Meeting Abstract
Hypospadias occurs when the urethra does not exit at the tip of the penis, but along the ventral shaft. Incidence of hypospadias has increased 400% in the past 40 years, and is thought to be due to fetal exposure to endocrine disrupting chemicals (EDCs). Although model EDCs such as vinclozolin (V), a fungicide, are used to investigate the developmental processes causing hypospadias, we do not understand the molecular mechanisms driving variation in hypospadias severity. A first step toward understanding how variation in gene expression relates to variation in hypospadias severity requires that we can experimentally induce differences in hypospadias severity. To characterize variation induced by V, we conducted dose-response experiments at two overlapping developmental windows (DW). In the first DW, 12 pregnant dams were gavaged with either 0 (corn oil control), 100, 125, and 150 (mg/kg) of V on embryonic (E) days 14.5-16.5. In the second DW 12 pregnant dams were assigned to the same V dosage groups but were exposed on E 13.5-16.5. Genitalia of all pups were collected at E 18.5 and prepared for histology. To test the hypothesis that V induces variation in hypospadias severity across doses and exposure times, genitalia were cross sectioned at 10 m, tubercle length, urethral length (UL) were measured and the morphology of the proximal urethra opening was characterized. Severity of hypospadias increased with increasing V exposure, but the first DW induced a shallower dose response than the second DW. Our data shows that to induce variance in hypospadias severity, timing and dose is critical. Exposure during E13.5 is important in genitalia development, and should be included in studies that attempt to understand the genetic mechanisms driving differences in hypospadias severity.
