This study utilizes morphological and mechanistic endpoints to characterize the onset
of bilateral atresia of the vas deferens in a recently derived cystic fibrosis (CF)
rat model. Embryonic reproductive structures, including Wolffian (mesonephric) duct,
Mullerian (paramesonephric) duct, mesonephric tubules, and gonad, were shown to mature
normally through late embryogenesis, with involution of the vas deferens and/or epididymis
typically occurring between birth and postnatal day 4 (P4), although timing and degree
of atresia varied. No evidence of mucus obstruction, which is associated with pathology
in other CF-affected tissues, was observed at any embryological or postnatal time
point. Reduced epididymal coiling was noted post-partum and appeared to coincide with,
or predate, loss of more distal vas deferens structure. Remarkably, α smooth muscle
actin expression in cells surrounding duct epithelia was markedly diminished in CF
animals by P2.5 when compared to wild type counterparts, indicating reduced muscle
development. RNA-seq and immunohistochemical analysis of affected tissues showed disruption
of developmental signaling by Wnt and related pathways. The findings have relevance
to vas deferens loss in humans with CF, where timing of ductular damage is not well
characterized and underlying mechanisms are not understood. If vas deferens atresia
in humans begins in late gestation and continues through early postnatal life, emerging
modulator therapies given perinatally might preserve and enhance integrity of the
reproductive tract, which is otherwise absent or deficient in 97% of males with cystic
fibrosis.