrine regulation, immune function, and oxidative stress responses. These insights provide a mechanistic foundation for future environmental monitoring and the development of targeted intervention strategies.

Male infertility; Molecular docking; Network toxicology; PPD-Qs; Reproductive toxicity.