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Departments of Obstetrics and Gynecology, Oncology, Biochemistry, Pharmacology, and Toxicology Medical Research Council Group in Fetal and Neonatal Health and Development University of Western Ontario and London Regional Cancer Center London, Ontario, Canada N6A 4L6
The sex hormone-binding globulin gene
(shbg) is expressed in the liver and testis as well as in
several other tissues that play important roles in reproduction.
Expression of shbg in the human liver results in the
production of plasma sex hormone-binding globulin (SHBG), which
regulates the bioavailability of sex steroids in the blood. Although
shbg is not expressed in rodent livers postnatally, it
gives rise to the androgen-binding protein in their testes upon sexual
maturation. Human shbg is also expressed in the testis, but
its products and their function are less well characterized. To study
the expression of human shbg in different tissues and the
consequences of overexpressing this gene in vivo, we have
produced several lines of mice containing 
11-kilobase (kb;
shbg11) or 4.3-kb (shbg4) human
shbg genomic fragments that comprise all eight exons
encoding SHBG as well as 6 kb or 0.9 kb of 5'-flanking DNA,
respectively. Northern blots indicated that human shbg
transcripts were most abundant in liver, kidney, and testis of the
shbg11 mice. The 4.3-kb shbg transgenes were
expressed at similar levels in liver and kidney, but the abundance of
human shbg transcripts in their testes was much lower than
that in shbg11 mice. Primer extension analysis indicated
that transcription starts 60 bp from the translation initiation codon
for SHBG in liver and kidney of shbg11 mice, and that the
shbg transcripts in their testis are derived from a
separate promoter flanking an alternative exon that replaces the exon
containing the translation initiation codon for SHBG or
androgen-binding protein. At the cellular level, the human
shbg transgenes are expressed in clusters of hepatocytes
located mainly within the periportal region of hepatic lobules and in
the epithelial cells lining the proximal convoluted tubules of the
kidney. This results in high levels of human SHBG in serum (1.45–1.72
nmol/ml) and urine (6–16 pmol/ml) of mature male shbg
mice. The abundance and distribution of human shbg
transcripts in the Sertoli cells of shbg11 mice vary
throughout the spermatogenic cycle, with levels increasing in the
Sertoli cell cytoplasm until stage VII of spermatogenesis and declining
after stage IX. At stages X–XII of spermatogenesis, these transcripts
concentrate at the adluminal compartment of the Sertoli cells, and this
suggests that they have a role in the elongation phase of
spermiogenesis. The presence of human SHBG in the blood of
shbg transgenic mice may result in serum levels of
testosterone that are 10–100 times higher than those in wild-type
littermates. Despite this, their reproductive performance is normal,
and there is no obvious phenotypic abnormalities even in animals
homozygous for the transgenes.
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