ESR2 and hypospadias: Our results demonstrated that SP1 directly interacts with five proteins encoded by hypospadias risk genes, involving four signaling pathways, being AR (androgen receptor) in androgen production and signaling, ESR1 and ESR2 in estrogen production and signaling, MAP3K1 in gonadal development and signaling, and ATF3 in the estrogen pathway (Fig. 5).