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.

中文翻译：

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囊性纤维化大鼠非阻塞性输精管和附睾丢失

本研究利用形态学和机械学终点来表征最近衍生的囊性纤维化 (CF) 大鼠模型中输精管双侧闭锁的发生。胚胎生殖结构，包括 Wolffian（中肾）管、Mullerian（副中肾）管、中肾小管和性腺，在胚胎发育晚期显示正常成熟，输精管和/或附睾退化通常发生在出生和出生后第 4 天之间(P4)，尽管闭锁的时间和程度各不相同。在任何胚胎学或出生后时间点均未观察到与其他 CF 影响组织的病理学相关的粘液阻塞的证据。产后注意到附睾卷曲减少，并且似乎与更远端输精管结构的丢失同时发生或早于丢失。值得注意的是，与野生型对应物相比，CF 动物中导管上皮周围细胞中的 α 平滑肌肌动蛋白表达显着减少 P2.5，表明肌肉发育减少。受影响组织的 RNA-seq 和免疫组织化学分析表明 Wnt 和相关通路破坏了发育信号。这些发现与 CF 患者的输精管丢失有关，其中输精管损伤的时间没有很好地表征，潜在的机制也不清楚。如果人类输精管闭锁在妊娠晚期开始并持续到出生后早期，围产期给予的新兴调节剂疗法可能会保持和增强生殖道的完整性，否则 97% 的囊性纤维化男性不存在或缺乏生殖道。