PD06-11 LOSS OF WNT4 IN THE GUBERNACULUM CAUSES UNILATERAL CRYPTORCHIDISM AND FERTILITY DEFECTS DUE TO IMBALANCE OF MALE AND FEMALE GENES

Abstract

You have accessJournal of UrologyCME1 Apr 2023PD06-11 LOSS OF WNT4 IN THE GUBERNACULUM CAUSES UNILATERAL CRYPTORCHIDISM AND FERTILITY DEFECTS DUE TO IMBALANCE OF MALE AND FEMALE GENES Abhishek Seth, Hunter Flores, Ahmed Chahdi, and Carolina Jorgez Abhishek SethAbhishek Seth More articles by this author , Hunter FloresHunter Flores More articles by this author , Ahmed ChahdiAhmed Chahdi More articles by this author , and Carolina JorgezCarolina Jorgez More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003230.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Undescended testis (UDT) is the most common urological birth defect affecting 6% of male births. Despite surgical correction, some men with unilateral UDT may experience infertility with the contralateral descended testis (CDT) showing no A-dark spermatogonia. We hypothesized that WNT4 plays a significant role in gonadal development since mutations in WNT4 are associated with ambiguous genitalia, and overexpression of WNT4 in mice deficient in E2F1 leads to infertility. METHODS: A Wnt4 gubernaculum-specific knock-out mouse was created and phenotyped by crossing RARß2-cre mice to Wnt4-flox mice. Fertility was determined by 6-month paired mating of a wild type (WT) female to a Wnt4f/f;cre+ (Wnt4-cKO) male. RESULTS: All Wnt4-cKO mice presented with a smaller left unilateral UDT, and an equal number of mice had inguinal vs. abdominal UDT. The abdominal UDT had a Sertoli cell-only phenotype. The inguinal UDT had a combination of normal and abnormal seminiferous tubules (ST), including maturation arrest. Half of the mice with inguinal UDT had no sperm in the left epididymis, and the ones with sperm had 33% fewer sperm with a 96% decrease in motility compared to those of WT mice. The left gubernaculum of Wnt4-cKO was longer and thinner with increased collagen and reduced muscle content compared to the right CDT. The fertility of the Wnt4-cKO male was significantly reduced as they produced 23 litters and 88 pups within the same time that 8 WT mice produced 48 litter and 395 pups. Wnt4-cKO mice with abdominal UDT had an increase in serum FSH and LH. Wnt4-cKO UDT and CDT had an increase in ER-a in Leydig cells. Wnt4-cKO CDT and inguinal UDT had an increase in the number of SOX9-positive cells in which SOX9 expression was high in both the cytoplasm and nucleus. Wnt4-cKO testes revealed an up-regulation of genes essential for female gonadal development and function, such as Rspo1, Wnt4,and Foxl2 in both CDT and UDT. Several WNT4 variants were identified in boys with UDT that could potentially cause or contribute to their condition. CONCLUSIONS: Conditional loss of Wnt4 in the gubernaculum leads to aberrant testicular decent and development unilaterally. Although these mice have one normal descended testis, the existence of fertility defects and molecular alterations in the CDT supports our hypothesis that unilateral UDT is a bilateral defect. Our results indicate that the androgen-estrogen imbalance affects both testes and suggest that estrogen impacts the ability of SOX9 to translocate into the nucleus to activate the male developmental pathway. Source of Funding: NIH grant 1R01HD100985 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e160 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Abhishek Seth More articles by this author Hunter Flores More articles by this author Ahmed Chahdi More articles by this author Carolina Jorgez More articles by this author Expand All Advertisement PDF downloadLoading ...