Impact of a constitutively active luteinizing hormone receptor on testicular gene expression and postnatal Leydig cell development

The actions of luteinizing hormone (LH) mediated through its receptor (LHR) are critical for testicular steroidogenesis and Leydig cell differentiation. We have previously characterized transgenic mice expressing a genetically engineered, constitutively active yoked hormone-receptor complex (YHR), in which a fusion protein of human chorionic gonadotropin (hCG) was covalently linked to LHR. Elevated testosterone levels were detected in male mice expressing YHR (YHR+) at 3 and 5 weeks of age, accompanied by decreases in testicular weight and serum levels of LH and follicle stimulating hormone (FSH). Here we report a temporal study to identify testicular genes whose expression is altered in YHR+ mice during postnatal development. The mRNA expression levels for the steroidogenic enzymes, P450 17α-hydroxylase, 17β-hydroxysteroid dehydrogenase3 and 5α-reductase1 were down-regulated in 3- and 5-week-old YHR+ testis. This result coupled with an immunohistochemical analysis of Leydig cell specific proteins and quantification of Leydig cell numbers identified a decrease in adult Leydig cells in YHR+ mice. Surprisingly, no change was detected for cytochrome P450 side-chain cleavage or steroidogenic acute regulatory protein RNA levels between WT and YHR+ mice. In contrast, mRNA levels for insulin-like growth factor binding protein 3 were up-regulated in 3- and 5-week-old YHR+ mice. The mRNA levels for several germ cell-specific proteins were up-regulated at 5 weeks of age in both WT and YHR+ mice. We conclude that premature high levels of testosterone alter the expression of a select number of testicular genes and impair the differentiation of adult Leydig cells in mice.