Male reproductive phenotype in cystic fibrosis: comparison of existing animal models

In men, cystic fibrosis (CF) leads to infertility in over 95% of cases, due to early and progressive atresia of the vas deferens, resulting in obstructive azoospermia. The advent of highly effective modulator therapy has enabled more men with CF to consider parenthood, raising important questions regarding the impact of these treatments on male fertility. Animal models provide major insights into the mechanism of CF-related reproductive tract abnormalities, yet high interspecies variability complicates model selection. Mouse models display heterogeneous phenotype: knock-in or partial knockout models usually remain fertile, whereas complete knockouts may develop vas deferens atresia with aging. Among currently studied models, CF transmembrane conductance regulator (CFTR)-knockout rats more closely reproduce the human phenotype, showing bilateral absence of the vas deferens and epididymal hypoplasia, although they exhibit more pronounced hypospermatogenesis than observed in men. In larger animal models, including ferrets, pigs, sheep and rabbits, absence of the vas deferens duct and epididymis is frequently observed, often with normal testicular histology; however, most studies in these species have mainly focused on neonatal stages, leaving long-term reproductive outcomes uncharacterized. No single model fully replicates human male reproductive pathology in CF. Combining rodent and large-animal models is probably essential to elucidate the mechanisms of vas deferens absence and to assess the long-term effects of CFTR modulators on male spermatogenesis and reproductive outcomes.