Risk Of Hypospadias Research Articles

HAAO rs3816183 Polymorphisms [T] Increase Anterior/Middle Hypospadias Risk in Southern Han Chinese Population.

Hypospadias is one of the most common congenital external genital malformations, which is characterized by abnormal urethral meatus. However, the etiology remains to be incompletely understood. HAAO is a gene that encodes a protein, which catalyzes the synthesis of quinolinic acid, and has been identified as a risk gene for hypospadias. Thus, this study was conducted to elaborate the association between HAAO gene polymorphism rs3816183 T>C and hypospadias in the largest hypospadias cohort from Asia, including 577 patients and 654 healthy controls in China. The strength of interrelation was evaluated using 95% confidence intervals (CIs) and odds ratios (ORs). Based on the stratified analysis of hypospadias subtypes, it was found that the HAAO risk allele rs386183[T] enhances the susceptibility for hypospadias among patients with anterior/middle hypospadias subtypes (adjusted OR = 1.31, 95% CI = 1.05–1.64, p = 0.017). Enhanced risk of hypospadias in the entirety could not be demonstrated (OR = 1.20, 95% CI = 1.00–1.47, p = 0.054). In summary, our study found that the rs3816183[T] polymorphism is associated with increased risk of anterior/middle hypospadias among Southern Han Chinese children. The mechanisms by which the variations in the HAAO gene require further research.

The Role of Maternal and Environmental Factors During Pregnancy on the Risk of Hypospadias Occurrence.

Introduction and ObjectivesHypospadias is a congenital disorder in boys in which the urethral meatus is located on the ventral penis. The incidence rate of hypospadias is increasing, however, there is still no literature regarding how significant is the role of maternal and environmental factors to the risk of hypospadias, especially in Indonesia. This study aims to analyze the maternal and environmental factors during pregnancy to the risk of hypospadias.Materials and MethodsThis study was an analytical observational study with a case control design. The subjects were mothers who gave birth to children with hypospadias, compared to normal, who visited the urology, pediatric-surgery, plastic-surgery, and pediatric clinic at Hasan Sadikin General Hospital.ResultsA total of 120 samples (60 cases and 60 control) were included in this study. There were 14 maternal factors, which 5 of them found significantly correlated with hypospadias, including maternal occupation as an industrial worker (P = .003; OR:4.789), pregnancy-enhancing drugs usage (P = .004; OR: 5.783), smoking consumption (P = .034; OR: 2.294), mosquito-repellant usage (P = .0001; OR: 82.600), and preterm birth (P = .013; OR: 2.895). There were 2 environmental factors, and one of them was significant, which was the distance from home to industrial/rice fields/waste areas, approximately 780 m (P = .0001; OR: 6.102). Based on multivariate analysis, we found that maternal occupation, mosquito repellent usage, and the distance from home to industrial area had a strong relationship in predicting hypospadias occurrence.ConclusionSeveral maternal and environmental factors were found significantly correlated to hypospadias occurrence. Among these, mosquito-repellant usage was found to be the most significant factor.

OP06.07: Association of abnormal placental perfusion with the risk of male hypospadias

OP06.07: Association of abnormal placental perfusion with the risk of male hypospadias

Association of a GATA Binding Protein 4 Polymorphism with the Risk of Hypospadias in the Chinese Children

Purpose: GATA binding protein 4 (GATA4) has been implicated in the etiology of congenital malformation of the urogenital system. The present study investigated the influence of GATA4 polymorphisms on susceptibility to hypospadias. Methods: We genotyped 4 potentially functional polymorphisms (rs12458, rs12825, rs884662, and rs904018) in GATA4 in the hospital-based case-control study including 410 child patients and 520 nonmalformed individuals by the TaqMan MGB method. Risk associations were assessed using unconditional logistic regression, adjusted for potential confounding factors. Results: A significant association was found between rs12458 (3′-UTR of GATA4) and susceptibility to hypospadias (p = 0.008). Compared with rs12458 AA genotype individuals, those harboring the variant allele (rs12458 AT/TT) were correlated with significantly higher risk of hypospadias (AT/TT vs. AA: OR = 1.42, 95% CI = 1.17–2.35, p = 0.036). Furthermore, the rs12458T allele showed significantly decreased activity in a luciferase reporter assay, indicating a possible role of rs12458 variant in regulating the combination of microRNAs with the GATA4 mRNA. Conclusions: The present results indicate that the functional GATA4 rs12458 variant confers individuals’ susceptibility to hypospadias, possibly through regulating the GATA4 expression level.

Hypospadias

Hypospadias

PD29-01 ASSOCIATION OF PRECONCEPTION PATERNAL HEALTH AND MALE GENITAL MALFORMATIONS

You have accessJournal of UrologyInfertility: Epidemiology & Evaluation II (PD29)1 Sep 2021PD29-01 ASSOCIATION OF PRECONCEPTION PATERNAL HEALTH AND MALE GENITAL MALFORMATIONS Kyla Velaer, Chiyuan Zhang, Shufeng Li, and Michael Eisenberg Kyla VelaerKyla Velaer More articles by this author , Chiyuan ZhangChiyuan Zhang More articles by this author , Shufeng LiShufeng Li More articles by this author , and Michael EisenbergMichael Eisenberg More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002030.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The etiologies of hypospadias and cryptorchidism are largely unknown. Prior studies have shown an association between maternal exposures that may disrupt hormone development. Recent studies have demonstrated that increased preconception paternal metabolic syndrome (MetS) may be associated with adverse pregnancy and infant outcomes. The association between paternal health and genital malformations remains unknown. METHODS: We used the IBM Marketscan® Research claims database to identify infants with one male and one female parent at birth with at least one year of observation before conception. We included all infants that had at least one year of enrollment time data. We identified parental comorbidities using diagnosis codes from inpatient and outpatient records. MetS diagnosed components included hypertension, hyperlipidemia, diabetes, and obesity. We used diagnosis and CPT codes to identify infants diagnosed with hypospadias and cryptorchidism and infants that had surgery for these conditions. RESULTS: We identified 193,275 male infants that met criteria from 2009 to 2016 with the average follow up time of 3.9 years. The mean age at delivery of fathers was 35 years and 33 years for mothers. 21% of sons were sired by men with at least one component of the metabolic syndrome. While 0.86% of sons whose fathers had no components of MetS had surgery for hypospadias, 1.2% of sons whose fathers had two or more MetS diagnoses had hypospadias repair. Similar findings were found for hypospadias diagnoses alone. After adjusting for maternal and paternal age, smoking status, neonatal intensive care stay, low birth weight, prematurity, baby region, maternal MetS and follow up in years, infants born to fathers with increased MetS components had increased odds of undergoing surgery for hypospadias (2+MetS OR 1.37, 95% CI 1.18-1.59). 0.61% of sons whose fathers had no components of MetS had an orchiopexy for undescended testes, and 0.68% of sons whose fathers had two or more MetS diagnoses had hypospadias repair. On multivariable adjustment, there was no difference in the odds of cryptorchidism or orchiopexy based on preconception paternal MetS (OR 1.08, 0.89-1.31). CONCLUSIONS: Increased preconception paternal comorbidity may be associated with the development of hypospadias. Although the paternal effect remains modest, these findings highlight that paternal health in addition to maternal and environmental exposures may increase risk of hypospadias. Source of Funding: Translational Science Award (UL1 TR001085) and internal Stanford University funding © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e526-e526 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kyla Velaer More articles by this author Chiyuan Zhang More articles by this author Shufeng Li More articles by this author Michael Eisenberg More articles by this author Expand All Advertisement Loading ...

Impact of gestational and parental factors and maternal intake of progesterone on the development of hypospadias: A retrospective case–control study

ObjectiveImpact of environmental, maternal, paternal, and fetal factors on the development of hypospadias have been questioned in association with disrupted hormonal balance. We aimed to examine the association between maternal progesterone use and the associated risk factors and hypospadias. Materials and methodsThere were 429 male children as the cases with hypospadias (n = 280, Group 1) and the controls without hypospadias (n = 149, Group 2). Those working in agriculture and industry, cleaners, and hairdressers were determined as risky occupational groups concerning the exposure of estrogenic endocrine disrupters. The association of progestin usage and the other risk factors with hypospadias were the study outcomes. ResultsThe median gestational age was significantly lower in Group 2 (p = 0.019). Prematurity was more common in Group 1 (p = 0.043). Although the median birth weight in Group 1 was significantly lower (p < 0.001), there was no significant difference between the ratios of low birth weight babies in the groups. The risky occupations were more frequently detected in Group 2 (p = 0.001). The rate and duration of progestin usage in Group 1 were significantly higher than that in Group 2 (p < 0.001). ConclusionLow birth weight and the use and duration of progestins during pregnancy were significantly associated with increased hypospadias risk.

Contribution of prenatal endocrine-disrupting chemical exposure to genital anomalies in males: The pooled results from current evidence

The etiology of hypospadias and cryptorchidism, which are the two most common genital anomalies in males, has not been elucidated. Although prenatal exposure to endocrine-disrupting chemicals (EDCs) may increase the risks of hypospadias and cryptorchidism, the associations have not been confirmed. Therefore, we performed a meta-analysis to establish the relationships between prenatal exposure to EDCs and male genital anomalies. A systematic search of PubMed, EMbase, and Cochrane Library CENTRAL for relevant published studies providing quantitative data on the associations between prenatal EDCs exposure and hypospadias/cryptorchidism in humans was conducted. In total, sixteen case-controlled studies were included. Prenatal exposure to overall EDCs was associated with an increased risk of hypospadias in males (OR, 1.34, 95 % CI 1.12 to 1.60). Although there was no statistically significant association between overall EDCs exposure and cryptorchidism (OR, 1.11, 95 % CI 0.99 to 1.24), exposure to phenol substances was associated with an increased risk of cryptorchidism (OR, 1.81, 95 % CI, 1.12 to 2.93). Using the GRADE tool, we found the overall evidence to be of moderate certainty. In conclusion, the current evidence suggests prenatal EDCs exposure may increase the risk of hypospadias in males.

Maternal exposure to sulfur dioxide before and after conception and the risk of hypospadias in offspring

As far as we know, there have been no studies exploring the association between maternal sulfur dioxide (SO2 ) exposure and the risk of hypospadias in offspring. We aimed to evaluate this association during the 3 months before conception and the first trimester. A population-based case-control study was conducted in male infants, consisting of 348 cases of hypospadias and 4023 controls. Maternal exposure to SO2 , particulate matter with aerodynamic diameters ≤10 μm (PM10 ), and nitrogen dioxide (NO2 ) was assessed by averaging the concentrations recorded at all stations in the mother's city of residence. Air pollutants were tested for multicollinearity using variance inflation factor analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by multivariable logistic regression models. SO2 exposure during the 3 months before conception was significantly associated with the risk of hypospadias (highest tertile: OR=7.40, 95% CI:3.54-15.62). When focusing on shorter exposure windows, similar associations were observed for SO2 exposure in the first and second month before and the first month after conception. In conclusion, maternal exposure to SO2 during the 3 months before and the first and second months after conception may increase the risk of hypospadias in offspring.

Petroleum and Chlorinated Solvents in Meconium and the Risk of Hypospadias: A Pilot Study.

Background: Hypospadias is a male congenital malformation that occurs in ~2 of 1,000 births. The association between hypospadias and fetal exposure to environmental chemicals has been studied, but the results are inconsistent. Although several petroleum and chlorinated solvents are suspected to have teratogenic effects, their role in the occurrence of hypospadias has been little studied and never using biomarkers of exposure. We aimed to evaluate the association between fetal exposure to petroleum and chlorinated solvents measured in meconium and the occurrence of hypospadias.Methods: We conducted a pilot case-control study in the maternity of the University Hospital of Rennes (France). Eleven cases of hypospadias and 46 controls were recruited between October 2012 and January 2014. Data from hospital records and maternal self-reported questionnaires, including socio-demographic characteristics and occupational and non-occupational exposure to chemicals, were collected. Meconium samples were collected using a standardized protocol. Levels of petroleum solvents (toluene, benzene, ethylbenzene, and p, m, and o xylene), certain metabolites (mandelic acid, hippuric acid, methylhippuric acid, S-phenylmercapturic acid, S-benzylmercapturic acid, and phenylglyoxylic acid), and two chlorinated solvents (trichloroethylene and tetrachloroethylene) were measured in meconium by gas and liquid chromatography, both coupled to tandem mass spectrometry. Associations between the concentration of each chemical and the occurrence of hypospadias were analyzed using exact logistic regressions adjusted for maternal age, educational level, pre-pregnancy body mass index, and alcohol, and tobacco consumption during pregnancy. Results are presented with odds ratios (ORs) and their 95% confidence intervals (CIs).Results: Quantification rates for petroleum and chlorinated solvents or metabolites ranged from 2.2% (for methylhippuric acid) to 77.1% (for trichloroethylene) of the meconium samples. We found a significant association between the quantification of phenylglyoxylic acid (metabolite of styrene and ethylbenzene) in the meconium and a higher risk of hypospadias (OR = 14.2, 95% CI [2.5–138.7]). The risk of hypospadias was non-significantly elevated for most of the other solvents and metabolites.Conclusion: This exploratory study, on a limited number of cases, suggests an association between petroleum solvents and hypospadias. Additional studies are needed to confirm these results and identify the determinants for the presence of these solvents in meconium.

The association between ambient air pollution and birth defects in five major ethnic groups in Liuzhou, China

BackgroundStudies suggest that exposure to ambient air pollution during pregnancy may be associated with increased risks of birth defects (BDs), but conclusions have been inconsistent. This study describes the ethnic distribution of major BDs and examines the relationship between air pollution and BDs among different ethnic groups in Liuzhou city, China.MethodsSurveillance data of infants born in 114 registered hospitals in Liuzhou in 2019 were analyzed to determine the epidemiology of BDs across five major ethnic groups.Concentrations of six air pollutants (PM2.5, PM10, SO2, CO, NO2, O3) were obtained from the Liuzhou Environmental Protection Bureau. Logistic regression was used to examine the associations between ambient air pollution exposure and risk of BDs.ResultsAmong 32,549 infants, 635 infants had BDs, yielding a prevalence of 19.5 per 1000 perinatal infants. Dong ethnic group had the highest prevalence of BDs (2.59%), followed by Yao (2.57%), Miao (2.35%), Zhuang (2.07%), and Han (1.75%). Relative to the Han ethnic group, infants from Zhuang, Miao, Yao and Dong groups had lower risks of congenital heart disease, polydactyly, and hypospadias. The Zhuang ethnic group had higher risks of severe thalassemia, cleft lip and/or palate, and syndactyls. Overall BDs were positively correlated with air pollutants PM10 (aOR =1.14, 95% CI:1.12 ~ 2.43; aOR =1.51, 95% CI:1.13 ~ 2.03 for per 10μg/mg3 increment) and CO (aOR =1.36, 95% CI:1.14 ~ 2.48; aOR =1.75, 95% CI:1.02 ~ 3.61 for every 1 mg /m3 increment) in second and third month of pregnancy. SO2 was also significantly associated with BDs in the second month before the pregnancy (aOR = 1.31; 95% CI: 1.20 ~ 3.22) and third month of pregnancy (aOR =1.75; 95% CI:1.02 ~ 3.61). Congenital heart disease, polydactyl, cleft lip and/or palate were also significantly associated with PM10, SO2 and CO exposures. However, no significant association was found between birth defects and O3, PM2.5 and NO2 exposures (P > 0.05).ConclusionThis study provides a comprehensive description of ethnic differences in BDs in Southwest China and broadens the evidence of the association between air pollution exposure during gestation and BDs.

Increased hypospadias risk by GREM1 rs3743104[G] in the southern Han Chinese population.

Hypospadias is a common congenital genitourinary malformation characterized by ventral opening of the urethral meatus. As a member of the bone morphogenic protein antagonist family, GREM1 has been identified as associated with susceptibility to hypospadias in the European population. The present study was designed to elaborate on the mutual relationship between replicated single-nucleotide polymorphisms (SNPs) and hypospadias in Asia's largest case-control study in the Southern Han Chinese population involving 577 patients and 654 controls. Our results demonstrate that the GREM1 risk allele rs3743104[G] markedly increases the risk of mild/moderate and severe hypospadias (P<0.01, 0.28≤OR≤0.66). GTEx expression quantitative trait locus data revealed that the eQTL SNP rs3743104 has more associations of eQTL SNP rs3743104 and GREM1 targets in pituitary tissues. Additionally, Bioinformatics and Luciferase Assays show that miR-182 is identified as a suppressor for GREM1 expression, likely through regulation of its binding affinity to rs3743104 locus. In conclusion, the GREM1 risk allele rs3743104[G] increases hypospadias susceptibility in mild/moderate and severe cases among the southern Han population. rs3743104 regulates GREM1 expression by altering the binding affinity of miR-182 to their locus. Collectively, this study provides new evidence that GREM1 rs3743104 is associated with an increased risk of hypospadias. These findings provide a promising biomarker and merit further exploration.

Exploring the risk of hypospadias in children born from mothers living close to a vineyard.

Hypospadias (H) is a common birth defect affecting the male urinary tract. It has been suggested that exposure to endocrine disrupting chemicals might increase the risk of H by altering urethral development. However, whether H risk is increased in places heavily exposed to agricultural pesticides, such as vineyards, remains debated and difficult to ascertain. The objective of the work is to test the possible association of H with residential proximity to vineyards. Residential address at birth of 8,766 H cases born 1980–2011 was taken from 17 specialized surgery centers. The geographical distribution of vineyards was obtained from the European Land Parcel Identification System (LPIS) and the distance of address to the nearest vineyard was computed. A first estimate of the variation of H relative risk with distance to vineyards was obtained using as controls 13,105 cryptorchidism (C) cases operated during the same period in the same centers. A separate estimate was obtained from a case-control study using “virtual controls” (VC) defined as points of the map sampled to match the demographic distribution of births within the recruitment territories of the study centers. Non-exposed patients were defined as those with a residence between 5,000 and 10,000 m from the closest vineyard. The residential distance to vineyard was smaller for H than for C cases (p<10−4). We found 42/8766 H cases (0.48%) and 50/13,105 C cases (0.38%) born to mothers living within 20 m of a vineyard. The odds ratios for H were 2.48 (CI: 1.0 to 5.1) and 2.4 (CI: 1.3 to 4.4), vs C or vs VC, respectively, when pregnant mothers lived 10–20 m from a vineyard. In conclusion, our study supports that children born to mothers living close to a vineyard have a two-fold increased risk of H. For environmental research, the use of VC provides an alternative to classical case control technique.

Association between prenatal air pollution exposure and risk of hypospadias in offspring: a systematic review and meta-analysis of observational studies.

Background: The findings of associations between prenatal air pollution exposure and hypospadias risk in offspring are inconsistent. No systematic review or meta-analysis has yet summarized the present knowledge on the aforementioned topic.Methods: Relevant manuscripts were identified by searching PubMed and Web of Science databases through January 31, 2020. Summary odds ratios (ORs) with 95% confidence intervals (CIs) in meta-analyses were estimated based on a random effects model. Publication bias was evaluated by funnel plots, Begg’s test, and Egger’s test.Results: The search identified 3,032 relevant studies. Sixteen studies cumulatively involving 21,701 hypospadias cases and 1,465,364 participants were included. All of these studies were classified as having a low risk of bias. We classified pollutants as nitrogen oxides, particulate matter (PM), ozone, and other exposures. The exposure window to pollutants varied from three months before conception to seven days after delivery. In the meta-analyses, only PM2.5 exposure in the first trimester was related to increased risk of hypospadias (per 10 μg/m3 OR = 1.34; 95% CI: 1.06–1.68).Conclusion: We found evidence for an effect of PM2.5 exposure on hypospadias risk. Improvements in the areas of study design, exposure assessment, and specific exposure window are needed to advance this field.

Maternal Exposure to Disinfection By-Products and Risk of Hypospadias in the National Birth Defects Prevention Study (2000-2005).

The purpose of this study was to estimate the association between 2nd and 3rd degree hypospadias and maternal exposure to disinfection by-products (DBPs) using data from a large case-control study in the United States. Concentration estimates for total trihalomethanes (TTHMs), the sum of the five most prevalent haloacetic acids (HAA5), and individual species of each were integrated with data on maternal behaviors related to water-use from the National Birth Defects Prevention Study (NBDPS) to create three different exposure metrics: (1) household DBP concentrations; (2) estimates of DBP ingestion; (3) predicted uptake (i.e., internal dose) of trihalomethanes (THMs) via ingestion, showering, and bathing. The distribution of DBP exposure was categorized as follows: (Q1/referent) < 50%; (Q2) ≥ 50% to < 75%; and (Q3) ≥ 75%. Logistic regression was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). Generally, null associations were observed with increasing TTHM or HAA5 exposure. An increased risk was observed among women with household bromodichloromethane levels in the second quantile (aOR: 1.8; 95% CI: 1.2, 2.7); however, this association did not persist after the inclusion of individual-level water-use data. Findings from the present study do not support the hypothesis that maternal DBP exposures are related to the occurrence of hypospadias.

Association of abnormal placental perfusion with the risk of male hypospadias: a hospital-based retrospective cohort study

BackgroundThe effect and extent of abnormal placental perfusion (APP) on the risk of male hypospadias are poorly understood. We compared the prevalence of male hypospadias in the offspring of women with APP and quantify the extent of the APP effect on the anomaly.MethodsA hospital-based retrospective analysis of births from 2012 to 2016 was conducted in 2018. Women of singleton pregnancy and male infants born to them were included (N = 21,447). A multivariate analysis was performed to compare the prevalence of male hypospadias in infants exposed to APP with those that were not exposed to APP.ResultsCompared with the infants of women without APP, infants of women with APP showed an increased risk of male hypospadias (odds ratio, 2.40; 95% confidence interval, 1.09–5.29). The male hypospadias cumulative risk increased with the severity of APP. Infants exposed to severe APP had a significantly higher risk of male hypospadias than those without APP exposure (9.2 versus 1.7 per 1000 infants, P < 0.001). A path analysis indicated that 28.18–46.61% of the risk of hypospadias may be attributed to the effect of APP.ConclusionsMale hypospadias risk was associated with APP and increased with APP severity, as measured in the second trimester. APP had an important role in the development of the anomaly.

Spatial analysis of hypospadias cases in northern France: taking clinical data into account

BackgroundStrong evidence for a causal role of environmental factors in a congenital anomaly is still difficult to produce. The collection of statistical data is crucial for gaining a better understanding of the epidemiology and pathophysiology of these anomalies. We aimed to evaluate spatial variations in hypospadias within our region and it’s association to socioeconomic and ecological factors, taking clinical data into account.MethodsAll boys with hypospadias born in northern France and seen in Lille University Medical Center (Lille, France) between 1999 and 2012 were included in the analysis. We retrospectively collected geographic data, clinical data (especially known confounding factors associated with an elevated risk of hypospadias), and demographic, socio-economic and ecological data. We analyzed the entire study population and subsequently the subset of boys lacking confounding factors.ResultsThe study sample of 975 cases of hypospadias over the 13-year period resulted in an incidence of 25.4/10,000 male births, and was characterized by significant spatial heterogeneity (p < 0.005) and autocorrelation (p < 0.001). We detected two high-incidence clusters that differed with regard to their land use. After the exclusion of 221 patients with confounding factors, two high-incidence clusters with significant disease risks (1.65 and 1.75, respectively; p < 0.001) and a significant difference in land use (p < 0.001) again appeared. The first cluster contained a higher median [interquartile range] proportion of artificialized land (0.40 [0.22;0.47]) than the remaining “neutral areas” (0.19 [0.08;0.53]) did (p < 0.001). Conversely, the second cluster contained a higher median proportion of rural land (0.90 [0.78;0.96]) than the “neutral areas” (0.81 [0.47;0.92]) did (p < 0.001). The median deprivation index was significantly lower in the urban cluster (0.47 [0.42;0.55]) and significantly higher in the rural cluster (0.69 [0.56;0.73]) (p < 0.001).ConclusionsOur results evidenced the heterogeneous spatial distribution of cases of hypospadias in northern France. We identified two clusters with different environmental and social patterns – even after the exclusion of known confounding factors.

Association between prenatal exposure to ambient particulate matter and risk of hypospadias in offspring: A systematic review and meta-analysis

BackgroundEpidemiological studies on whether prenatal exposure to PM2.5, PM2.5-10, and PM10 increases the risk of hypospadias are limited and the results are inconsistent. ObjectivesWe conducted this systematic review and meta-analysis to evaluate these associations. MethodsRelevant studies were identified by searching the PubMed and Embase databases up to the end of February 2020. Observational studies that investigated the relationships between prenatal exposure to PM10, PM2.5, and PM2.5-10 and the risk of hypospadias in offspring were eligible for the review. The risk of bias was evaluated using the Newcastle-Ottawa scale. Random-effects models were used to estimate pooled relative risks (RRs) and 95% confidence intervals (CIs) for the associations. ResultsNine studies (two cohort and seven case-control studies) with a total of 2806 hypospadias cases were included. Eight studies were at low risk of bias and only one study was at high risk of bias. Five studies reported the association between per interquartile range increase in PM2.5 exposure within the first trimester and the risk of hypospadias. The pooled RR was 1.17 (95% CI: 1.00, 1.36). Two studies reported the per interquartile range increase in PM2.5 exposure during 1 month before pregnancy associated with the risk of hypospadias, with a pooled RR of 1.25 (95% CI: 1.03, 1.51). No association was observed between PM2.5-10 and PM10 exposure during pregnancy and the risk of hypospadias in offspring. ConclusionThis study suggested a modest association between prenatal PM2.5 exposure during 1 month before pregnancy or within the first trimester and the risk of hypospadias in offspring. Further large-scale cohort studies are required to verify this association.

Dysregulated expression of androgen metabolism genes and genetic analysis in hypospadias.

BackgroundThe aberrant expression of genes involved in androgen metabolism and genetic contribution are unclear in hypospadias.MethodsWe compared gene expression profiles by RNA sequencing from five non‐hypospadiac foreskins, five mild hypospadiac foreskins, and five severe hypospadiac foreskins. In addition, to identify rare coding variants with large effects on hypospadias risk, we carried out whole exome sequencing in three patients in a hypospadias family.ResultsThe average expression of androgen receptor (AR) and CYP19A1 were significantly decreased in severe hypospadias (p < .01) and mild hypospadias (p < .05), whereas expression of several other androgen metabolism enzymes, including CYP3A4, HSD17B14, HSD3B7, HSD17B7, CYP11A1 were exclusively significantly expressed in severe hypospadias (p < .05). Compound rare damaging mutants of AR gene with HSD3B1 and SLC25A5 genes were identified in the different severe hypospadias.ConclusionsIn conclusion, our findings demonstrated that dysregulation of AR and CYP19A1 could play a crucial role in the development of hypospadias. Inconsistent AR expression may be caused by the feedback loop of ESR1 signaling or combined genetic effects with other risk genes. This findings complement the possible role of AR triggered mechanism in the development of hypospadias.

Polymorphic Variants of BH4 Pathway Genes and Isolated Hypospadias Risk

Background: Hypospadias (HS) is one of the most common congenital malformations. Complications of corrective surgery in HS correlate with patients’ opinions on their voiding ability and sexual life as adults. Etiology of HS involves both genetic and environmental factors. GCH1, which belongs to recently identified urothelial genes influencing voiding behavior, encodes rate-limiting enzyme catalyzing the production of tetrahydrobiopterin (BH4). A requirement for BH4, a metabolite structurally related to folic acid and riboflavin, in embryonic development was reported. Objectives: The aim of the present study was to investigate the association of selected polymorphic variants of BH4 pathway genes with hypospadias. Methods: We performed an analysis of 6 SNPs of GCH1, PAH and AGMO-DGKB loci in a group of 166 boys with isolated hypospadias and a properly matched control group. Results: There was no evidence for either allelic or genotypic association with the risk of HS for the tested nucleotide variants (rs12425434, rs7485331, rs17128050, rs8004018, rs17128077, rs2191349). The lack of association with single SNPs was confirmed at the haplotype level. The exhaustive multifactor dimensionality reduction (MDR) analysis revealed no significant interactive effect of polymorphic variants of BH4 pathway genes on HS susceptibility. Conclusions: The presented results did not support an association between SNPs of GCH1 and PAH and the risk of HS.