Activating Transcription Factor 3 Is Up-Regulated in Patients with Hypospadias

Abstract

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)...

Activating transcription factor 3: a hormone responsive gene in the etiology of hypospadias

“…This effect may be due to disturbances on estrogenic responses during development (15,16,18). Moreover, ATF3 expression has also been reported to be up-regulated by the androgen receptor's activation by both androgens and estrogens in cell lines (27); this aspect indicate that variants in ATF3 may underlie androgenestrogen imbalances and influence the responsiveness to endocrine disrupters.…”

“…The up-regulation of estrogen-responsive genes has been documented in hypospadias (15,16). From these genes, the activating transcription factor 3 (ATF3), a member of the ATF/CREB family of transcription factors (17), has been the gene with the greatest up-regulation.…”

Timing of androgen receptor disruption and estrogen exposure underlies a spectrum of congenital penile anomalies

“…We also monitored expression of Atf3, a gene associated with hypospadias in humans and previously reported to have sexually dimorphic expression (31,32). Atf3 expression was not significantly different between males and females at prenatal stage E15.5, nor was it affected by testosterone or EB treatment at this stage ( Fig.…”

Current understanding of hypospadias: relevance of animal models

“…9 this latter finding emphasizes the risks associated with exposure to 'antiandrogenic' agents. studies from the past 10 years [63][64][65][66][67][68][69] have better defined the genes associated with hypospadias. a genome-wide association study of pooled Dna samples from 436 indivi duals with hypospadias and 494 without revealed a strong association between two common variants of diacylglycerol kinase κ (DGKK; rs1934179 and rs7063116).…”

“…expression studies in human urethral tissue have shown that ZEBI and ATF3 are especially promising candidates, owing to their known localization within the developing urethra. [68][69][70] Conclusive data regarding protein expression and function in human tissue are currently limited to a possible association of hypospadias with ATF3 overexpression 68 71 Further genetic studies are required in order to fully understand the basis of genetic s usceptibility to hypospadias.…”