Klinefelter syndrome (XXY males) is the most common sex chromosome aneuploidy, occurring in about 1 per 500 men. To study the underlying molecular mechanisms caused by the extra X chromosome, we have developed an experimental mouse model for men with Klinefelters syndrome. We have demonstrated that adult XXY mice have absence of germ cells, decreased serum testosterone levels, and elevated gonadotropin levels. Testicular failure begins early as a result of massive germ cell loss that precedes the initiation of meiosis. Loss of germ cells is mediated through apoptosis. Gene microarray with testicular RNA samples from 1-day-old mice showed inactive X specific transcripts (Xist) expression increased 4.14-fold, indicating the extra X chromosome is inactivated in XXY testes. Proapoptotic Bcl2-interacting killer-like and caspase 7 have 1.59- and 1.68-fold increase, and antiapoptotic transcripts IAP and Bcl2-like-10 have 3.73- and 2.08-fold decrease respectively in XXY mice. By immunohistochemistry, we found c-kit expression in gonocytes occurred earlier in XXY than XY siblings, suggesting early differentiation of gonocytes may contribute to germ cell loss in XXY mice. In addition to germ cell defect, androgen receptor expression in Sertoli cells is nearly depleted in adult XXY mice, suggestive of Sertoli cell dysfunction. By transplantation of XY germ cells into adult XXY testes, we found a few donor XY spermatogonia were able to survive for 10 weeks without further differentiation. Leydig cells in adult XXY mouse testes are both hypertrophic and hyperplastic. Testosterone production from XXY Leydig cells is impaired. Besides reproductive dysfunction, we have demonstrated that XXY mice have impaired learning, memory, and social interaction. By giving testosterone implants to adult XXY mice, we demonstrated that testosterone treatment significantly improves the learning ability of adult XXY mice.
28 Apr - 02 May 2007
European Society of Endocrinology