Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Alleviates the Defective Epididymis and Sperm Function in Lipopolysaccharide (LPS) Induced Acute Mouse Epididymitis.

Abstract

This study investigated the protective effects of pituitary adenylate cyclase-activating polypeptide (PACAP) against lipopolysaccharide (LPS)-induced acute epididymitis in mice, with a particular emphasis on its antioxidant and anti-inflammatory mechanisms within the epididymal microenvironment responsible for sperm maturation. Acute epididymitis was triggered by injecting LPS intraperitoneally, with concurrent PACAP administration. Epididymal tissues were collected for histological, immunofluorescence, RT-PCR, and in vitro fertilization analyses. The results demonstrated that PACAP markedly decreased the expression of Il-6 mRNA (2.87 fold decrease, p < 0.05) and Tnf-α mRNA (2.45 fold decrease, p < 0.05) in the cauda epididymis following LPS adminstration for 6 h, alleviated histopathological changes, and improved sperm motility (from 37.8 ± 4.1% in LPS group to 52.7 ± 3.3% in LPS + PACAP group, p < 0.05) and morphology (abnormal sperm rate decreased from 45.7% ± 5.6-22.1% ± 3.8%, p < 0.05). PACAP also preserved the expression of epididymal function-associated proteins (AQP1 and KRT5), suppressed inflammatory gene expression, and enhanced antioxidant gene expression in the cauda epididymidis tissues during acute epididymitis. In vitro fertilization experiments revealed that PACAP significantly restored sperm fertilizing capacity, as evidenced by an increase in sperm-oocyte binding (from 8.7 ± 1.5 to 15.6 ± 2.7, p < 0.05), and improved embryonic development rates compromised by LPS (the two-cell embryo rate increased from 35.7% ± 4.8-62.3% ± 5.1%, p < 0.05). These results demonstrated that PACAP exerted a protective effect by suppressing inflammation and oxidative stress in acute epididymitis, thereby preserving epididymal function and sperm quality. PACAP may represent a potential therapeutic agent for epididymitis and related fertility issues.