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Submitted on July 29, 2003
Accepted on December 29, 2003
Physiologie de la Reproduction et des Comportements, UMR 6073 INRA-CNRS-Université F. Rabelais de Tours, 37380 Nouzilly, France; Department of Veterinary Anatomy & Public Health, Texas A & M University, College Station, Texas, 77843-4458, USA; Institut National de la Santé et de la Recherche Médicale, Unité 515, Croissance, différenciation et processus tumoraux, Hôpital Saint-Antoine, 75571 PARIS Cedex 12, France; Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208, USA.
* To whom correspondence should be addressed. E-mail: monget{at}tours.inra.fr.
Adult transgenic mice overexpressing human-IGFBP-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 an irregular copulatory behavior, 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 vesicles 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 the 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 2-cells eggs (P = 0.002) and of implanted embryos at day 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 3
-HSD 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), suggestive of an alteration of LH pulsatile secretion in vivo. In conclusion, these data suggest that the breeding impairment of hIGFBP-1 transgenic males is due at least in part to an alteration of the process of spermatogenesis, leading to a diminution of the sperm production and of its quality. Minor impairment of steroidogenesis may also contribute the reduced reproductive capacity of these animals. Our observations are consistent with idea that normal spermatogenesis and perhaps also steroidogenesis are dependent upon the actions of sufficient concentrations of unbound IGF1.
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