Expression and regulation of human sex hormone-binding globulin transgenesin mice during development

Human sex hormone-binding globulin (SHBG) is produced by hepatocytes and tr ansports sex steroids in the blood. The rat gene encoding SHBG is expressed transiently in the liver during fetal Life, but it is not expressed in the liver postnatally, and the small amounts of SHBG in rat blood are derived from gonadal sources. To study the biosynthesis and function of human SHBG in an in vivo context, we have produced several lines of transgenic mice th at contain either 11 kb (shbg11) or 4.3 kb (shbg4) portions of the human sh bg locus. The expression and regulation of these transgenes have now been s tudied during fetal and postnatal development. In situ hybridization of an shbg11 transgenic mouse fetus at 17.5 days postcoitus located human shbg tr anscripts only in duodenal epithelial cells and hepatocytes. Temporal diffe rences in the hepatic expression of mouse shbg and human shbg transgenes du ring late fetal development were reflected in corresponding differences in mouse and human SHBG levels in fetal and neonatal mouse blood. Serum concen trations of human SHBG increased during the first weeks of Life regardless of gender until about 20 days of age in shbg11 mice, but after this time th ey continued to increase only in the males. This sexual dimorphism was refl ected in corresponding differences in human SHBG messenger RNA (mRNA) abund ance in the livers of these animals. However, it was not observed in shbg4 mice, in which hepatic production of plasma SHBG continued to increase afte r puberty regardless of gender. Serum testosterone and SHBG levels correlat ed in all sexually mature shbg transgenic mice. Human shbg transcripts were detectable only in testes of shbg11 mice and increased progressively in ab undance from 10 days of age until the animal reached sexual maturity at 30 days of age, with appreciable increases occurring well before any changes i n serum testosterone concentration. In the kidney, SHBG mRNA levels accumul ated earlier in shbg11 than in shbg4 mice, and the expression of both types of transgenes was sexually dimorphic, with much higher SHBG mRNA levels in the kidneys of male mice. As increases in SHBG mRNA in the male kidneys co incided with increases in serum testosterone during sexual maturation, we r easoned that shbg transgene expression is androgen dependent in the kidney. This was confirmed by demonstrating that a decrease in SHBG mRNA abundance in male mouse kidneys after castration could be reversed by 5 alpha-dihydr otestosterone treatment. Moreover, exogenous androgen increased human SHBG mRNA levels in the kidneys of female mice. In summary, comparisons of how d ifferent human shbg transgenes are expressed in vivo provides information a bout the positions of potential regulatory sequences that may control the h ormonal regulation and tissue-specific expression of this gene during devel opment.