AOP report: Adverse outcome pathway network for developmental androgen signaling inhibition leading to hypospadias

Area of Science:

• Endocrinology and Toxicology
• Developmental Biology
• Reproductive Health

Background:

• Hypospadias is a congenital penile malformation resulting from disrupted fetal masculinization.
• Androgen receptor (AR) signaling is critical for normal development of the male genitalia.
• Reduced AR signaling during gestation is a known cause of hypospadias in mammals.

Purpose of the Study:

• To summarize an adverse outcome pathway network (AOPN) detailing the link between reduced fetal androgen signaling and hypospadias.
• To present three distinct adverse outcome pathways (AOPs) representing anti-androgenic mechanisms.
• To assess existing and introduce new key events (KEs) and key event relationships (KERs) within the AOPN.

Main Methods:

• Literature review and data synthesis to construct the AOPN.
• Systematic weight-of-evidence approach to evaluate evidence for AOPs and KERs.
• Identification and assessment of upstream events, nodal KEs, and the adverse outcome (AO) of hypospadias.

Main Results:

• Three AOPs (AOP-wiki IDs 477, 570, 571) were identified, converging on decreased AR activation (KE-1614).
• The adverse outcome 'hypospadias' (AO-2082) was confirmed as a shared endpoint.
• One new KE and three new KERs were reported, strengthening the mechanistic links.

Conclusions:

• The AOPN provides robust mechanistic evidence connecting anti-androgenic activity to hypospadias.
• The network is applicable to male mammals, with primary support from rodent and human studies.
• The findings establish a foundation for quantitative assessment and predictive modeling of hypospadias risk.