Targeted Overexpression of Androgen Receptor with a Liver-Specific Promoter in Transgenic Mice

• Published in: Proceedings of the National Academy of Sciences - PNAS 1996-01, Vol.93 (2), p.728-733
• Main Authors: Chatterjee, Bandana, Song, Chung S., Jung, Myeong H., Chen, Shuo, Walter, Christi A., Herbert, Damon C., Weaker, Frank J., Mancini, Michael A., Roy, Arun K.
• Format: Article
• Language: English
• Subjects: Androgens; Animals; Complementary DNA; Exons; Female; Gene Expression; Gene Expression Regulation, Developmental; Gene Expression Regulation, Enzymologic; Gene Targeting - methods; Genetics; Humans; Immunohistochemistry; Liver; Liver - metabolism; Male; Male animals; Medical research; Messenger RNA; Mice; Mice, Transgenic; Phenylalanine Hydroxylase - genetics; Polymerase Chain Reaction; Promoter Regions, Genetic - genetics; Prostate; Rats; Receptors, Androgen - biosynthesis; Receptors, Androgen - genetics; Recombinant Fusion Proteins - biosynthesis; Reverse transcriptase polymerase chain reaction; Rodents; Sex Characteristics; Sulfotransferases - biosynthesis; Sulfotransferases - genetics; Tissue Distribution; Transgenes; Transgenic animals
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.93.2.728

The rodent liver displays marked age- and sex-dependent changes in androgen sensitivity due to the sexually dimorphic and temporally programmed expression of the androgen receptor (AR) gene. We have altered this normal phenotype by constitutive overexpression of the rat AR transgene in the mouse liver by targeting it via the human phenylalanine hydroxylase (hPAH) gene promoter. These transgenic animals in their heterozygous state produce an ≈ 30-fold higher level of the AR in the liver as compared with the nontransgenic control. Androgen inactivation via sulfonation of the hormone by dehydroepiandrosterone sulfotransferase (DST), an androgen-repressible enzyme, also contributes to the age- and sex-dependent regulation of hepatic androgen sensitivity. DST has a broad range of substrate specificity and is responsible for the age- and sex-specific activation of certain polycyclic aromatic hepatocarcinogens as well, by converting them to electrophilic sulfonated derivatives. In the transgenic female, the hepatic expression of DST was ≈ 4-fold lower than in normal females, a level comparable to that in normal males. The hPAH-AR mice will serve as a valuable model for studying the sex- and age-invariant expression of liver-specific genes, particularly those involved in the activation of environmental hepatocarcinogens such as the aromatic hydrocarbons.