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Departments of Obstetrics and Gynecology, and Pharmacology and Toxicology, and the Medical Research Council Group in Fetal and Neonatal Health and Development, University of Western Ontario, London, Ontario, Canada N6A 4L6
Address all correspondence and requests for reprints to: Geoffrey L. Hammond, Ph.D., London Regional Cancer Center, 790 Commissioners Road East, London, Ontario, Canada N6A 4L6. E-mail: ghammond{at}julian.uwo.ca
Human sex hormone-binding globulin (SHBG) is produced by hepatocytes
and transports 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 that contain either 11
kb (shbg11) or 4.3 kb (shbg4) portions of
the human shbg locus. The expression and regulation of
these transgenes have now been studied during fetal and postnatal
development. In situ hybridization of an
shbg11 transgenic mouse fetus at 17.5 days postcoitus
located human shbg transcripts only in duodenal
epithelial cells and hepatocytes. Temporal differences in the hepatic
expression of mouse shbg and human shbg
transgenes during late fetal development were reflected in
corresponding differences in mouse and human SHBG levels in fetal and
neonatal mouse blood. Serum concentrations 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 they
continued to increase only in the males. This sexual dimorphism was
reflected in corresponding differences in human SHBG messenger RNA
(mRNA) abundance in the livers of these animals. However, it was not
observed in shbg4 mice, in which hepatic production of
plasma SHBG continued to increase after puberty regardless of gender.
Serum testosterone and SHBG levels correlated in all sexually mature
shbg transgenic mice. Human shbg
transcripts were detectable only in testes of shbg11
mice and increased progressively in abundance from 10 days of age until
the animal reached sexual maturity at 30 days of age, with appreciable
increases occurring well before any changes in serum testosterone
concentration. In the kidney, SHBG mRNA levels accumulated 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 coincided with increases in serum
testosterone during sexual maturation, we reasoned 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
-dihydrotestosterone treatment. Moreover, exogenous androgen
increased human SHBG mRNA levels in the kidneys of female mice. In
summary, comparisons of how different human shbg
transgenes are expressed in vivo provides information
about the positions of potential regulatory sequences that may control
the hormonal regulation and tissue-specific expression of this gene
during development.
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K.-M. Ng, M.-T. So, and W. M. Lee Expression of Rabbit Sex Hormone-Binding Globulin during Pregnancy and Prenatal Development and Identification of a Novel Isoform Endocrinology, April 1, 2005; 146(4): 1965 - 1972. [Abstract] [Full Text] [PDF]
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D. M. Selva, K. N. Hogeveen, and G. L. Hammond Repression of the Human Sex Hormone-binding Globulin Gene in Sertoli Cells by Upstream Stimulatory Transcription Factors J. Biol. Chem., February 11, 2005; 280(6): 4462 - 4468. [Abstract] [Full Text] [PDF]
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S. Miguel-Queralt, M. Knowlton, G. V. Avvakumov, R. Al-Nouno, G. M. Kelly, and G. L. Hammond Molecular and Functional Characterization of Sex Hormone Binding Globulin in Zebrafish Endocrinology, November 1, 2004; 145(11): 5221 - 5230. [Abstract] [Full Text] [PDF]
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D. M. Selva, K. N. Hogeveen, K. Seguchi, F. Tekpetey, and G. L. Hammond A Human Sex Hormone-binding Globulin Isoform Accumulates in the Acrosome during Spermatogenesis J. Biol. Chem., November 15, 2002; 277(47): 45291 - 45298. [Abstract] [Full Text] [PDF]
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 F. Munell, C. A. Suarez-Quian, D. M. Selva, O. M. Tirado, and J. Reventos Androgen-Binding Protein and Reproduction: Where Do We Stand? J Androl, September 1, 2002; 23(5): 598 - 609. [Full Text] [PDF]
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K. N. Hogeveen, M. Talikka, and G. L. Hammond Human Sex Hormone-binding Globulin Promoter Activity Is Influenced by a (TAAAA)n Repeat Element within an Alu Sequence J. Biol. Chem., September 21, 2001; 276(39): 36383 - 36390. [Abstract] [Full Text] [PDF]
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