Dataset Information

Effects of Recombinant Human Growth Hormone on the Onset of Puberty, Leydig Cell Differentiation, Spermatogenesis and Hypothalamic KISS1 Expression in Immature Male Rats.

ABSTRACT:

Purpose

Recombinant human growth hormone (rhGH) has been used to treat short stature and rhGH-related syndromes. However, there are concerns that rhGH-treatment may cause precocious puberty. We investigated the effects of rhGH-treatment on the puberty onset, sexual maturation, androgen production, and hypothalamic gene expression in prepubertal male rats.

Materials and methods

Sprague-Dawley male rats were injected subcutaneously daily with 1 or 2 IU/kg/d rhGH or 0.1 mL saline from postnatal day (PND) 21 to 30. At PND 31 bodyweight, reproductive organs weight, preputial separation, testis histology, circulating testosterone, and expression of testicular steroidogenic pathway genes and hypothalamic Kiss1 were examined.

Results

By day 4 of injection bodyweights of rhGH groups were significantly higher than those of controls. rhGH 2 IU group showed earlier preputial separation compared to the control group. At PND 31, the weights of testes, epididymides, seminal vesicles, prostates, and preputial glands of the 2 IU-rhGH group were significantly higher than control group. Serum testosterone levels of the 2 IU-rhGH group were significantly higher than control group. Testicular steroidogenic pathway gene Hsd17b3 and Nr5a1 mRNA and cell counts and areas of Leydig cells in rhGH groups were significantly higher than control group, suggesting functional differentiation of Leydig cells. Hypothalamic Kiss1 mRNA levels of the 1 IU-rhGH group were significantly lower than control group, suggesting negative feedback of Kiss1 by elevated testosterone.

Conclusions

Prepubertal rhGH-treatment in male rats may induce early onset of puberty, sexual maturation, elevation of testosterone, and spermatogenesis, and accompanies downregulation of hypothalamic KISS1.

SUBMITTER: Huh K

PROVIDER: S-EPMC7994663 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: The timing of puberty is highly sensitive to environmental factors, including endocrine disruptors. Among them, bisphenol A (BPA) has been previously analyzed as potential modifier of puberty. Yet, disparate results have been reported, with BPA advancing, delaying, or being neutral in its effects on puberty onset. Likewise, mechanistic analyses addressing the central and peripheral actions/targets of BPA at puberty remain incomplete and conflictive.Objective: We aimed to provide a comprehensive characterization of the impact of early BPA exposures, especially at low, real-life doses, on the postnatal development of hypothalamic Kiss1/NKB neurons, and its functional consequences on female pubertal maturation.Methods: Pregnant CD1 female mice were orally administered BPA at 5, 10, or 40μg/kg body weight (BW)/d from gestational day 11 to postnatal day 8 (PND8). Vaginal opening, as an external marker of puberty onset, was monitored daily from PND19 to PND30 in the female offspring. Blood and brain samples were collected at PND12, 15, 18, 21, and 30 for measuring circulating levels of gonadotropins and analyzing the hypothalamic expression of Kiss1/kisspeptin and NKB.Results: Perinatal exposure to BPA, in a range of doses largely below the no observed adverse effect level (NOAEL; 5mg/kg BW/d, according to the FDA), was associated with pubertal differences in the female progeny compared with those exposed to vehicle alone, with an earlier age of vaginal opening but consistently lower levels of circulating luteinizing hormone. Mice treated with BPA exhibited a persistent, but divergent, impairment of Kiss1 neuronal maturation, with more kisspeptin cells in the rostral (RP3V) hypothalamus but consistently fewer kisspeptin neurons in the arcuate nucleus (ARC). Detailed quantitative analysis of the ARC population, essential for pubertal development, revealed that mice treated with BPA had persistently lower Kiss1 expression during (pre)pubertal maturation, which was associated with lower Tac2 (encoding NKB) levels, even at low doses (5μg/kg BW/d), in the range of the tolerable daily intake (TDI), recently updated by the European Food Safety Authority.Conclusions: Our data attest to the consistent, but divergent, effects of gestational exposures to low concentrations of BPA, via the oral route, on phenotypic and neuroendocrine markers of puberty in female mice, with an unambiguous impact on the developmental maturation not only of Kiss1, but also of the NKB system, both essential regulators of puberty onset. https://doi.org/10.1289/EHP5570.