Epigenetic Disruption as a Molecular Signature in Idiopathic Nonobstructive Azoospermia

Area of Science:

• Reproductive biology
• Epigenetics
• Molecular genetics

Background:

• Idiopathic nonobstructive azoospermia (iNOA) is diagnosed when no cause for sperm absence is found.
• Epigenetic alterations are implicated in spermatogenesis dysfunction.

Purpose of the Study:

• To compare gene expression of DNA methyltransferase (DNMT) 1 (DNMT1), DNMT3A, DNMT3B, and Zinc Finger CCHC-Type Containing 13 (ZCCHC13) in iNOA versus obstructive azoospermia (OA).
• To assess the diagnostic potential of these epigenetic regulators in iNOA.

Main Methods:

• Quantitative real-time PCR was used to analyze DNMT1, DNMT3A, DNMT3B, and ZCCHC13 expression in testicular tissue from 60 azoospermic men (30 iNOA, 30 OA).
• iNOA patients were stratified into successful (iNOA+) and unsuccessful (iNOA-) sperm retrieval groups based on microdissection testicular sperm extraction (micro-TESE).
• Receiver operating characteristic (ROC) analysis evaluated diagnostic accuracy.

Main Results:

• DNMT1 and ZCCHC13 expression were significantly lower in iNOA compared to OA (p = .01).
• DNMT3B expression was significantly higher in iNOA, especially in the iNOA- subgroup (p < .0001).
• DNMT3B demonstrated the highest diagnostic accuracy (AUC = 0.84), followed by ZCCHC13 (AUC = 0.69) and DNMT1 (AUC = 0.68).

Conclusions:

• Epigenetic dysregulation, particularly involving DNMT3B and ZCCHC13, contributes to spermatogenesis impairment in iNOA.
• These epigenetic biomarkers offer potential for molecularly distinguishing iNOA from OA and guiding therapeutic strategies.