Accumulated HSV1-TK proteins interfere with spermatogenesis through a disruption of the integrity of Sertoli-germ cell junctions.
Transgenic rats show spermatid-specific ectopic expression of the reporter gene, herpes simplex virus type1 thymidine kinase (HSV1-TK), in the testes and have demonstrated male infertility. However, the disruption of spermatogenesis and the underlying molecular mechanisms in these transgenic animals have not been well clarified. In this study, light and electron microscopic observations were performed to characterize the morphological changes in the testes. To explore the molecular mechanisms of male infertility in the HSV1-TK transgenic rat, cDNA microarray and quantitative real-time PCR analyses were performed. The seminiferous tubules of 3-month-old transgenic rats showed morphological alterations including seminiferous epithelial sloughing, vacuolization, and degeneration of spermatogenic cells, suggesting a failure of Sertoli-germ cell interaction. Components of the epididymal lumen from transgenic rats included abnormal spermatozoa, degenerating round spermatids and abnormal elongated spermatids indicating an appearance of direct impairment of spermiogenesis. cDNA microarray and real-time PCRanalyses revealed significant changes (P<0.05) in the gene expression level in six genes, testin, versican, mamdc1, fgf7, ostf1 and cnot7. Among them, testin drew most of our attention, since the testin gene is a sensitive marker for disruption of Sertoli-germ cell adhesion. Thus, our results suggest that the accumulation of HSV1-TK in the spermatids not only directly interferes with spermiogenesis but also disrupts spermatogenesis through a disruption of Sertoli-germ cell adhesions. It is important to explore the testicular actions of the HSV1-TK protein in transgenic experimental models and thereby gain clues to find an appropriate treatment for HSV-infected patients exhibiting human male infertility, as has been recently observed.
Department of Reproductive Medicine, The Affiliated Wuxi Hospital for Maternal and Children Health Care of Nanjing Medical University, Jiangsu Province 214002, China. caili76@hotmail.co.jp
Li-Yi
LY
Cai
Takako
T
Kato
Mo
M
Chen
HongHua
H
Wang
Ei-ichiro
E
Sekine
Shun-ichiro
S
Izumi
Yukio
Y
Kato
D000818:Animals; D003433:Crosses, Genetic; D004822:Epididymis / Q000378:metabolism / Q000648:ultrastructure; D020869:Gene Expression Profiling; D006558:Herpes Genitalis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D018259:Herpesvirus 1, Human / Q000201:enzymology*; D006801:Humans; D007248:Infertility, Male / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D007365:Intercellular Junctions / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic; D011994:Recombinant Proteins / Q000378:metabolism; D012708:Sertoli Cells / Q000378:metabolism* / Q000648:ultrastructure; D013091:Spermatogenesis; D013094:Spermatozoa / Q000378:metabolism* / Q000648:ultrastructure; D013737:Testis / Q000378:metabolism / Q000648:ultrastructure; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
D011506:Proteins; D011994:Recombinant Proteins; D014764:Viral Proteins; C489180:testin protein, rat; D013937:Thymidine Kinase