Gpr54−/− mice show more pronounced defects in spermatogenesis than Kiss1−/− mice and improved spermatogenesis with age when exposed to dietary phytoestrogens

Abstract

Mice with mutations in the kisspeptin signaling pathway (Kiss1 K/K or Gpr54) have low gonadotrophic hormone levels, small testes, and impaired spermatogenesis. Between 2 and 7 months of age, however, the testes of the mutant mice increase in weight and in Gpr54 K/K mice, the number of seminiferous tubules containing spermatids/spermatozoa increases from 17 to 78%. In contrast, the Kiss1 K/K mice have a less severe defect in spermatogenesis and larger testes than Gpr54 K/K mice at both 2 and 7 months of age. The reason for the improved spermatogenesis was investigated. Plasma testosterone and FSH levels did not increase with age in the mutant mice and remained much lower than in wild-type (WT) mice. In contrast, intratesticular testosterone levels were similar between mutant and WT mice. These data indicate that age-related spermatogenesis can be completed under conditions of low plasma testosterone and FSH and that intratesticular testosterone may contribute to this process. In addition, however, when the Gpr54 K/K mice were fed a phytoestrogen-free diet, they showed no age-related increase in testes weight or improved spermatogenesis. Thus, both genetic and environmental factors are involved in the improved spermatogenesis in the mutant mice as they age although the mice still remain infertile. These data show that the possible impact of dietary phytoestrogens should be taken into account when studying the phenotype of mutant mice with defects in the reproductive axis.

Visualisation of Kiss1 Neurone Distribution Using a Kiss1‐CRE Transgenic Mouse

“…Around 4-5 months of age, however, condensed sperm heads were found in mutant mice, indicating an increased level of spermiogenesis in older males. We have observed a similar increase previously in Kiss1 KO mice, which we have shown to be a result of exposure to phyto-oestrogens in the mouse chow (16).…”

Does Kisspeptin Signaling have a Role in the Testes?

“…It might be possible to initiate spermatogenesis in the mutant mice with pulsatile FSH and subcutaneous testosterone delivery. Although we have shown that Kiss1 and Gpr54 mutant mice can initiate a low level of spermatogenesis when given a chow diet containing phytoestrogens (23), the number of sperm that can be isolated from the vas deferens and epididymis is too small for functional studies. It is noteworthy, however, that several male patients with mutations in GPR54 and hypogonadotropic hypogonadism have responded to exogenous hormone treatment and achieved fertility [for review, see Ref.…”

The Blood-Testis Barrier and Its Implications for Male Contraception

“…In addition, mice with mutations in the kisspeptin signaling pathway [e.g., Kiss1(Ϫ/Ϫ) or Gpr54(Ϫ/Ϫ) mice; kisspeptins are a family of peptide hormones that, together with the kisspeptin receptor (previously known as G-protein-coupled receptor 54), play a critical role in the regulation of the hypothalamic-pituitary-testicular axis, such as in the release of 1) gonadotropin-releasing hormone from the hypothalamus and 2) LH and FSH from the pituitary gland (d'Anglemont de Tassigny and Colledge, 2010;Hameed et al, 2011)] were found to have smaller testes and impaired spermatogenesis versus wild-type animals, lacking spermatids in the epithelium as the result of postmeiotic defects. On the other hand, diets supplemented with phytoestrogens (e.g., genistein and daidzein from soy/soybeans) were shown to have a significant improvement in spermatogenesis over a 7-month period with regard to testis weight and the number of elongated spermatids and spermatozoa (Mei et al, 2011). In summary, these findings illustrate that estrogens support somatic cells in the testis and the epididymis, as well as regulate germ cell apoptosis and spermiogenesis, in particular the transition of spermatocytes into round spermatids (Carreau and Hess, 2010;.…”