EFFECTS OF BOVINE GROWTH-HORMONE (GH) EXPRESSION IN TRANSGENIC MICE ON SERUM AND PITUITARY IMMUNOREACTIVE MOUSE GH LEVELS AND PITUITARY GH-RELEASING FACTOR-BINDING SITES

Pituitary and serum levels of homologous growth hormone (GH) and chara cteristics of specific GH-releasing factor (GHRF) binding to pituitary homogenates were examined in transgenic mice expressing bovine GH (bG H) gene regulated by different promoters [mouse metallothionein-I (MT) or phosphoenol-pyruvate carboxykinase (PEPCK)] and in their normal li ttermates. Pituitary GH concentration and GHRF binding were reduced by approximately 50% in transgenic MT-bGH mice in which serum bGH levels were about 20 mug/l and by approximately 95% in transgenic PEPCK-bGH mice in which serum bGH levels were tenfold higher. Suppression of pla sma immunoreactive mouse GH (mGH) levels was detected in MT-bGH but no t in PEPCK-bGH animals. presumably due to cross-reaction of the antise rum employed with bGH. Scatchard plots of GHRF binding to washed homog enates of pituitary glands from normal and young adult MT-bGH transgen ic mice were curvilinear, indicating the presence of two types of bind ing sites, with low and high affinities. Both types of binding sites w ere reduced in number in MT-bGH transgenic mice without changes in the ir affinity. In 5-7-month-old MT-bGH transgenic mice there were change s in pituitary GH levels, in GHRF binding levels and in characteristic s of GHRF binding that closely resembled the alterations described pre viously in aging rats. We conclude that over-expression of heterologou s GH genes in transgenic mice can lead to partial or virtually complet e suppression of somatotroph function, depending on the levels of hete rologous GH in the circulation, and that transgenic MT-bGH mice exhibi t symptoms of remarkably early onset of neuroendocrine aging.