Murine Inhibin α-Subunit Haploinsufficiency Causes Transient Abnormalities in Prepubertal Testis Development Followed by Adult Testicular Decline

Abstract

Activin production and signaling must be strictly regulated for normal testis development and function. Inhibins are potent activin inhibitors; mice lacking the inhibin-α gene (Inha-/- mice) cannot make inhibin and consequently have highly elevated activin and FSH serum concentrations and excessive activin signaling, resulting in somatic gonadal tumors and infertility. Dose-dependent effects of activin in testicular biology have been widely reported; hence, we hypothesized that male mice lacking one copy of the Inha gene would produce less inhibin and have an abnormal reproductive phenotype. To test this, we compared hormone concentrations, testis development, and sperm production in Inha+/+ and Inha+/- mice. Serum and testicular inhibin-α concentrations in adult Inha+/- mice were approximately 33% lower than wild type, whereas activin A, activin B, FSH, LH, and T were normal. Sixteen-day-old Inha+/- mice had a mixed phenotype, with tubules containing extensive germ cell depletion juxtaposed to tubules with advanced Sertoli and germ cell development. This abnormal phenotype resolved by day 28. By 8 weeks, Inha+/- testes were 11% larger than wild type and supported 44% greater daily sperm production. By 26 weeks of age, Inha+/- testes had distinct abnormalities. Although still fertile, Inha+/- mice had a 27% reduction in spermatogenic efficiency, a greater proportion of S-phase Sertoli cells and lower Leydig cell CYP11A1 expression. This study is the first to identify an intratesticular role for inhibin/inhibin-α subunit, demonstrating that a threshold level of this protein is required for normal testis development and to sustain adult somatic testicular cell function.

4-Nonylphenol induces disruption of spermatogenesis associated with oxidative stress-related apoptosis by targeting p53-Bcl-2/Bax-Fas/FasL signaling

“…In contrast, decreases in Ki67 and PCNA1 expression in testicular germ cells indicate a reduction in proliferative activity and spermatogenesis. Hormonal balance can be severely influenced by testicular germ cell apoptosis, specifically by LG and SC (Aksglaede et al, ; Itman et al, ). The absence of LG and SC secretory function is detrimental to spermatogenesis and spermatozoa (Itman et al, ).…”

“…Hormonal balance can be severely influenced by testicular germ cell apoptosis, specifically by LG and SC (Aksglaede et al, ; Itman et al, ). The absence of LG and SC secretory function is detrimental to spermatogenesis and spermatozoa (Itman et al, ). Thus, we speculate that NP‐induced toxicity in male reproduction probably depends on an imbalance between proliferation and apoptotic cell death in testis.…”

Prenatal and lactation nicotine exposure affects Sertoli cell and gonadotropin levels in rats

“…The gonadal-derived inhibin A and B are essential factors in mammalian reproduction, negatively regulating pituitary production of FSH (Walton et al 2015). Changes exhibited by chronic inhibin insufficiency on Sertoli and Leydig cells reflect impairment of: i) functionality of the testicular somatic environment; ii) their compromised capacity to support complete, ongoing spermatogenesis; and iii) daily sperm production and can cause testicular abnormalities, without affecting hormone concentrations (Itman et al 2015). It is possible that a similar situation occurred in the present research, through the nicotine exposure.…”

Antagonistic regulation of spermatogonial differentiation in zebrafish (Danio rerio) by Igf3 and Amh

“…Recent work in mammals identified an intratesticular role for Inhibin in balancing Activin signaling, which stimulates Sertoli cell proliferation and regulates the integrity of the blood-testis barrier (Itman et al, 2015;Nicholls et al, 2012). Therefore, it is possible that Inhibin may mediate inhibitory effects of Amh also in zebrafish spermatogenesis by reducing Sertoli cell proliferation.…”