Evidence for pituitary regulation of somatic growth, insulin-like growth factors-I and -II, and their binding proteins in the fetal rat.

Top of pageAbstract ABSTRACT: We investigated pituitary regulation of late-gestation fetal growth in the spontaneous dwarf rat, a strain with an autosomal recessive mutation (gene symbol dr) in the growth hormone (GH) gene resulting in complete isolated GH deficiency. GH-normal/GH-deficient (Dr/dr) females were crossed with Dr/dr or dr/dr males, producing both GH-deficient and GH-normal fetuses within the same litter. Pups were killed within 3 h after birth to approximate the developmental state of a late-gestation fetus. The body weight of GH-deficient fetuses was inhibited by 14% in comparison to GH-normal animals, but tail length remained unaffected. The brain and lungs were the only organs whose growth appeared to be pituitary-independent. Other organs showed moderate pituitary dependence in proportion to body weight. Serum IGF-I and IGF-II were reduced by 73% and 52%, respectively, in the absence of GH. The major IGF-binding proteins (IGFBP) were analyzed by Western ligand blot. The predominant 26- to 30-kD IGFBP band normally seen in neonatal rat serum was greatly increased in GH-deficient sera, to 250% of GH-normal sera as measured by densitometry. However, addition of α-Hec 1 antibody to IGFBP-2, which has been used to identify IGFBP-2 as the major neonatal IGFBP, resulted in immunoprecipitation of only a small amount of the 26- to 30-kD band from the GH-deficient fetuses, suggesting the presence of an additional IGFBP. Northern analysis of GH-deficient livers did not reveal any visible increase in IGFBP-1, IGFBP-2, or IGFBP-4 mRNA. We conclude that pituitary GH exerts a modest, but significant, selective effect on fetal body weight and organ growth. Serum levels of both IGF-I and IGF-II, as well as their binding proteins, were shown to be pituitary-GH–dependent in the fetal period. The increase of low-molecular-weight binding proteins in the GH-deficient fetus, which we were unable to attribute to IGFBP-1, -2, -3, or -4, may indicate the presence of unique fetal binding protein(s). The spontaneous dwarf rat may be an important model for further investigation of the development of pituitary dependence in fetal growth.