Slc26a3 deficiency is associated with epididymis dysplasia and impaired sperm fertilization potential in the mouse

Abstract

Members of the solute carrier 26 (SLC26) family have emerged as important players in mediating anions fluxes across the plasma membrane of epithelial cells, in cooperation with the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Among them, SLC26A3 acts as a chloride/bicarbonate exchanger, highly expressed in the gastrointestinal, pancreatic and renal tissues. In humans, mutations in the SLC26A3 gene were shown to induce congenital chloride-losing diarrhea (CLD), a rare autosomal recessive disorder characterized by life-long secretory diarrhea. In view of some reports indicating subfertility in some male CLD patients together with SLC26-A3 and -A6 expression in the male genital tract and sperm cells, we analyzed the male reproductive parameters and functions of SLC26A3 deficient mice, which were previously reported to display CLD gastro-intestinal features. We show that in contrast to Slc26a6, deletion of Slc26a3 is associated with severe lesions and abnormal cytoarchitecture of the epididymis, together with sperm quantitative, morphological and functional defects, which altogether compromised male fertility. Overall, our work provides new insight into the pathophysiological mechanisms that may alter the reproductive functions and lead to male subfertility in CLD patients, with a phenotype reminiscent of that induced by CFTR deficiency in the male genital tract.

Capacitation-associated alkalization in human sperm is differentially controlled at the subcellular level

“…In this regard, HCO 3 − transporters from the SLC4 (NBC) family, such as the electroneutral Na + -driven Cl − /HCO 3 − exchanger, NDCBE (SLC4A8) and NBCn2 (SLC4A10) have been detected in human testis, albeit only at the transcriptional level (Damkier et al, 2007;Pushkin et al, 2000) but the protein has not been immunolocalized. Additionally, other proteins related to HCO 3 − transport have been found in mammalian sperm, such as the SLC26 family members SLC26A3 and SLC26A6 (Chávez et al, 2012;El Khouri et al, 2018), as well as SLC26A8 (Touré et al, 2007). Carbonic anhydrase activity has also been detected in human sperm (José et al, 2015;Wandernoth et al, 2010).…”

“…On the other hand, our group and others have described the expression and participation of an additional set of proteins during mammalian sperm capacitation, which are related to HCO 3 − transport and thus could also potentially participate in pH i balance. These proteins include members of the SLC26 (Chávez et al, 2012;El Khouri et al, 2018) and SLC4 (Demarco et al, 2003;Parkkila et al, 1993;Puga Molina et al, 2018;Zeng et al, 1996) HCO 3 − transporter families. An unidentified member of the SLC4 family, namely the electrogenic Na + /HCO 3 − cotransporter (NBC), appears to mediate HCO 3 − influx, which is required for downstream activation of signaling networks essential for capacitation, such as the cAMP-activated protein kinase (protein kinase A, PKA) pathway (Demarco et al, 2003;Puga Molina et al, 2018).…”

Genetics of the congenital absence of the vas deferens

“…This activation is suppressed by a missense mutation in the STAT domain, the frequency of which is significantly increased in infertile men of Finnish origin (Wedenoja et al 2017). In addition, in male SLC26A3 −/− mice, fertility is reduced mainly due to severe disorganization of epididymal cytoarchitecture (El Khouri et al 2018).…”

Importance of SLC26 Transmembrane Anion Exchangers in Sperm Post-testicular Maturation and Fertilization Potential

“…All the above phenotypes are in line with the nearly restricted tissue expression profiles observed for most of SLC26 genes. Notably, mutant mouse models have been generated for all SLC26 members, and all reproduced the clinical features of the SLC26 human-related diseases when applicable (Liberman et al, 2002; Forlino et al, 2005; Schweinfest et al, 2006; Touré et al, 2007; Dallos et al, 2008; Dror et al, 2010; El Khouri et al, 2018). In addition, studies of members not so far associated with human diseases (SLC26A7 and A11) revealed their functions in various tissues such as kidney, gastro intestinal tract, enamel, vestibular membrane of the cochlea, and brain (Xu et al, 2009; Rahmati et al, 2013, 2016; Kim et al, 2014; Yin et al, 2017), predicting that further investigations might lead to the identification of novel SLC26 gene mutations associated with pathophysiological conditions in humans (Table 1).…”

“…Last year, El Khouri et al (2018) investigated in vivo , the function of SLC26A3 and SLC26A6 proteins, in sperm functionality by analyzing ubiquitous knock out mouse models previously generated to study their functions in the gastrointestinal system (Singh et al, 2010; Xiao et al, 2012). They showed that in addition to the previously reported phenotype of congenital diarrhea (Xiao et al, 2012; Singh et al, 2013), SLC26A3−null mice displayed severe lesions and abnormal cytoarchitecture of the cauda epididymis, which strongly impacted the reserve of sperm cells in epididymides (El Khouri et al, 2018). This phenotype is in line with the subfertility previously observed for a few CLD affected men (Hoglund et al, 2006).…”