Non-obstructive vas deferens and epididymis loss in cystic fibrosis rats

Plyler, Zackery E.; Birket, Susan E.; Schultz, Bruce D.; Hong, Jaemin; Rowe, Steven M.; Petty, Courtney Fernandez; Crowley, Michael R.; Crossman, David K.; Schoeb, Trenton R.; Sorscher, Eric J.

doi:10.1016/j.mod.2018.10.002

Cited by 10 publications

(8 citation statements)

References 49 publications

(62 reference statements)

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“…Several recent studies based on animal CF models ( CFTR−/− ) have invalidated the hypothesis of a process initiated by mucus accumulation. Therefore, neither in CF pigs (Pierucci-Alves et al 2011 ) nor in CF rats (Plyler et al 2019 ) were traces of PAS-positive mucosal plugs or signs of obstruction in the normally developing genital tract observed. On the other hand, in the recent study by Plyler et al, CFTR−/− neonatal rats showed significant structural alterations in some portions of the vas deferens and epididymal duct, including underdevelopment of the periductal smooth muscle and disorganization of the adjacent epithelium.…”

Section: Physiopathology: Atresia or Agenesis?mentioning

confidence: 99%

“…Degenerative lesions that gradually lead to VD atresia and then to their disappearance might occur mainly in prepubescent children, as shown by the first autopsy reports of CF children (Oppenheimer and Esterly 1969 ; Valman and France 1969 ). However, this first hypothesis implied that duct atrophy would be a direct result of lumen obstruction, which, so far, has never been proven either in fetuses or experimentally (Gaillard et al 1997 ; Plyler et al 2019 ). This pathogenesis remains speculative and is still based on an extrapolation of the pathophysiology of the CF pancreas.…”

Section: Physiopathology: Atresia or Agenesis?mentioning

confidence: 99%

“…On the other hand, in the recent study by Plyler et al, CFTR−/− neonatal rats showed significant structural alterations in some portions of the vas deferens and epididymal duct, including underdevelopment of the periductal smooth muscle and disorganization of the adjacent epithelium. These lesions progress rapidly after birth and, within a few days, lead to the underdevelopment of the epididymis and collapsed VDs which eventually disappear or become atretic in mature CFTR−/− rats (Plyler et al 2019 ).…”

Section: Physiopathology: Atresia or Agenesis?mentioning

confidence: 99%

“…The first evidence concerns the relationship with Wnt/β-catenin signaling pathway which is involved in WD differentiation (Carroll et al 2005 ). RNAseq and immunohistochemical analysis of male reproductive cord of newborn CFTR− / − rats showed that the expression of Wnt9b in the epididymis was strongly diminished or even undetectable compared to control neonates (Plyler et al 2019 ). Another evidence concerns the regulation of the tight junction (TJ) complexes that are essential for the integrity of epithelial cells and the formation of tubular structures.…”

Section: Physiopathology: Atresia or Agenesis?mentioning

confidence: 99%

“…5 . Moreover, endocrine (androgens and estrogens) and paracrine (lumicrine) factors are involved in these different pathophysiological process induced by CFTR, ADGRG2, or SLC9A3 dysfunction contributing in particular to the timing of the progressive deterioration of the reproductive tractus (Plyler et al 2019 ; Breton et al 2016 ).…”

Section: Physiopathology: Atresia or Agenesis?mentioning

confidence: 99%

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Genetics of the congenital absence of the vas deferens

2020

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Congenital absence of the vas deferens (CAVD) may have various clinical presentations depending on whether it is bilateral (CBAVD) or unilateral (CUAVD), complete or partial, and associated or not with other abnormalities of the male urogenital tract. CBAVD is usually discovered in adult men either during the systematic assessment of cystic fibrosis or other CFTR-related conditions, or during the exploration of isolated infertility with obstructive azoospermia. The prevalence of CAVDs in men is reported to be approximately 0.1%. However, this figure is probably underestimated, because unilateral forms of CAVD in asymptomatic fertile men are not usually diagnosed. The diagnosis of CAVDs is based on clinical, ultrasound, and sperm examinations. The majority of subjects with CAVD carry at least one cystic fibrosis-causing mutation that warrants CFTR testing and in case of a positive result, genetic counseling prior to conception. Approximately 2% of the cases of CAVD are hemizygous for a loss-of-function mutation in the ADGRG2 gene that may cause a familial form of X-linked infertility. However, despite this recent finding, 10-20% of CBAVDs and 60-70% of CUAVDs remain without a genetic diagnosis. An important proportion of these unexplained CAVDs coexist with a solitary kidney suggesting an early organogenesis disorder (Wolffian duct), unlike CAVDs related to CFTR or ADGRG2 mutations, which might be the result of progressive degeneration that begins later in fetal life and probably continues after birth. How the dysfunction of CFTR, ADGRG2, or other genes such as SLC29A3 leads to this involution is the subject of various pathophysiological hypotheses that are discussed in this review.

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Section: Physiopathology: Atresia or Agenesis?mentioning

confidence: 99%

Section: Physiopathology: Atresia or Agenesis?mentioning

confidence: 99%

Section: Physiopathology: Atresia or Agenesis?mentioning

confidence: 99%

Section: Physiopathology: Atresia or Agenesis?mentioning

confidence: 99%

Section: Physiopathology: Atresia or Agenesis?mentioning

confidence: 99%

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Genetics of the congenital absence of the vas deferens

2020

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Characterization of two rat models of cystic fibrosis—KO and F508del CFTR—Generated by Crispr‐Cas9

Dreano

Bacchetta

Simonin

et al. 2019

Anim Models and Exp Med

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BackgroundGenetically engineered animals are essential for gaining a proper understanding of the disease mechanisms of cystic fibrosis (CF). The rat is a relevant laboratory model for CF because of its zootechnical capacity, size, and airway characteristics, including the presence of submucosal glands.MethodsWe describe the generation of a CF rat model (F508del) homozygous for the p.Phe508del mutation in the transmembrane conductance regulator (Cftr) gene. This model was compared to new Cftr−/− rats (CFTR KO). Target organs in CF were examined by histological staining of tissue sections and tooth enamel was quantified by micro‐computed tomography. The activity of CFTR was evaluated by nasal potential difference (NPD) and short‐circuit current measurements. The effect of VX‐809 and VX‐770 was analyzed on nasal epithelial primary cell cultures from F508del rats.ResultsBoth newborn F508del and Knock out (KO) animals developed intestinal obstruction that could be partly compensated by special diet combined with an osmotic laxative. The two rat models exhibited CF phenotypic anomalies such as vas deferens agenesis and tooth enamel defects. Histology of the intestine, pancreas, liver, and lungs was normal. Absence of CFTR function in KO rats was confirmed ex vivo by short‐circuit current measurements on colon mucosae and in vivo by NPD, whereas residual CFTR activity was observed in F508del rats. Exposure of F508del CFTR nasal primary cultures to a combination of VX‐809 and VX‐770 improved CFTR‐mediated Cl− transport.ConclusionsThe F508del rats reproduce the phenotypes observed in CFTR KO animals and represent a novel resource to advance the development of CF therapeutics.

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The Adolescent or Young Adult with DSD

Hutson¹,

Grover²

2020

Disorders|Differences of Sex Development

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Non-obstructive vas deferens and epididymis loss in cystic fibrosis rats

Cited by 10 publications

References 49 publications

Genetics of the congenital absence of the vas deferens

Genetics of the congenital absence of the vas deferens

Characterization of two rat models of cystic fibrosis—KO and F508del CFTR—Generated by Crispr‐Cas9

The Adolescent or Young Adult with DSD

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