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Even though hypospadias is one of the most common congenital anomalies, the cause of hypospadias is largely unknown. With regard to molecular biology and microarray technology, it appears that hypospadias is potentially related to disrupted gene expression. Genomic analysis of hypospadiac tissue indicated a potential role for activating transcripti...
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... of the 25 hypospadiac patients were excluded because of a history of previous orchidopexy, testosterone replacement ther- apy, or diagnosed concomitant undescended testis. The lo- cation of the meatus in the hypospadiac patients is pre- sented in Table 1. None of the hypospadiac patients had a proximally located meatus (Table 1). ...Context 2
... lo- cation of the meatus in the hypospadiac patients is pre- sented in Table 1. None of the hypospadiac patients had a proximally located meatus (Table 1). ATF3 protein was localized in the nuclei of stromal cells and the vascular endothelium in the subcutaneous tissue of the prepuce. ...Context 3
... cells and the vascular endothelium in the subcutaneous tissue of the prepuce. All of the patients had dorsal prepitual skin. Of the 46 specimens examined by immunohistochemistry, 16 (80%) of the 20 patients with hypospadias showed ex- pression of ATF3 protein, and only 3 (11%) of the 26 patients undergoing circumcision stained positive (p＜0.05) ( Table TABLE 3. Expression of ATF3 protein in hypospadiac samples Location of IHC IHC p-value hypospadiac meatus positive negative Coronal 4 1 p＞0.05 Subcoranal 7 2 Distal 3 1 Midshaft 2 0 ATF3: activating transcription factor 3, IHC: immunohistoche- mical 2). Intra-and interobserver agreement was excellent with kappa (Cohen statistics) values of 0.88 and 0.80, respec- ...Similar publications
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Citations
... Intracytoplasmic sperm injection (ICSI) increased the risk of hypospadias in most [97][98][99][100][101][102] but not all studies ( [103,104]), whereas in vitro fertilization (IVF) did not increase hypospadias risk in most studies, or the results were inconclusive [82,98,[102][103][104], except for two studies that did find increased risks after IVF treatment [29,105]. A systematic review concluded that ICSI is associated with a slightly higher risk of hypospadias than IVF, although not statistically significant [106]. In addition, fathers of hypospadias patients were reported to have lower sperm concentration, sperm count [107,108], and sperm motility, as well as a higher proportion of sperm with abnormal morphology [109]. ...
... Other genes for which evidence is quite strong are activating transcription factor 3 (ATF3), mastermind-like domain containing 1 (MAMLD1), and diacylglycerol kinase κ (DGKK). ATF3 is an estrogen-responsive gene showing strong upregulation in hypospadias [72,[104][105][106][107], and several studies found mutations in this gene in hypospadias patients or polymorphisms in this gene to be associated with hypospadias (Table 11.1). MAMLD1, previously known as CXorf6, contains the NR5A1 target sequence [108] and mutations, and polymorphisms in MAMLD1 were found in patients with hypospadias (Table 11.1). ...
In this chapter, we give a comprehensive review of the currently available literature on environmental factors involved in the etiology of hypospadias. We begin with a description about the prevalence of hypospadias, the clustering of hypospadias in families, the testicular dysgenesis syndrome, and the estrogen hypothesis. We focus the remainder of this chapter on the evidence for environmental factors that may be involved in the etiology of hypospadias and divided the chapter in several parts: exogenous exposure to estrogens, endogenous hormone levels, clinical factors, behavioral factors, occupational factors, and living environment. We summarized the results in a quick overview table. We used the review article that we published in 2012 as basis and updated it with new information and references. We focused on the etiology of isolated hypospadias in humans. Therefore, we did not systematically review animal studies.KeywordsEtiologyAssociationEnvironmentHypospadiasRisk factor
... Intracytoplasmic sperm injection (ICSI) increased the risk of hypospadias in most [97][98][99][100][101][102] but not all studies ( [103,104]), whereas in vitro fertilization (IVF) did not increase hypospadias risk in most studies, or the results were inconclusive [82,98,[102][103][104], except for two studies that did find increased risks after IVF treatment [29,105]. A systematic review concluded that ICSI is associated with a slightly higher risk of hypospadias than IVF, although not statistically significant [106]. In addition, fathers of hypospadias patients were reported to have lower sperm concentration, sperm count [107,108], and sperm motility, as well as a higher proportion of sperm with abnormal morphology [109]. ...
... Other genes for which evidence is quite strong are activating transcription factor 3 (ATF3), mastermind-like domain containing 1 (MAMLD1), and diacylglycerol kinase κ (DGKK). ATF3 is an estrogen-responsive gene showing strong upregulation in hypospadias [72,[104][105][106][107], and several studies found mutations in this gene in hypospadias patients or polymorphisms in this gene to be associated with hypospadias (Table 11.1). MAMLD1, previously known as CXorf6, contains the NR5A1 target sequence [108] and mutations, and polymorphisms in MAMLD1 were found in patients with hypospadias (Table 11.1). ...
In this chapter, I give an overview of the current knowledge on genes involved in the etiology of hypospadias. I begin with a short description of genes involved in the embryology of the male external genitalia and focus the remainder of this chapter on the evidence for genes relevant to the etiology of hypospadias. I used the review article that we published in 2012 as basis, updated it with new information, and subsequently summarized the main facts in order not to be too detailed. I focus on the etiology of isolated hypospadias in humans. Therefore, I do not review animal studies or syndromic forms of hypospadias.KeywordsEtiologyAssociationGeneHypospadiasMutationPolymorphism
... Allele variations and single nucleotide polymorphisms (SNPs) of the SRD5A2 have also been associated with hypospadias risk (13,27,29,34). Similarly, upregulation of ATF3 in preputial tissue from hypospadiac boys has been reported (30,(35)(36)(37). SNPs and haplotypes in ESR1 (17,38,39) and longer variants of (CA)n polymorphism in ESR2 (40) have been identified and associated with hypospadias. ...
Background and Objective: Mild hypospadias is a birth congenital condition characterized by the relocation of the male urethral meatus from its typical anatomical position near the tip of the glans penis, to a lower ventral position up to the brim of the glans corona, which can also be accompanied by foreskin ventral deficiency. For the most part, a limited number of cases have known etiology. We have followed a high-throughput proteomics approach to study the proteome in mild hypospadias patients.
Methods: Foreskin samples from patients with mild hypospadias were collected during urethroplasty, while control samples were collected during elective circumcision ( n = 5/group). A high-throughput, quantitative proteomics approach based on multiplexed peptide stable isotope labeling (SIL) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis was used to ascertain protein abundance changes in hypospadias patients when compared to control samples.
Results: A total of 4,815 proteins were quantitated (2,522 with at least two unique peptides). One hundred and thirty-three proteins from patients with mild hypospadias showed significant abundance changes with respect to control samples, where 38 proteins were increased, and 95 proteins were decreased. Unbiased functional biological analysis revealed that both mitochondrial energy production and apoptotic signaling pathways were enriched in mild hypospadias.
Conclusions: This first comprehensive proteomics characterization of mild hypospadias shows molecular changes associated with essential cellular processes related to energy production and apoptosis. Further evaluation of the proteome may expand the search of novel candidates in the etiology of mild hypospadias and could also lead to the identification of biomarkers for this congenital urogenital condition.
... Zeb1 mutant mice exhibit various developmental defects, although no defect of the sex organs has yet been described, nor have variants in this gene been associated with hypospadias. Like ZEB1 , the transcription factor ATF is an oestrogen-responsive gene that is strongly upregulated in the penile skin of patients with hypospadias [Liu et al., 2005;Wang et al., 2007;Zhou et al., 2009;Gurbuz et al., 2010;Karabulut et al., 2013]. Furthermore, it is overexpressed in the urethral plate surrounding the ectopic orifice of the urethra in human foetuses with hypospadias [Kalfa et al., 2008b]. ...
Hypospadias results from a failure of urethral closure in the male phallus and affects 1 in 200-300 boys. It is thought to be due to a combination of genetic and environmental factors. The development of the penis progresses in 2 stages: an initial hormone-independent phase and a secondary hormone-dependent phase. Here, we review the molecular pathways that contribute to each of these stages, drawing on studies from both human and mouse models. Hypospadias can occur when normal development of the phallus is disrupted, and we provide evidence that mutations in genes underlying this developmental process are causative. Finally, we discuss the environmental factors that may contribute to hypospadias and their potential immediate and transgenerational epigenetic impacts.
... Whereas expression levels were unchanged for the estrogendependent co regulators, including p160 family (Ncoa1, Ncoa2, Ncoa3), Crebbp, Kat2b, Med1, Ncor2, Carm1 and the nuclear receptors Ar and Esr1 ( Fig. 5d and Supplementary Fig. 4a), we observed a significant upreg ulation of mRNA levels of three estrogenresponsive genes, including activating transcription factor 3 (Atf3), connective tissue growth fac tor (Ctgf) and cysteinerich angiogenic inducer 61 (Cyr61), in the tes tes of the VAMP7BAC transgenic mice (Fig. 5d and Supplementary Fig. 4a). These observations are of key importance, as ATF3, CTGF and CYR61 are estrogenresponsive genes that are strongly upregu lated in patients with hypospadias [29][30][31][32][33] . Moreover, variants of ATF3 are associated with hypospadias in humans 34,35 . ...
Despite the fact that genitourinary defects are among the most common birth defects in newborns, little is known about their etiology. Here we analyzed children born with congenital genitourinary tract masculinization disorders by array-comparative genomic hybridization, which revealed in 1.35% of cases the presence of de novo copy number gains at Xq28 encompassing the VAMP7 gene, which encodes a vesicle-trafficking protein that is part of the SNARE complex. Transgenic mice carrying a bacterial artificial chromosome encoding human VAMP7 mimicked the defective urogenital traits observed in boys with masculinization disorders such as cryptorchidism, urethral defects and hypospadias. Transgenic mice also exhibited reduced penile length, focal spermatogenic anomalies, diminished sperm motility and subfertility. VAMP7 colocalized with estrogen receptor α (ESR1) in the presence of its cognate ligand, 17β-estradiol. Elevated levels of VAMP7 markedly intensified ESR1-potentiated transcriptional activity by increasing ESR1 protein cellular content upon ligand stimulation and upregulated the expression of estrogen-responsive genes including ATF3, CYR61 and CTGF, all of which have been implicated in human hypospadias. Hence, increased gene dosage of VAMP7, and thus higher expression levels of its protein product, enhances estrogen receptor action in male genitourinary tissues, affects the virilization of the reproductive tract and results in genitourinary birth defects in humans.
... Hypospadias has multifactorial origins that involve the actions of environmental factors with a genetic background [8]. The previous microarray studies indicated that, activating transcription factor 3 (ATF3), connective tissue growth factor (CTGF) and cysteine-rich, angiogenic inducer 61 (CYR61) genes were upregulated in hypospadias and all three genes were also estrogen-responsive8910. The ATF3 gene is upregulated in the skin of patients with hypospadias compared to normal prepuce . ...
Hypospadias is a congenital hypoplasia of the penis, with displacement of the urethral opening along the ventral surface, and has been reported to be one of the most common congenital anomalies, occurring in approximately 1:250 to 1:300 live births. As hypospadias is reported to be an easily diagnosed malformation at the crossroads of genetics and environment, it is important to study the genetic component in order to elucidate its etiology. In this study, the gene expression profiles both in human hypospadias tissues and normal penile tissues were studied by Human Gene Expression Array. Twenty-four genes were found to be upregulated. Among these, ATF3 and CYR61 have been reported previously. Other genes that have not been previously reported were also found to be upregulated: BTG2, CD69, CD9, DUSP1, EGR1, EIF4A1, FOS, FOSB, HBEGF, HNRNPUL1, IER2, JUN, JUNB, KLF2, NR4A1, NR4A2, PTGS2, RGS1, RTN4, SLC25A25, SOCS3 and ZFP36 (p <0.05). Further studies including genome-wide association studies (GWAS) with expression studies in a large patient group will help us for identifiying the candidate gene(s) in the etiology of hypospadias.
... Further investigations using other methods of analysis would be helpful to clarify a relationship between ATF3 and hypospadias, as well as similar studies from other cities because hypospadias is a multifactorial condition. [6] ...
Background:
The aetiology of hypospadias is largely uncharacterized. Some of the researchers have advocated that activating transcription factor 3 (ATF3), an oestrogen-responsive transcription factor, is up-regulated in patients with hypospadias. The purpose is to evaluate the universality of this fact; we studied the expression of ATF3 protein in prepuce tissue obtained from hypospadias and phimosis patients living in metropolitan Tokyo.
Materials and methods:
Prepuce tissue was obtained from outer foreskin at the time of surgery, quickly prepared for paraffin-embedded sectioning and stained immunohistochemically for ATF3. Two researchers blindly evaluated immunoreactivity and scored it semi-quantitatively as nil = 0, weak = 1, or strong = 2, to give a final staining intensity score (SIS). Subjects were 18 hypospadias patients and 17 phimosis patients (as controls) who had surgery between January, 2009 and March, 2010.
Results:
All subjects lived in metropolitan Tokyo, Japan. Mean ages at surgery were 2.9 ± 1.0 and 3.9 ± 2.4 years, respectively (P > 0.05). SIS was not statistically different between hypospadias patients (1.4 ± 0.5) and controls (1.5 ± 0.5), (P > 0.05).
Conclusions:
Our data suggest that ATF3 is not highly associated with hypospadias in metropolitan Tokyo. Differences in ethnicity might have influenced our results.
... Some additional genes are also suggested to be involved in the development of hypospadias. Activating transcription factor 3 (ATF3) is an estrogen-responsive gene showing strong up-regulation in hypospadias patients (Liu et al., 2005;Wang et al., 2007;Kalfa et al., 2008a;Gurbuz et al., 2010). Studies focusing on the relation between this gene and hypospadias found mutations and associations with several SNPs ( Tables I and II). ...
Hypospadias is a common congenital malformation of the male external genitalia. Most cases have an unknown aetiology, which is probably a mix of monogenic and multifactorial forms, implicating both genes and environmental factors. This review summarizes current knowledge about the aetiology of hypospadias.
Pubmed was used to identify studies on hypospadias aetiology published between January 1995 and February 2011. Reference lists of the selected manuscripts were also searched to identify additional studies, including those published before 1995.
The search provided 922 articles and 169 articles were selected for this review. Studies screening groups of patients with hypospadias for single gene defects found mutations in WT1, SF1, BMP4, BMP7, HOXA4, HOXB6, FGF8, FGFR2, AR, HSD3B2, SRD5A2, ATF3, MAMLD1, MID1 and BNC2. However, most investigators are convinced that single mutations do not cause the majority of isolated hypospadias cases. Indeed, associations were found with polymorphisms in FGF8, FGFR2, AR, HSD17B3, SRD5A2, ESR1, ESR2, ATF3, MAMLD1, DGKK, MID1, CYP1A1, GSTM1 and GSTT1. In addition, gene expression studies indentified CTGF, CYR61 and EGF as candidate genes. Environmental factors consistently implicated in hypospadias are low birthweight, maternal hypertension and pre-eclampsia, suggesting that placental insufficiency may play an important role in hypospadias aetiology. Exogenous endocrine-disrupting chemicals have the potential to induce hypospadias but it is unclear whether human exposure is high enough to exert this effect. Other environmental factors have also been associated with hypospadias but, for most, the results are inconsistent.
Although a number of contributors to the aetiology of hypospadias have been identified, the majority of risk factors remain unknown.
This study aimed to investigate the expression of Fos proto-oncogene, AP-1 transcription factor subunit (c-Fos) in the genital tubercle (GT) of rats with di(2-ethylhexyl) phthalate (DEHP)-induced hypospadias and in the prepuce of patients with hypospadias compared with unaffected controls. Pregnant rats were given 750 mg/kg/day DEHP orally from gestational days 12–19. Western blotting showed that c-Fos expression was increased in DEHP-induced hypospadiac male offspring. In addition, 30 prepuce tissue specimens obtained during hypospadias repair surgery were divided into 2 groups: the mild hypospadias group (n = 15) and the severe hypospadias group (n = 15). Fifteen normal prepuce tissue specimens were harvested during elective circumcision as normal controls. Real-time quantitative polymerase chain reaction, western blotting and immunohistochemistry analyses were used to assess c-Fos expression. c-Fos protein levels were higher in the GT of DEHP-induced rats than in that of control rats. c-Fos mRNA and protein levels were also higher in the hypospadias groups than in the control group (p < 0.05, p < 0.001), and c-Fos protein levels were significantly higher in the severe hypospadias group than in the mild hypospadias group (p < 0.01). The expression of c-Fos was increased in both the GT of DEHP-induced hypospadiac rats and the prepuce of hypospadias patients. Thus, c-Fos overexpression might contribute to hypospadias.
Abbreviations: DEHP: di(2-ethylhexyl) phthalate; c-Fos: Fos proto-oncogene, AP-1 transcription factor subunit; Mafb: the masculinization-regulatory gene v-maf musculoaponeurotic fibrosarcoma oncogene family, protein B; GT: genital tubercle; ED: embryonic day; AGD: anogenital distance; AGI: anogenital distance index; ED: embryonic day.
The study elucidated the effects associated with silencing growth factor-β R1 (TGF-β R1) and TGF-β R2 genes on the proliferation and apoptosis of penile urethral epithelial cells (UECs) in hypospadiac male rats. Seventy-five male rats were distributed into the normal, model, TGF-β R1/2-siRNA, TGF-β R1-siRNA and TGF-β R2-siRNA groups. The UECs of the rats included in the study were cultured in vitro and subsequently divided into the control, blank, TGF-β R1/2-siRNA, TGF-β R1-siRNA and TGF-β R2-siRNA groups. The mRNA and protein expressions of TGF-β R1/R2 were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Cell proliferation and apoptosis were evaluated by cell counting kit-8 (CCK-8) assay as well as by flow cytometry. Compared with the normal group, the apoptotic rate of the UECs in the model, TGF-β R1/2-siRNA, TGF-β R1-siRNA and TGF-β R2-siRNA groups displayed remarkable increases; compared with the model group, the apoptotic rate of the UECs in the TGF-β R1/2-siRNA, TGF-β R1-siRNA and TGF-β R2-siRNA groups displayed significant decreases, similar observations were made regarding mRNA and protein expressions of TGF-β R1 and TGF-β R2. Compared with the TGF-β R1/2-siRNA group, the apoptotic rates of the UECs in the TGF-β R1-siRNA and TGF-β R2-siRNA groups were up regulated, while cell proliferation in the TGF-β R1-siRNA and TGF-β R2-siRNA groups decreased accompanied by an increased rate of apoptosis. This study ultimately demonstrated that the silencing of TGF-β R1 and TGF-β R2 genes could promote cell proliferation and inhibit apoptosis of penile UECs in hypospadiac male rats. This article is protected by copyright. All rights reserved.
