Hypospadias is one of the most common congenital defects in humans. The molecular events required in the genitourinary tract for normal development of the external genitalia are just beginning to be elucidated. Identifying the cause of hypospadias may be relevant not only in the field of pediatric urology, but also for worldwide public health. This article discusses the possible causes of hypospadias and the genes and growth factors involved. The potential effects of genetic susceptibility and environmental pollutants are also discussed.
Hypospadias is one of the most common congenital defects in humans. The molecular events required in the genitourinary tract for normal development of the external genitalia are just beginning to be elucidated. A cause is identified in approximately 20% of hypospadias, mainly in severe forms, but remains unknown in a vast majority of cases. ATF3 and mastermind-like domain-containing 1 gene ( MAMLD1 , formerly CXorf6 ) are new candidate genes that have been recently identified. ATF3 , an estrogen responsive gene implicated in the stress response, has its expression increased in hypospadiac boys and exhibits genetic variants. MAMLD1 , which is expressed in the gonad during sex differentiation and interacts with SF-1, is also mutated in patients with isolated hypospadias or disorder of sex differentiation.
Penile and urethral development is a fragile process requiring a correct genetic program, hormonal action (mainly testosterone and its 5α reduced form, dihydrotestosterone [DHT]), time- and space-adapted cellular differentiation, and complex tissue interactions. A failure of these regulatory processes may induce a defect in the development of the ventral aspect of the penis and an ectopic opening on the urethral meatus. This congenital malformation, often considered as a lack of virilization of male external genitalia, is the second most frequent genital malformation in newborn males after cryptorchidism. Its incidence ranges from 1 in 1000 to 1 in 100, with significant variations according to ethnic origin.
Management of hypospadias is based on surgery to ensure an acceptable cosmetic aspect, a good urinary function without obstruction or fistula, and a correction of the ventral curvature, which is frequent in severe forms of hypospadias and which may impair future sexual life if left uncorrected. There has been a recent effort to better elucidate the cause of hypospadias. First, several investigators have reported increasing trends in birth prevalence of hypospadias from 1960s to 1990s, even if recent reports cast doubt upon them. Second, hypospadias may be a smaller component of a much larger disease group (including reproductive disorder, testicular cancer, and cryptorchidism) and may reflect current exposure to environmental pollutants and a subsequent testicular dysgenesis. Identifying the cause of hypospadias may thus be relevant not only in the field of pediatric urology but also for worldwide public health.
Classic causes of hypospadias: a developmental fetal story
The role of fetal androgens is crucial, especially during the first trimester of pregnancy. Two steps are required to reach well-masculinized genitalia: sexual determination with testicular formation and sexual differentiation based on an effective hormonal biosynthesis and action.This hormonal factor has to interact with a normal genital tubercle (GT) and implicate the presence and action of penile developmental genes.
Hypospadias and Testicular Differentiation
Heterozygous mutations of WT1 (Wilms tumor 1 gene implicated in male gonadal determination) are associated with severe hypospadias and other genital abnormalities. In animals, knockout of WT1 induces anorchidism, defective GT development along with bilateral renal agenesis. In humans, mutations of WT1 are associated with syndromic hypospadias. SRY (sex-determining region of the Y chromosome) and its targets ( SOX9 , DMRT1 , GATA4 ) encode a transcriptional activator that acts immediately before the differentiation of the gonad into testis. Testicular dysgenesis and secondary hypospadias have been described along with mutations of these genes.
Hypospadias and Androgen Biosynthesis and Action
Androgenic steroids, synthesized by the Leydig cells of the testes, are first seen just before the onset of androgen-induced genital differentiation. 5α-Reductase type 2 is highly expressed in the mesenchymal stroma surrounding the urethra, and androgen receptor (AR) gene is expressed in the epithelium of the urethra. Mutations of these 2 genes may induce hypospadias. Mutations of 5α-reductase have been identified in severe variants of hypospadias in combination with other genital abnormalities. Mutations of AR gene have been mainly found in patients with severe forms of hypospadias, that is, perineal-scrotal hypospadias and hypospadias associated with cryptorchidism and micropenis. The phenotype is variable in partial androgen insensitivity syndrome, and a mutation in one of the 8 exons is found in less than 10% of cases.
Hypospadias and Penile Development
Homeobox A ( HOXA ) and homeobox D ( HOXD ) genes are expressed in the fetal urogenital structures and are implicated in penile development in a non–endocrine-dependant manner. These genes induce the expression of fibroblast growth factor (FGF) 8 and bone morphogenetic protein 7. In mice, heterozygosity of HOXA13 genes is associated with a defect in penile development and in penile patterning. In humans, mutations of HOXA13 are associated with genital abnormalities, including hypospadias in males and the hand-foot-genital syndrome. Beside this nonendocrine action, HOXA13 also acts in AR gene expression and mediates glans vascularization.
Active research to elucidate the cause of hypospadias
MAMLD1
A recent candidate gene that is critical for the development of the male genitalia is MAMLD1 (formerly CXorf6 ). This gene was discovered in the course of identifying the gene responsible for X-linked myotubular myopathy, MTM1 , which maps to proximal Xq28. Myopathic individuals with intragenic mutations of MTM1 have normal sexual development, whereas those with microdeletions of MTM1 extending to the CXorf6 locus exhibit abnormal external genitalia. Subsequent studies have demonstrated that CXorf6 is mutated in 46,XY disorders of sexual development (46,XY DSD). Fukami and colleagues have identified 3 nonsense mutations in 4 individuals with 46XY, DSD, including micropenis, bifid scrotum, and penoscrotal hypospadias. The authors show that mutations are also present in almost 10% of patients with isolated hypospadias. Mutation 1295T→C (V432A) was found in a patient with a proximal hypospadias. Two deletions at the beginning of the first translated exon were also identified (E109fsX121). A CAG repeat amplification of the second polyglutamine domain of the protein was found in a boy with an isolated subcoronal hypospadias (CAG 10 →CAG 13 ). None of these mutations were noted in the control group.
The mechanism by which MAMLD1 mutations induce hypospadias is under study, and these mutations may impair or interfere with androgen metabolism. In situ hybridization studies indicate that MAMLD1 is expressed in fetal Sertoli and Leydig cells during the critical period for sex development. Moreover, MAMLD1 is coexpressed with adrenal 4 binding protein/steroidogenic factor 1 (Ad4bp/Sf-1) in mouse. SF-1 is known to regulate multiple genes involved in sex development by binding to specific DNA sequences. Fukami and colleagues further showed that MAMLD1 harbors a putative SF-1 binding sequence in introns 1 and 2. Luciferase assays confirmed that SF-1 binds to the putative target sequence and exerts a transactivation function. These findings suggest that MAMLD1 is regulated by SF-1. Finally, knockdown analysis with small interfering RNAs of m- CXorf6 using mouse Leydig tumor cells showed reduced capability of testosterone production and responsiveness after human chorionic gonadotropin stimulation.
ATF3
A previous microarray study of the foreskin of normal and hypospadiac patients found 3 upregulated genes, the most prominent being activation transcription factor 3 (ATF3). ATF3 is a transcription factor whose expression is induced in a variety of cell types by many stress signals, including peripheral nerve injury, nutrient deprivation, and DNA damaging agents, as well as mitogenic agents and cytokines, suggesting that ATF3 is a key regulator in cellular stress responses. Although induction of ATF3 is neither tissue specific nor stimulus specific, one common theme of all the signals that induce ATF3 is that they also induce cellular damage. ATF3 may be a part of the cellular response that leads to detrimental outcomes. Transgenic mice expressing ATF3 in selective tissues have malfunction in the target tissues. For instance, increased expression of ATF3 in the liver or pancreas of transgenic mice results in reduced expression of gluconeogenic genes and insulin-dependent diabetes mellitus, respectively. Therefore, ATF3 appears to be a part of the cellular response that leads to detrimental outcomes.
Several studies argue for a major role of this gene and protein in hypospadias in the urethra. As discussed earlier, microarray analysis of tissues from normal and hypospadiac patients revealed upregulation of this gene in hypospadias. This result was confirmed by immunohistochemical analysis of human foreskin showing 86% of the hypospadias samples to be positive for expression of ATF3, whereas only 13% of those from normal penises were positive. ATF3 expression and promoter activity in foreskin fibroblasts were responsive to in vitro exposure to ethinyl estradiol. It is noteworthy that this aberrant expression of ATF3 is mainly present on the pathologic hypospadiac part of the urethra in human fetuses.
Hypospadias and Defects in Urethral Patterning and Structuring
Appropriate cell-cell interactions between mesenchyme and urothelium are necessary during male genital organogenesis to achieve the complete closure of the urethral plate. Sonic Hedgehog (Shh), a secreted signaling factor that regulates cell function and fate in development and adulthood, is implicated in the interaction between mesenchyme and urothelium. Urothelium-derived Shh has been shown to orchestrate the induction of fetal mouse bladder differentiation and patterning. Shh was thus suspected to participate in penile patterning and urethral development in a similar manner. In mice, Shh is expressed in the endodermally derived urethral plate epithelium situated along the ventral side of the GT and is required for outgrowth and patterning of the GT. Mice with a targeted deletion of Shh have penile and clitoral agenesis, consistent with the crucial role of Shh in genital development. No mutations have yet been reported in children with hypospadias.
Growth factors
Growth factors also participate in the development of genital structures. The FGF family is linked to genital development. FGF receptor 2 gene (FGFR2) is a transcriptional target of AR. Knockout of FGF10 is associated with hypospadias. Genetic variants of FGF8, FGF10, and FGFR2 increase the risk of hypospadias. Another group of growth factors strongly suspected to participate in the urethral tube development is the transforming growth factor (TGF) β family. In mice, genes involved in the TGF-β pathway, as well as in Wnt-Frizzled and thrombospondin 4 (a member of a cell-migration molecule family) pathways, exhibit increased expression profiles in GT during urethral tube development at ED 14, ED 15, ED 16, and ED 17. Immunohistochemical analysis confirms expression of TGF-β1 and TGF-β receptor III in urethral epithelia from ED 14 to ED 17. In the same manner that proteins of the TGF-β signaling pathway are involved in regulation of palate fusion in mammals, it could regulate the ventral closure of urethra.
More interestingly, the TGF-β signaling pathway could be connected to the ATF3 hypothesis. First, the most upregulated estrogen responsive genes are ATF3 and CTGF (which encodes connective tissue growth factor), and CTGF is part of the TGF-β signaling pathway. Second, ATF3 responds to signals in epithelial cells via the TGF-β pathway. ATF3 lies at the center of interactions between the TGF-β signaling pathway and steroid hormone receptors and may play a central role in the well-coordinated epithelial-mesenchymal interactions during the male GT development.
Environment Acting on a Genetic Susceptibility
Multiple chemical substances found in the environment can potentially interfere with male genital development because of their similarity to hormones. Such substances are called endocrine disruptors and have both estrogenic and antiandrogenic activities. It has been proposed that hypospadias and other disorders of the otherwise androgen-dependent male sexual development may occur as a result of androgen-estrogen imbalances. This is suggested by subtle developmental defects of the genital masculinization such as the genital distance, a witness of male reproductive tract development, which is reduced in children with hypospadias and in case of prenatal exposure to phthalates.
More recently, the concept of individual susceptibility, whereby different individuals may not react in the same manner after a toxic exposure, emerged. Genetic background could be the main basis of individual susceptibility to environment. Polymorphisms of hormone responsive genes have been investigated in a hypospadiac population and compared with controls. Genomic variants of the ATF3 genes were identified in 10% of boys with hypospadias. None of these genomic variants were present in controls. A missense variant (L23 M, a highly conserved amino acid) was identified in a boy with anterior hypospadias. Three genomic variants (C53070T, C53632A, Ins53943A) were found in or close to exon 6 in patients with perineal, penoscrotal, and anterior hypospadias. This important exon includes splice sites for an alternative transcript that codes for a regulating isoform, ATF3ΔZip , which regulates the function of ATF3 . The authors hypothesize that these genomic defects impair the regulation of ATF3 function and release its cell cycle suppression effect. Beleza-Meireles and colleagues also identified that 3 common single nucleotide polymorphisms (SNPs), spanning a region of about 16 kb in intron 1 of ATF3 , are associated with hypospadias. The authors note that these SNPs are not linked, their effects are independent, and the combination of the 3 risk SNPs yields the highest significance. Functional studies remain to be performed to confirm the cell cycle suppression effect of these polymorphisms.
Genomic variants of the androgen and estrogen signaling pathways are also under study. There is an increased number of GGN trinucleotide repeats in the AR gene, which reduce the transcriptional activity of the gene in hypospadiac patients. But the role of amplification of the CAG repeats remains to be determined. The V89L variant of the SRD5A2 gene is a risk factor for hypospadias (Maimoun L, personal data, 2010). The polymorphisms of estrogen receptor (ESR) may also facilitate the deleterious effects of xenoestrogen because their effects are mainly mediated through this receptor. AGAGA haplotype of ESR 1 gene is strongly associated with hypospadias. The ESR1 C-A haplotype, for ESR1 XbaI and ESR2 2681-4A>G, respectively, also increases the risk of malformation. Increased number of CA repeats (and subsequent increased ESR activity) also increases the risk of malformation.
The interaction between genes and environment is not limited to genomic variants modulating the response to toxic substances. The expression of genital development genes also varies according to the exposition to estrogenlike substances. Using a mouse model of steroid hormone–dependent GT development, ATF3 messenger RNA (mRNA) levels were found to be elevated in all estrogen-exposed fetal GTs compared with controls. Di-(2-ethylhexyl) phthalate (DEHP), the most common plasticizer, has been suspected to contribute to hypospadias of male offspring of pregnant women exposed to it. In a fetal murine model, DEHP activates ATF3 both at the mRNA and protein levels in GT with an apoptosis dysregulation. Exogenous administration of estrogens results in an increased expression of ESR α (but not of ESR β). Endocrine disruptors also modulate expression of TGF-β1. Reverse-transcription polymerase chain reaction and Western blot studies showed that the expression of TGF-β1 is upregulated in DEHP-treated mice along with a significant inhibition of male fetal genital tubercule.
These data about environment should nevertheless be interpreted with caution. The undisputable proof of detrimental effects of environment is still pending, and some studies provide contradictory results in similar fashion to epidemiologic studies that provide inconclusive evidence on temporal trends in hypospadias. Some recent reports describe an increased incidence, whereas others showed no trend over time. Epidemiologic studies on maternal exposition are also inconclusive. Three studies report the possible relationship between exposure to pesticides and hypospadias. Kristensen and colleagues published a moderate increase of odds ratio (OR) for hypospadias in individuals exposed to farm chemicals (OR, 1.5%). Weidner and colleagues stated that maternal farming or gardening led to a low risk of hypospadias (OR, 1.27). More recently, studies on occupational exposures to phthalates and hair spray suggest that antiandrogenic endocrine-disrupting chemicals may play a role in hypospadias. In contrast, Longnecker and colleagues did not confirm any significant risk of hypospadias (OR, 1.2) when mothers were exposed to dichlorodiphenyltrichloroethane. No relationship was identified between exposure to polybrominated biphenyl or polychlorinated biphenyls and hypospadias. A recent meta-analysis indicates only a modestly increased risk for hypospadias associated with pesticide exposure. Although several xenoestrogens consistently induce hypospadias in murine male offspring exposed in utero, extrapolation to humans may not be comparable.
Overall, the proportion of hypospadias cases for which a precise and undisputed cause is detected varies according to studies, but it remains the minority, especially for less severe cases. The occurrence of hypospadias remains unexplained in most cases. A multifactorial explanation and the implication of genetic susceptibility and environmental pollutants remain a plausible working hypothesis.
Supported by Grant DK058105 from the National Institutes of Health , Washington, DC, USA, and by PHRC UF8270 from University Hospital of Montpellier , France.
Active research to elucidate the cause of hypospadias
MAMLD1
A recent candidate gene that is critical for the development of the male genitalia is MAMLD1 (formerly CXorf6 ). This gene was discovered in the course of identifying the gene responsible for X-linked myotubular myopathy, MTM1 , which maps to proximal Xq28. Myopathic individuals with intragenic mutations of MTM1 have normal sexual development, whereas those with microdeletions of MTM1 extending to the CXorf6 locus exhibit abnormal external genitalia. Subsequent studies have demonstrated that CXorf6 is mutated in 46,XY disorders of sexual development (46,XY DSD). Fukami and colleagues have identified 3 nonsense mutations in 4 individuals with 46XY, DSD, including micropenis, bifid scrotum, and penoscrotal hypospadias. The authors show that mutations are also present in almost 10% of patients with isolated hypospadias. Mutation 1295T→C (V432A) was found in a patient with a proximal hypospadias. Two deletions at the beginning of the first translated exon were also identified (E109fsX121). A CAG repeat amplification of the second polyglutamine domain of the protein was found in a boy with an isolated subcoronal hypospadias (CAG 10 →CAG 13 ). None of these mutations were noted in the control group.
The mechanism by which MAMLD1 mutations induce hypospadias is under study, and these mutations may impair or interfere with androgen metabolism. In situ hybridization studies indicate that MAMLD1 is expressed in fetal Sertoli and Leydig cells during the critical period for sex development. Moreover, MAMLD1 is coexpressed with adrenal 4 binding protein/steroidogenic factor 1 (Ad4bp/Sf-1) in mouse. SF-1 is known to regulate multiple genes involved in sex development by binding to specific DNA sequences. Fukami and colleagues further showed that MAMLD1 harbors a putative SF-1 binding sequence in introns 1 and 2. Luciferase assays confirmed that SF-1 binds to the putative target sequence and exerts a transactivation function. These findings suggest that MAMLD1 is regulated by SF-1. Finally, knockdown analysis with small interfering RNAs of m- CXorf6 using mouse Leydig tumor cells showed reduced capability of testosterone production and responsiveness after human chorionic gonadotropin stimulation.
ATF3
A previous microarray study of the foreskin of normal and hypospadiac patients found 3 upregulated genes, the most prominent being activation transcription factor 3 (ATF3). ATF3 is a transcription factor whose expression is induced in a variety of cell types by many stress signals, including peripheral nerve injury, nutrient deprivation, and DNA damaging agents, as well as mitogenic agents and cytokines, suggesting that ATF3 is a key regulator in cellular stress responses. Although induction of ATF3 is neither tissue specific nor stimulus specific, one common theme of all the signals that induce ATF3 is that they also induce cellular damage. ATF3 may be a part of the cellular response that leads to detrimental outcomes. Transgenic mice expressing ATF3 in selective tissues have malfunction in the target tissues. For instance, increased expression of ATF3 in the liver or pancreas of transgenic mice results in reduced expression of gluconeogenic genes and insulin-dependent diabetes mellitus, respectively. Therefore, ATF3 appears to be a part of the cellular response that leads to detrimental outcomes.
Several studies argue for a major role of this gene and protein in hypospadias in the urethra. As discussed earlier, microarray analysis of tissues from normal and hypospadiac patients revealed upregulation of this gene in hypospadias. This result was confirmed by immunohistochemical analysis of human foreskin showing 86% of the hypospadias samples to be positive for expression of ATF3, whereas only 13% of those from normal penises were positive. ATF3 expression and promoter activity in foreskin fibroblasts were responsive to in vitro exposure to ethinyl estradiol. It is noteworthy that this aberrant expression of ATF3 is mainly present on the pathologic hypospadiac part of the urethra in human fetuses.
Hypospadias and Defects in Urethral Patterning and Structuring
Appropriate cell-cell interactions between mesenchyme and urothelium are necessary during male genital organogenesis to achieve the complete closure of the urethral plate. Sonic Hedgehog (Shh), a secreted signaling factor that regulates cell function and fate in development and adulthood, is implicated in the interaction between mesenchyme and urothelium. Urothelium-derived Shh has been shown to orchestrate the induction of fetal mouse bladder differentiation and patterning. Shh was thus suspected to participate in penile patterning and urethral development in a similar manner. In mice, Shh is expressed in the endodermally derived urethral plate epithelium situated along the ventral side of the GT and is required for outgrowth and patterning of the GT. Mice with a targeted deletion of Shh have penile and clitoral agenesis, consistent with the crucial role of Shh in genital development. No mutations have yet been reported in children with hypospadias.
Growth factors
Growth factors also participate in the development of genital structures. The FGF family is linked to genital development. FGF receptor 2 gene (FGFR2) is a transcriptional target of AR. Knockout of FGF10 is associated with hypospadias. Genetic variants of FGF8, FGF10, and FGFR2 increase the risk of hypospadias. Another group of growth factors strongly suspected to participate in the urethral tube development is the transforming growth factor (TGF) β family. In mice, genes involved in the TGF-β pathway, as well as in Wnt-Frizzled and thrombospondin 4 (a member of a cell-migration molecule family) pathways, exhibit increased expression profiles in GT during urethral tube development at ED 14, ED 15, ED 16, and ED 17. Immunohistochemical analysis confirms expression of TGF-β1 and TGF-β receptor III in urethral epithelia from ED 14 to ED 17. In the same manner that proteins of the TGF-β signaling pathway are involved in regulation of palate fusion in mammals, it could regulate the ventral closure of urethra.
More interestingly, the TGF-β signaling pathway could be connected to the ATF3 hypothesis. First, the most upregulated estrogen responsive genes are ATF3 and CTGF (which encodes connective tissue growth factor), and CTGF is part of the TGF-β signaling pathway. Second, ATF3 responds to signals in epithelial cells via the TGF-β pathway. ATF3 lies at the center of interactions between the TGF-β signaling pathway and steroid hormone receptors and may play a central role in the well-coordinated epithelial-mesenchymal interactions during the male GT development.
Environment Acting on a Genetic Susceptibility
Multiple chemical substances found in the environment can potentially interfere with male genital development because of their similarity to hormones. Such substances are called endocrine disruptors and have both estrogenic and antiandrogenic activities. It has been proposed that hypospadias and other disorders of the otherwise androgen-dependent male sexual development may occur as a result of androgen-estrogen imbalances. This is suggested by subtle developmental defects of the genital masculinization such as the genital distance, a witness of male reproductive tract development, which is reduced in children with hypospadias and in case of prenatal exposure to phthalates.
More recently, the concept of individual susceptibility, whereby different individuals may not react in the same manner after a toxic exposure, emerged. Genetic background could be the main basis of individual susceptibility to environment. Polymorphisms of hormone responsive genes have been investigated in a hypospadiac population and compared with controls. Genomic variants of the ATF3 genes were identified in 10% of boys with hypospadias. None of these genomic variants were present in controls. A missense variant (L23 M, a highly conserved amino acid) was identified in a boy with anterior hypospadias. Three genomic variants (C53070T, C53632A, Ins53943A) were found in or close to exon 6 in patients with perineal, penoscrotal, and anterior hypospadias. This important exon includes splice sites for an alternative transcript that codes for a regulating isoform, ATF3ΔZip , which regulates the function of ATF3 . The authors hypothesize that these genomic defects impair the regulation of ATF3 function and release its cell cycle suppression effect. Beleza-Meireles and colleagues also identified that 3 common single nucleotide polymorphisms (SNPs), spanning a region of about 16 kb in intron 1 of ATF3 , are associated with hypospadias. The authors note that these SNPs are not linked, their effects are independent, and the combination of the 3 risk SNPs yields the highest significance. Functional studies remain to be performed to confirm the cell cycle suppression effect of these polymorphisms.
Genomic variants of the androgen and estrogen signaling pathways are also under study. There is an increased number of GGN trinucleotide repeats in the AR gene, which reduce the transcriptional activity of the gene in hypospadiac patients. But the role of amplification of the CAG repeats remains to be determined. The V89L variant of the SRD5A2 gene is a risk factor for hypospadias (Maimoun L, personal data, 2010). The polymorphisms of estrogen receptor (ESR) may also facilitate the deleterious effects of xenoestrogen because their effects are mainly mediated through this receptor. AGAGA haplotype of ESR 1 gene is strongly associated with hypospadias. The ESR1 C-A haplotype, for ESR1 XbaI and ESR2 2681-4A>G, respectively, also increases the risk of malformation. Increased number of CA repeats (and subsequent increased ESR activity) also increases the risk of malformation.
The interaction between genes and environment is not limited to genomic variants modulating the response to toxic substances. The expression of genital development genes also varies according to the exposition to estrogenlike substances. Using a mouse model of steroid hormone–dependent GT development, ATF3 messenger RNA (mRNA) levels were found to be elevated in all estrogen-exposed fetal GTs compared with controls. Di-(2-ethylhexyl) phthalate (DEHP), the most common plasticizer, has been suspected to contribute to hypospadias of male offspring of pregnant women exposed to it. In a fetal murine model, DEHP activates ATF3 both at the mRNA and protein levels in GT with an apoptosis dysregulation. Exogenous administration of estrogens results in an increased expression of ESR α (but not of ESR β). Endocrine disruptors also modulate expression of TGF-β1. Reverse-transcription polymerase chain reaction and Western blot studies showed that the expression of TGF-β1 is upregulated in DEHP-treated mice along with a significant inhibition of male fetal genital tubercule.
These data about environment should nevertheless be interpreted with caution. The undisputable proof of detrimental effects of environment is still pending, and some studies provide contradictory results in similar fashion to epidemiologic studies that provide inconclusive evidence on temporal trends in hypospadias. Some recent reports describe an increased incidence, whereas others showed no trend over time. Epidemiologic studies on maternal exposition are also inconclusive. Three studies report the possible relationship between exposure to pesticides and hypospadias. Kristensen and colleagues published a moderate increase of odds ratio (OR) for hypospadias in individuals exposed to farm chemicals (OR, 1.5%). Weidner and colleagues stated that maternal farming or gardening led to a low risk of hypospadias (OR, 1.27). More recently, studies on occupational exposures to phthalates and hair spray suggest that antiandrogenic endocrine-disrupting chemicals may play a role in hypospadias. In contrast, Longnecker and colleagues did not confirm any significant risk of hypospadias (OR, 1.2) when mothers were exposed to dichlorodiphenyltrichloroethane. No relationship was identified between exposure to polybrominated biphenyl or polychlorinated biphenyls and hypospadias. A recent meta-analysis indicates only a modestly increased risk for hypospadias associated with pesticide exposure. Although several xenoestrogens consistently induce hypospadias in murine male offspring exposed in utero, extrapolation to humans may not be comparable.
Overall, the proportion of hypospadias cases for which a precise and undisputed cause is detected varies according to studies, but it remains the minority, especially for less severe cases. The occurrence of hypospadias remains unexplained in most cases. A multifactorial explanation and the implication of genetic susceptibility and environmental pollutants remain a plausible working hypothesis.
Supported by Grant DK058105 from the National Institutes of Health , Washington, DC, USA, and by PHRC UF8270 from University Hospital of Montpellier , France.
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