This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cryptorchidism, or undescended testis, is one of the most common male congenital anomalies, occurring in 2-4% of boys. It is non-syndromic and unilateral in the majority of cases, yet is often associated with bilateral impairment of germ cell development and subsequent infertility and/or malignancy. Neither the physiology nor the pathogenesis of this complex and heterogeneous disease is well understood but available data suggest the presence of multiple susceptibility loci. In addition, estrogens, antiandrogens and many environmental pollutants with endocrine-disrupting effects produce cryptorchidism in experimental animals after fetal exposure. It is likely that manifestation of the human disease is the result of gene-environment interactions. Several genes have been identified as strong candidates for cryptorchidism in targeted deletion studies. These include insl3, Great/LGR8, Desrt/MRF2, hoxA10 and hoxA11. We hypothesize that allelic variants in these genes are associated with susceptibility to cryptorchidism and that this risk is modulated by the fetal hormonal milieu, which can be altered by genetic as well as extrinsic environmental factors. The overall goals of this project are to elucidate the molecular mechanisms of normal and abnormal testicular descent in spontaneously cryptorchid rats and to initiate a case-control study to measure biomarkers of effect and candidate genes that are associated with human cryptorchidism.
Specific aims will be to: (1) identify candidate genes for cryptorchidism based on differential expression studies of mutant and wild type rat strains; (2) initiate a case-control study of cryptorchidism to study biomarkers of exposure and effect including (a) expression of androgen and estrogen receptors using real time RT-PCR and (b) germ cell differentiation using FACS analysis of spermatogonial markers in target tissues and (3) identify and study allelic variants in candidate genes for cryptorchidism using a case-control design that will be validated by transmission disequilibrium testing. The long-term goals of this work will be to study gene-environment interaction in the etiology of cryptorchidism and to identify, predict and, when possible, minimize risk factors that contribute to this common disease.
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