Endocrine Abstracts

Background: The etiology of hypospadias may be at the crossroad of genetics and environment. The study of these factors taken individually failed to find an unequivocal explanation in most cases. But the interactions between exposure to endocrine disruptors chemicals (EDC) and genetic background have not yet been studied. We thus aimed to find a genetic susceptibility to the environment in hypospadias.

Methods: Through a multicenter prospective comparative study, we gathered environmental and genetic data from patients with isolated hypospadias to determine at-risk polymorphisms when combined to exposure to EDC compared to a control group. 300 boys with hypospadias and 300 controls were included and evaluated by: 1-Questionnaire QLK4-1999-01422 to detect personal, environmental, professional exposures to pollutants. 2-Next-generation-sequencing of 336 genes implicated in genital and gonadal development and hypospadias. The interaction between genetics and environment was studied using logistic regression analysis.

Results: We identified 4 variants at risk for hypospadias when combined to exposure to EDC in the following genes: BRAF (rs3789806), AKR1C3 (rs10508293), AHR (rs2074113) and CITED2 (rs4076025). Surprisingly, beside their role in steroidogenesis and sensitivity to chemicals, these genes are also identified as oncogenes. The in-silico predictions of these variants are to modify the transcription factor binding sites for proteins encoded by other oncogenes and genital development genes. We thus hypothesized a connection between hypospadias and cancers. To further evaluate this association, we used data from the International Birth-Defect Surveillance Systems and from the International Agency for Research on Cancer (WHO). We found a geographical correlation, across 17 countries, between the incidence of hypospadias and the overall incidence of cancers (r=0.81). This correlation was particularly observable for urological tumors and leukemias, two cancers highly suspected to be linked to pollutants.

Conclusions: Hypospadias is at the crossroad of genetics and environment. Susceptibility to EDC may be associated with genetic variants on genes both implicated in fetal development and oncogenesis. Moreover, the incidence of hypospadias is geographically correlated to that of cancers worldwide. Hypospadias may thus not be a simple defect of the urethra but a witness of the global health population and of EDC impregnation.

Source of funding: This work was supported by Programme Hospitalier de Rercherche Clinique PHRC UF 8270 and Public funding from the National Reference Network for Rare Disease, Genital Development DSD DevGen.