Group IVA phospholipase A ₂ regulates testosterone biosynthesis by murine Leydig cells and is required for timely sexual maturation

In the present paper, we report that PLA ₂G4A (Group IVA phospholipase A ₂) is important in the development and function of rodent testes. Interstitial cells of rat testes had high PLA ₂ (phospholipase A ₂) activity that was very sensitive to the PLA ₂G4A-preferential inhibitor AACOCF ₃(arachidonyl trifluoromethyl ketone). PLA ₂G4A protein was expressed primarily in the interstitial cells of wild-type mouse testes throughout maturation. Although Pla2g4a knockout (Pla2g4a ^-/-) male mice are fertile, their sexual maturation was delayed, as indicated by cauda epididymal sperm count and seminal vesicle development. Delayed function of Pla2g4a ^-/-mice testes was associated with histological abnormalities including disorganized architecture, swollen appearance and fewer interstitial cells. Basal secretion of testosterone was attenuated significantly and steroidogenic response to hCG (human chorionic gonadotropin) treatment was reduced in Pla2g4a ^-/- mice compared with their Pla2g4a ^+/+ littermates during the sexual maturation period. Chemical inhibition of PLA ₂G4A activity by AACOCF ₃ or pyrrophenone significantly reduced hCG-stimulated testosterone production in cultured rat interstitial cells. AACOCF ₃ inhibited forskolin- and cAMP analogue-stimulated testosterone production. These results provide the first evidence that PLA ₂G4A plays a role inmale testes physiology and development. These results may have implications for the potential clinical use of PLA ₂G4A inhibitors.