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Reproductive abnormalities in human insulin-like growth factor-binding protein-1 transgenic male mice
Pascal Froment1, Christophe Staub, Stéphanie Hembert
1Physiologie de la Reproduction et des Comportements, Unité Mixte de Recherche 6073, Institut National de la Recherche Agronomique-Centre National de la Recherche Scientifique-Université F. Rabelais de Tours, 37380 Nouzilly, France.
Abstract:
Adult transgenic mice overexpressing human insulin-like growth factor-binding protein-1 in the liver present reproductive abnormalities in both sexes. In the present work, we have investigated the mechanisms responsible for limiting breeding capacity in these transgenic male mice. Homozygous adult transgenic male mice (3-6 months old) exhibited irregular copulatory behavior and a reduction of the number of pregnancies per female as well as of litter size per pregnancy. Genital tract weight, more specifically epididymal and seminal vesicle weights, were reduced by 45% in homozygous transgenic vs. nontransgenic mice. Homozygous transgenic mice exhibited a 30% reduction of the length of seminiferous tubules (P = 0.007), a 30% decrease in daily sperm production per testis (P = 0.019), and a 50% decrease in the number of spermatozoa in testis (P = 0.037), associated with morphological abnormalities of the sperm heads leading to an approximately 50% reduction of fertilized two-cell eggs (P = 0.002) and of implanted embryos on d 5.5 after mating (P = 0.004). The round spermatids also appeared altered in their morphology. In addition, Leydig cells in homozygous transgenic mice exhibited an altered appearance, with a 1.8-fold increase in lipid droplets in their cytoplasm (P < 0.001). Moreover, the concentration of 3beta-hydroxysteroid dehydrogenase was 66% lower in testis from transgenics compared with those from normal mice (P = 0.01), leading to a tendency toward lower plasma testosterone levels (P = 0.1). Interestingly, LH concentrations were increased by 40% in transgenic pituitary extracts (P = 0.02), and basal LH secretion by pituitary explants in vitro was increased by 60% in homozygous transgenic vs. normal mice (P = 0.04), suggesting an alteration of LH pulsatile secretion in vivo. In conclusion, these data suggest that the breeding impairment of human insulin-like growth factor-binding protein-1 transgenic males is due at least in part to an alteration of the process of spermatogenesis, leading to a diminution of sperm production and of its quality. Minor impairment of steroidogenesis may also contribute to the reduced reproductive capacity of these animals. Our observations are consistent with the idea that normal spermatogenesis and perhaps also steroidogenesis are dependent on the actions of sufficient concentrations of unbound IGF-I.
Insights
Transgenic male mice overexpressing human insulin-like growth factor-binding protein-1 exhibit impaired fertility due to reduced sperm production and quality. Leydig cell alterations and potential changes in luteinizing hormone secretion also contribute to reproductive issues.
Area of Science:
- Reproductive Biology
- Endocrinology
- Genetics
Background:
- Overexpression of human insulin-like growth factor-binding protein-1 (IGF-BP1) in the liver of adult transgenic mice leads to reproductive abnormalities in both sexes.
- This study focuses on elucidating the mechanisms behind the reduced breeding capacity observed in male transgenic mice.
Purpose of the Study:
- To investigate the causes of impaired fertility in male mice overexpressing hepatic human IGF-BP1.
- To determine the impact of IGF-BP1 overexpression on male reproductive organs, sperm production, and steroidogenesis.
Main Methods:
- Comparison of reproductive parameters, genital tract weights, and sperm production between homozygous transgenic and non-transgenic male mice.
- Histological examination of seminiferous tubules and Leydig cells, including assessment of sperm morphology and fertilization rates.
- Measurement of pituitary luteinizing hormone (LH) concentrations and Leydig cell steroidogenic enzyme activity (3beta-hydroxysteroid dehydrogenase).
Main Results:
- Transgenic males showed reduced genital tract weights, decreased seminiferous tubule length, and significantly lower daily sperm production and sperm counts.
- Sperm morphology was abnormal, leading to reduced fertilization rates and embryo implantation.
- Leydig cells displayed increased lipid droplets, decreased 3beta-hydroxysteroid dehydrogenase activity, and a tendency towards lower testosterone levels.
- Pituitary LH concentrations and basal LH secretion were elevated, suggesting altered LH pulsatile secretion.
Conclusions:
- Impaired spermatogenesis, resulting in diminished sperm quantity and quality, is a primary cause of reduced fertility in these transgenic males.
- Minor impairment of steroidogenesis and altered LH secretion may also contribute to the reproductive deficit.
- These findings highlight the dependence of normal spermatogenesis and steroidogenesis on adequate levels of unbound insulin-like growth factor-I (IGF-I).
