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Hypospadias is a congenital anomaly of the genitalia characterized by abnormalities of the urethra and foreskin, with the urethral meatus located in an abnormal position anywhere from the distal ventral penile shaft to the perineum. Because the incidence of hypospadias is approximately 1/200 -1/300 live male births, it is one of the most common congenital malformations, but its etiology is largely uncharacterized. Genomic analysis of hypospadic tissue indicated a potential role for activating transcription factor 3 (ATF3) in the development of this anomaly. ATF3 may be involved in homeostasis, wound healing, cell adhesion, or apoptosis, and normally it is expressed at a steadystate in quiescent cells. Additionally, it has been shown to be an estrogen-responsive gene, and the etiology of hypospadias may be related to in utero exposure to estrogenic or anti-androgenic compounds. We examined the expression of ATF3 in tissues from 28 children with hypospadias compared with 20 normal penile skin tissue samples from elective circumcision. Eighty-six percent of the hypospadias samples were immunohistochemically positive, compared with 13% of normal tissue samples. Seventy-five percent of hypospadias samples were positive from in situ hybridization, compared with 1% of circumcision samples. Our results indicate that ATF3 is up-regulated in the penile skin tissues of boys with hypospadias, suggesting a role for this transcription factor in the development of this abnormality. Because the etiology of hypospadias may include exposure to estrogenic compounds, the responsiveness of ATF3 to estrogen is also discussed. Hypospadias is a congenital anomaly of the genitalia characterized by abnormalities of the urethra and foreskin (1). In mild hypospadias the urethral meatus is located in an abnormal position along the distal ventral penile shaft, coronal margin, or proximal glans. In moderate hypospadias the abnormal urethral opening exists on the middle of ventral aspect of the penis. Severe hypospadias is characterized by a proximal urethral opening that can occur at the penile scrotal junction or within the scrotal folds or perineum, and the more severe forms of hypospadias are associated with penile curvature. The incidence of hypospadias is approximately 1/200ϳ1/300 live male births, making hypospadias one of the most common congenital malformations in children. Some research has documented that the incidence of this anomaly has been increasing in the United States during the last three decades (2). The molecular events required in the genitourinary tract for normal development of the male external genitalia are just beginning to be elucidated (3-6), and the etiology of hypospadias remains unknown, although endocrine disruptors have been proposed as a possible explanation for the increasing incidence that has been reported in industrialized countries (4 -7). Many studies also suggest a genetic component in the transmission of this birth defect and it seems to be multifactorial (8,9).Activating transcription factor 3 (ATF3)...