Regulation of male fertility by CFTR and implications in male infertility

Background: The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated Cl.-and HCO.3-conducting channel, mutations of which are known to be associated with male infertility. However, the underlying mechanisms remain elusive. Methods: Literature databases were searched for papers on the topics related to CFTR and male fertility and infertility with relevant keywords. Unpublished data from authors' laboratory were also included for analysis. Results: Clinical evidence shows increased mutation frequency or reduced CFTR expression in men with congenital bilateral absence of vas deferens (CBAVD) or sperm abnormalities, such as azoospermia teratospermia and oligoasthenospermia. Studies on primary rodent Sertoli cells and germ cells, as well as testes from CFTR knockout mice or a cryptorchidism model, yield findings indicating the involvement of CFTR in spermatogensis through the HCO.3-/sAC/cAMP/CREB(CREM) pathway and the NF-κB/COX-2/PGE.2pathway. Evidence also reveals a critical role of CFTR in sperm capacitation by directly or indirectly mediating HCO.3-entry that is essential for capacitation. CFTR is emerging as a versatile player with roles in mediating different signaling pathways pertinent to various reproductive processes, in addition to its long-recognized role in electrolyte and fluid transport that regulates the luminal microenvironment of the male reproductive tract. CONCLUSIONS: CFTR is a key regulator of male fertility, a defect of which may result in different forms of male infertility other than CBAVD. It would be worthwhile to further investigate the potential of developing novel diagnostic and contraceptive methods targeting CFTR.