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.
The mechanisms responsible for reproductive abnormalities in transgenic female mice overexpressing human IGF binding protein-1 (IGFBP-1) in the liver have been investigated. At 2 months of age, none of these transgenic mice exhibited ovarian cyclicity. Genital tract and ovary tissue weights were reduced in transgenic mice, this weight reduction being disproportionate with the reduction of body weight. Examination of ovarian follicular population revealed a marked decrease in the number of corpora lutea and gonadotropin-dependent follicles, suggesting an alteration of terminal follicular growth and ovulation. Stimulation of ovaries by exogenous gonadotropins revealed that ovaries from transgenic mice ovulated less oocytes than nontransgenic mice. This lower responsiveness of ovaries from transgenic mice to gonadotropins was not associated with a decrease in FSH-, LH- or IGF-I receptor expression. Transgenic and nontransgenic mice have similar circulating LH and FSH concentrations at dioestrus, after castration, 46 h after equine CG administration, or 15 min after GnRH injection. However, LH concentrations were 8-fold higher in pituitaries from transgenic vs. nontransgenic mice. Moreover, the size of LH-immunoreactive cells was reduced and their number was increased, suggesting a subtle alteration of LH secretion. Overall, these data indicate that reduced fertility in transgenic female mice overexpressing human IGFBP-1 are mainly due to an alteration of terminal follicular growth leading to a decrease in natural and induced ovulation rate, likely due to an impairment of IGF-I action on follicular cells. Increased circulating IGFBP-1 concentrations may additionally lead to altered GnRH and LH pulsatility and thereby exacerbate the ovulation defect.
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