Genetic pathway of external genitalia formation and molecular etiology of hypospadias

Kojima, Yoshiyuki; Kohri, Kenjiro; Hayashi, Yutaro

doi:10.1016/j.jpurol.2009.11.007

Cited by 54 publications

(41 citation statements)

References 71 publications

(64 reference statements)

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“…Then, dihydrotestosterone is generated from testosterone via the 5a-reductase enzyme type II. Dihydrotestosterone is the most important androgen in the development of the male external genitalia, acting through the AR (Kojima et al, 2010). Because of the important role of the AR in male sex differentiation, the AR gene has been extensively examined in patients with hypospadias.…”

Section: Introductionmentioning

confidence: 99%

Androgen receptor gene CAG repeat polymorphism and risk of isolated hypospadias: results from a meta-analysis

et al. 2015

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ABSTRACT. Studies investigating the association between the CAG repeat polymorphism and the risk of isolated hypospadias have reported conflicting results. The aim of this study was to quantitatively summarize the evidence for such a relationship. Two investigators independently searched the Medline, Embase, CNKI, and Wanfang databases. Weighted mean difference and 95% confidence intervals for the CAG repeat polymorphism and isolated hypospadias were calculated using a random-effects model. Subgroup analyses were performed by race, study design, sample for DNA extraction, and hypospadias classifications. This meta-analysis included 6 case-control studies, including 444 isolated hypospadias cases and 727 controls. The results showed that patients with isolated hypospadias had longer CAG repeats in their androgen receptor gene sequence (weighted mean difference = 1.36, 95% confidence interval = 0.60-2.13; P = 0.0005). Similarly, stratified analyses also detected significant associations in all subgroups, excluding the group with severe hypospadias (weighted mean difference = 0.35, 95% confidence interval = -0.42-1.12; P = 0.38). This meta-analysis indicated that longer CAG repeats were 1581 ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (1): 1580-1588 (2015 CAG repeat polymorphism and isolated hypospadias associated with the risk of isolated hypospadias, and that longer CAG polymorphisms may be related to the etiology of isolated hypospadias. Future studies based on Asian and African-American patients should be performed to re-evaluate this association.

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Section: Introductionmentioning

confidence: 99%

Androgen receptor gene CAG repeat polymorphism and risk of isolated hypospadias: results from a meta-analysis

et al. 2015

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“…The majority of the previous studies have been performed to exploit polymorphisms in sex hormone and endocrine-related genes, such as insulin-like factor 3 (INSL3), INSL3 receptor (LGR8 or GREAT), androgen receptor, estrogen receptors 1 and 2 (ESR1 and ESR2), steroid-5a-reductase, mastermind-like domain containing 1 (Cxorf6), activating transcription factor 3, fibroblast growth factor 8 and FGF receptor 2. [6][7][8][9][10][11][12] However, few of these studies have focused on polymorphisms in genes involved in drug metabolism that might influence individual susceptibility to exogenous agents such as EEDs. It is well known that both the metabolism of EEDs and male sexual differentiation are mediated by a series of transcription factors and cytochrome P450 (CYP) enzymes.…”

Section: Introductionmentioning

confidence: 99%

Association of variants in genes involved in environmental chemical metabolism and risk of cryptorchidism and hypospadias

et al. 2012

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We hypothesized that single-nucleotide polymorphisms (SNPs) of genes involved in environmental endocrine disruptors (EEDs) metabolism might influence the risk of male genital malformations. In this study, we explored for association between 384 SNPs in 15 genes (AHR, AHRR, ARNT, ARNT2, NR1I2, RXRA, RXRB, RXRG, CYP1A1, CYP1A2, CYP1B1, CYP2B6, CYP3A4, CYP17A1 and CYP19A1) and risk of cryptorchidism (CO) and hypospadias (HS) in 334 Japanese (JPN) males (141 controls, 95 CO and 98 HS) and 187 Italian (ITA) males (129 controls and 58 CO). In the JPN study group, five SNPs from ARNT2 (rs2278705 and rs5000770), CYP1A2 (rs2069521), CYP17A1 (rs4919686) and NR1I2 (rs2472680) were significantly associated at both allelic and genotypic levels with risk of at least one genital malformation phenotype. In the ITA study group, two SNPs in AHR (rs3757824) and ARNT2 (rs1020397) were significantly associated with risk of CO. Interaction analysis of the positive SNPs using multifactor dimensionality reduction demonstrated that synergistic interaction between rs2472680, rs4919686 and rs5000770 had 62.81% prediction accuracy for CO (P ¼ 0.011) and that between rs2069521 and rs2278705 had 69.98% prediction accuracy for HS (P ¼ 0.001) in JPN population. In a combined analysis of JPN and ITA population, the most significant multi-locus association was observed between rs5000770 and rs3757824, which had 65.70% prediction accuracy for CO (P ¼ 0.055). Our findings indicate that genetic polymorphisms in genes involved in EED metabolism are associated with risk of CO and HS.

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“…These chemicals with endocrine disrupting properties are often industrial and agricultural by-and end-products, and they are now referred to as endocrine disrupting chemicals (EDCs). Several authors have documented an increasing trend in male external genital malformations in animals and humans over the last several decades and have focused on these EDCs as suspected causes (9)(10)(11)(13)(14)(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

‘Idiopathic’ partial androgen insensitivity syndrome in 28 newborn and infant males: impact of prenatal exposure to environmental endocrine disruptor chemicals?

Gaspari

Paris

Philibert

et al. 2011

European Journal of Endocrinology

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Objective: 46,XY disorders of sex differentiation (46,XY DSD) can be due to a testis determination defect, an androgen biosynthesis defect, or androgen resistance (complete or partial androgen insensitivity syndrome (PAIS), or 5a reductase deficiency). We aimed to evaluate the impact of a prenatal contamination by environmental xenoestrogens in 'idiopathic' PAIS-like phenotype. Subjects: We investigated 28 newborn/infant males with 46,XY DSD, normal androgen production, and no androgen receptor or steroid-5aR type II enzyme (SRD5A2) gene mutations. Methods: To exclude other genetic defects, we sequenced the steroidogenic factor 1 (SF1) and mastermind-like domain-containing 1 (MAMLD1) genes, which were recently found to be associated with the PAIS-like phenotype. Parents were interviewed about their environmental/occupational exposure to endocrine disrupting chemicals (EDCs) before/during the patients' fetal life. Total estrogenic bioactivity of patient serum was analyzed by ultrasensitive bioassay. Results: All the patients had normal SF1 sequence and one patient showed a double polymorphism of MAMLD1. Eleven (39.3%) of the 28 patients had reported parental fetal exposure to EDCs. The mean estrogenic bioactivity in these 11 patients with fetal EDC exposure (6.65G8.07 pg/ml) versus 17 cases without contamination (1.27G0.34 pg/ml) and controls (1.06G0.44 pg/ml; P!0.05) was elevated. Conclusions: Our results indicate that the 'idiopathic' PAIS-like phenotype may in some cases be related to EDC contamination during fetal life.

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Genetic pathway of external genitalia formation and molecular etiology of hypospadias

Cited by 54 publications

References 71 publications

Androgen receptor gene CAG repeat polymorphism and risk of isolated hypospadias: results from a meta-analysis

Androgen receptor gene CAG repeat polymorphism and risk of isolated hypospadias: results from a meta-analysis

Association of variants in genes involved in environmental chemical metabolism and risk of cryptorchidism and hypospadias

‘Idiopathic’ partial androgen insensitivity syndrome in 28 newborn and infant males: impact of prenatal exposure to environmental endocrine disruptor chemicals?

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