Differential role of r-met-hu G-CSF on male reproductive function and development in prepubertal domestic mammals

Abstract

The understanding of mammalian spermatogenesis niche factors active during sexual development may be leveraged to impact reproduction in farm animals. The aim of this study was to evaluate the effects of r-met-hu/G-CSF (filgrastim) on prepubertal sexual development of guinea pigs (Cavia porcellus) and ram lambs (Ovis aries). Individuals of both species were administered r-met-hu/G-CSF daily for 4 days. During and after administration protocols, testicular function and development were assessed through hematological responses, hormonal profiles (gonadotropins, testosterone and cortisol) testicular morphometry and germ cell kinetics. As expected, r-met-hu/G-CSF acutely mobilized white-lineage blood cells in both species. LH was increased by r-met-hu/G-CSF in guinea pigs (P<0.01) but T remained unchanged. In ram lambs gonadotropins and T increased in dose-response fashion (P<0.01) while cortisol values were stable and similar in treated and control animals (P>0.05). In guinea pigs there were no differences in testicular weights and volumes 2-mo after r-met-hu/G-CSF application (P>0.05). However, ram lambs showed a dose-response effect regarding testis weight (P<0.05). 66.66% of ram lambs had initial testes not yet in meiosis or starting the first spermatogenic wave. After 60-days only 25% of control animals were pubertal while all treated animals (1140-μg) had reached puberty. We propose an integrated hypothesis that G-CSF can stimulate spermatogenesis through two possible ways. 1) r-met-hu/G-CSF may go through the brain blood barrier and once there it can stimulate GnRH-neurons to release GnRH with the subsequent release of gonadotrophins. 2) a local testicular effect through stimulation of steroidogenesis that enhances spermiogenesis via testosterone production and a direct stimulation over spermatogonial stem cells self-renewal. In conclusion, this study shows that r-met-hu/G-CSF differentially affects prepubertal sexual development in hystricomorpha and ovine species, a relevant fact to consider when designing methods to hasten sexual developmental in mammalian species.

Effect of Filgrastim on adult male rats’ fertility and reproductive performance

“…Thus, the seminal ROS level can be used as an indicator for male infertility ( Agarwal et al, 2006 , Muratoğlu et al, 2018 ). In the current study, suppression in the testosterone concentrations was observed in the Filgrastim-treated rats in comparison with the Control Group and this disagrees with Aponte et al (2019) that reported that the level of testosterone level was unaltered in Guinea pig and increased in ram lambs after administration with G-CSF. FSH and LH level in the two treated groups were significantly higher than in the Control Group.…”

“…FSH and LH level in the two treated groups were significantly higher than in the Control Group. A study by Aponte et al (2019) reported the elevation of LH level and unchangeable of FSH level in guinea pig while both FSH and LH are increment in ram lambs.…”

Filgrastim (r‐met‐hu G‐CSF) enhances the efficiency of spermatogenesis in prepubertal Bos indicus bulls

“…However, in this work, only a few r‐met‐hu G‐CSF‐treated animals had advanced‐to‐elongated spermatids at the end of experiments, suggesting that, although non‐conclusively, r‐met‐hu G‐CSF to some extent may increase the rate of GC differentiation in prepubertal bulls. Previously, our group found a faster progression of GCs during prepubertal development in rams treated with recombinant‐human‐G‐CSF but not in guinea pigs (Aponte et al., 2019), maybe because rams and bulls are ruminants sharing similar reproductive temporal windows in contrast to male guinea pigs, which achieve sexual maturity at approximately 2–3 months (Aponte et al., 2019). The fact that rams and Bos indicus bulls share similar testicular cell kinetics during the prepubertal period in response to the drug may indicate a higher specificity of the human‐targeted drug to ruminant testicular receptors.…”

“…However, we found non‐significant differences between the control and treated animals regarding blood parameters, probably due to the limited number of animals used or other unexplained reasons. Bone marrow mobilization occurs after r‐met‐hu G‐CSF administration in a laboratory (guinea pig, Cavia porcellus ) and a farm (rams, Ovis aries ) animal (Aponte et al., 2019).…”