title: Reproductive abnormalities in human insulin-like growth factor-binding protein-1 transgenic male mice.
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.
authors.affiliation: Physiologie 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.
authors.forename: Pascal
authors.initials: P
authors.lastname: Froment
authors.forename: Christophe
authors.initials: C
authors.lastname: Staub
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Hembert
authors.forename: Claudine
authors.initials: C
authors.lastname: Pisselet
authors.forename: Michèle
authors.initials: M
authors.lastname: Magistrini
authors.forename: Bernadette
authors.initials: B
authors.lastname: Delaleu
authors.forename: Danielle
authors.initials: D
authors.lastname: Seurin
authors.forename: Jon E
authors.initials: JE
authors.lastname: Levine
authors.forename: Larry
authors.initials: L
authors.lastname: Johnson
authors.forename: Michel
authors.initials: M
authors.lastname: Binoux
authors.forename: Philippe
authors.initials: P
authors.lastname: Monget
mesh_terms: D000728:Androgens / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis; D005260:Female; D005298:Fertility; D006801:Humans; D007248:Infertility, Male / Q000209:etiology* / Q000503:physiopathology; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010902:Pituitary Gland / Q000503:physiopathology; D011247:Pregnancy; D013090:Spermatocytes; D013091:Spermatogenesis; D013739:Testosterone / Q000096:biosynthesis
chemical_list: D000728:Androgens; D018970:Insulin-Like Growth Factor Binding Protein 1; D013739:Testosterone; D007334:Insulin-Like Growth Factor I