Up-regulation of estrogen responsive genes in hypospadias: microarray analysis.
OBJECTIVE
An unexplained increase in the incidence of hypospadias has been reported, and yet to our knowledge the molecular events and their regulation leading to hypospadias remain unknown, although environmental compounds capable of endocrine activity are suspected. We screened on a global scale abnormalities in gene expression in human hypospadiac tissue compared to those in nonhypospadiac tissue. Additionally, microarray analysis of tissue from a pair of fraternal twins, including 1 with and 1 without hypospadias, served as a control for genetic variability. We hypothesized that gene expression would differ between hypospadiac vs nonhypospadiac tissue and fraternal twin data would show patterns similar to those of group data on hypospadiac and nonhypospadiac tissue.


METHODS
Microarray analysis was performed on tissue from patients with and without hypospadias, and from a pair of fraternal twins, including 1 with and 1 without hypospadias. Analysis incorporated the expression of 22,000 genes.


RESULTS
We found significant differences in gene expression, specifically with a group of genes, including CYR61, CTGF, ATF3 and GADD45beta, known to be responsive to estrogen or to interact with estrogen receptor.


CONCLUSIONS
Our findings provide support for the hypothesis that endocrine active environmental compounds may contribute to the development of hypospadias. Additionally, regulation of these genes may have a role in formation of the urethra.
Wang
Zhong
Z
Departments of Urology, Ninth People's Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China.
Liu
Ben Chun
BC
Lin
Gui Ting
GT
Lin
Ching-Shwun
CS
Lue
Tom F
TF
Willingham
Emily
E
Baskin
Laurence S
LS
D051700:Activating Transcription Factor 3 / Q000235:genetics* / Q000378:metabolism; D000943:Antigens, Differentiation / Q000235:genetics* / Q000378:metabolism; D016000:Cluster Analysis; D055513:Connective Tissue Growth Factor; D055515:Cysteine-Rich Protein 61; D004967:Estrogens / Q000378:metabolism; D052816:Foreskin / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007021:Hypospadias / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000378:metabolism; D007223:Infant; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D046228:Microarray Analysis / Q000379:methods; D012313:RNA / Q000235:genetics*; D011960:Receptors, Estrogen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D000097642:GADD45 Proteins
D051700:Activating Transcription Factor 3; D000943:Antigens, Differentiation; D055513:Connective Tissue Growth Factor; D055515:Cysteine-Rich Protein 61; D004967:Estrogens; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012313:RNA; D011960:Receptors, Estrogen; C490449:ATF3 protein, human; C501848:CCN1 protein, human; C526317:CCN2 protein, human; C086470:GADD45B protein, human; D000097642:GADD45 Proteins