Development Of Male Genitalia Research Articles

Novel cord blood and urinary phytoestrogens levels in male neonates with normal external genitalia

Objective: This was a new prospective study to determine the association between phytoestrogen levels in the cord blood and urine with normal and abnormal external genitalia in male newborns. Materials and Methods: One hundred and fifty-one term male newborns were enrolled. Cord blood and urine and medical photos of their external genitalia were obtained. Prematurity and multiple congenital anomalies or syndromic characteristics were excluded. Serum and urine levels of phytoestrogens (daidzein and genistein) were calculated using liquid chromatography/mass spectrometry. The normality of the appearance of the external genitalia of the males was determined by a consensus review by experts. Results: A total of 146 cord blood and 96 newborn urine samples were obtained; only two newborns had abnormal external genitalia. In the 144 babies with normal external genitalia, mean levels were determined to be as follows; serum daidzein 10.82 ng/ml, serum genistein 42.17 ng/ml, urine daidzein 69.91 ng/ml, and urine genistein 126.09 ng/ml. In the two babies with abnormal external genitalia, mean levels of each of the measured phytoestrogen were lower; however, there was no statistical significance between the two groups (P > 0.05). Conclusions: We successfully determined and developed a novel database on the levels of measurable phytoestrogens in serum and urine from male newborns with normal external genitalia. In the normal group, a higher concentration of serum and urinary phytoestrogens was correlated with the extension of the scrotal pigmentation above and proximal to the base of the penis. These data are useful to better understand the role of phytoestrogens in the development of male genitalia and for future research on newborns with abnormal external genitalia.

Comprehensive Analysis of miRNAs and Target mRNAs between Immature and Mature Testis Tissue in Chinese Red Steppes Cattle.

Simple SummaryMicroRNAs are small molecules that can regulate the relative abundance of their target genes by binding to the 3′ untranslated region of the target genes at the post-transcriptional level to affect various biological processes, such as biosynthesis, fat metabolism and proliferation, apoptosis, and cell differentiation. Fertility is one of the most important economic traits in livestock production. Bulls require the continuous production of high-quality spermatozoa in abundance. The quality of semen is an exceptionally important factor affecting the fertilization rate of the dairy cow and is also associated with the increasing conception rate in the process of artificial insemination. Therefore, accurately predicting fertility potential for a semen sample from donor bull for artificial insemination is crucial for consistently high reproductive efficiency. The present study performed a genome-wide sequencing analysis of microRNAs and mRNAs between immature and mature testes of Chinese Red Steppes. These results provide novel candidate microRNAs and functional genes related to bull reproduction traits and the networks between microRNAs and target genes, which will provide a useful genetic mechanism and epigenetic information for marker-assisted selection of bulls with excellent sperm quality in the future.This study aims to screen potential regulators and regulate fecundity networks between microRNAs (miRNAs) and target genes. The bovine testes of immature and mature Chinese Red Steppes were performed by genome-wide analysis of mRNAs and miRNAs. Compared with testicular tissues of newborns, 6051 upregulated genes and 7104 downregulated genes in adult cattle were identified as differentially expressed genes (DEGs). The DEGs were significantly enriched in 808 GO terms (p < 0.05) including male gonad development, male genitalia development, spermatogenesis, and sperm motility. Moreover, DEGs were also significantly enriched in 105 KEGG pathways (p < 0.05), including cGMP-PKG signaling pathway and calcium signaling pathway. To explore the expression of miRNA-regulated gene expression, 896 differentially expressed target genes negatively regulated with the expression levels of 31 differentially expressed miRNAs (DERs) were predicted and analyzed, and a network-integrated analysis was constructed. Furthermore, real-time PCR was performed to verify the expression levels of DEGs and DERs. Our results identified novel candidate DEGs and DERs correlated with male reproduction and intricate regulating networks between miRNAs and genes, which will be valuable for future genetic and epigenetic studies of sperm development and maturity, as well as providing valuable insights into the molecular mechanisms of male fertility and spermatogenesis in cattle.

Androgen receptor expression in preputial dartos tissue correlates with physiological androgen exposure in congenital malformations of the penis and in controls

The androgen receptor (AR) plays an important role in the development of male genitalia, and impaired androgen signalling has been hypothesised to underlie congenital penile malformations (CPM) such as hypospadias. Previous studies exploring the role of AR expression in the development of CPM have yielded conflicting results. To assess AR expression in human foreskin of boys/men born with hypospadias, buried penis versus controls. Foreskin samples of 428 boys and men undergoing primary penile surgery (198 controls, 197 hypospadias, and 33 buried penis) were collected between October 2013 and July 2018. AR staining was performed in all samples and semi-quantitatively scored by two researchers independently, using a modified quick score (mQuicks) that assesses the proportion and intensity of AR staining in smooth muscle fibres. The interobserver variability of the mQuicks had a high level of agreement for the total score, as well as for the subscores. Two phases of high AR expression were observed in all groups, the first following the postnatal gonadotropin surge (i.e., mini-puberty) and the second in (pre-) puberty. No differences in AR expression were found in hypospadias or buried penis cases as compared to controls matched for age at time of surgery. This study describes the physiological evolution in AR expression in the human foreskin of boys with CPM and explains the cause of the previously reported, conflicting results. Despite the very large cohort, the limitations of this study are the low number of cases younger than sixmonthsat the time of surgery and the lack of Tanner stages to correlate with the mQuicks in adolescents. The mQuicks is a straightforward and informative tool to semi-quantitatively assess AR expression in the dartos tissue. In this study, AR expression in human foreskin shows a bimodal distribution in boys with CMP and controls, following physiological androgen exposure. No statistically significant difference in AR expression could be found between both groups. Whether other local mechanisms are affected by these physiological changes is currently unclear. However, strict age-matching should be considered when exploring the mechanisms underlying disturbed penile and urethral development in CMP.

Wilms’ Tumor 1 Overexpression in Granulosa Cells Is Associated with Polycystic Ovaries in Polycystic Ovary Syndrome Patients

Background: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by chronic ovulatory dysfunction, hyperandrogenism, and polycystic ovaries. Wilms’ tumor 1 (WT1) encoding a transcription factor involved in the differentiation of granulosa cells (GCs) regulates androgen receptor in the development of male genitalia. However, the expression pattern and possible role of WT1 in ovaries of PCOS patients are still unknown. Methods: GCs from 95 PCOS patients (PCOS group) and 62 healthy controls (control group) were isolated. The expression of WT1 in GCs was quantified using the reverse transcription-polymerase chain reaction. The correlation between WT1 expression and clinical characteristics was evaluated in PCOS patients. Results: WT1 expression was increased in PCOS patients compared with the normal controls. The expression of WT1 was moderately correlated with testosterone (r = 0.334, p = 0.001) and luteinizing hormone (r = 0.357, p = 0.001) levels and the antral follicle counts (r = 0.337, p = 0.001). Conclusions: Our study provided novel insights into the relationship between hyperandrogenism and polycystic ovaries of PCOS and WT1.

The aldo-keto reductases (AKRs): Overview

The aldo-keto reductase (AKR) protein superfamily contains >190 members that fall into 16 families and are found in all phyla. These enzymes reduce carbonyl substrates such as: sugar aldehydes; keto-steroids, keto-prostaglandins, retinals, quinones, and lipid peroxidation by-products. Exceptions include the reduction of steroid double bonds catalyzed by AKR1D enzymes (5β-reductases); and the oxidation of proximate carcinogen trans-dihydrodiol polycyclic aromatic hydrocarbons; while the β-subunits of potassium gated ion channels (AKR6 family) control Kv channel opening. AKRs are usually 37kDa monomers, have an (α/β)8-barrel motif, display large loops at the back of the barrel which govern substrate specificity, and have a conserved cofactor binding domain. AKRs catalyze an ordered bi bi kinetic mechanism in which NAD(P)H cofactor binds first and leaves last. In enzymes that favor NADPH, the rate of release of NADP+ is governed by a slow isomerization step which places an upper limit on kcat. AKRs retain a conserved catalytic tetrad consisting of Tyr55, Asp50, Lys84, and His117 (AKR1C9 numbering). There is conservation of the catalytic mechanism with short-chain dehydrogenases/reductases (SDRs) even though they show different protein folds. There are 15 human AKRs of these AKR1B1, AKR1C1–1C3, AKR1D1, and AKR1B10 have been implicated in diabetic complications, steroid hormone dependent malignancies, bile acid deficiency and defects in retinoic acid signaling, respectively. Inhibitor programs exist world-wide to target each of these enzymes to treat the aforementioned disorders. Inherited mutations in AKR1C and AKR1D1 enzymes are implicated in defects in the development of male genitalia and bile acid deficiency, respectively, and occur in evolutionarily conserved amino acids. The human AKRs have a large number of nsSNPs and splice variants, but in many instances functional genomics is lacking. AKRs and their variants are now poised to be interrogated using modern genomic and informatics approaches to determine their association with human health and disease.

Time course of expression of the retinoid X receptor gene and induction of imposex in the rock shell, Thais clavigera, exposed to triphenyltin chloride

To examine the role of the retinoid X receptor (RXR) in the development of imposex in gastropods, we investigated the time course of expression of the RXR gene in various tissues (ctenidium, ovary or testis, digestive gland, penis-forming area or penis, and head ganglia) of female and male rock shells (Thais clavigera) exposed to triphenyltin (TPT) in a flow-through exposure system for 3 months. Accumulations of TPT in tissues were clearly observed in exposed individuals, whereas no accumulation of TPT was observed in the control groups. In females, 3-month exposure to TPT resulted in the development of imposex, and penis lengths in imposex-exhibiting females were significantly longer in small females (shell height <20 mm) than in large females (shell height > or = 20 mm). RXR gene expression in the ovary, penis-forming area or penis, and head ganglia of females exposed for 3 months was significantly higher than expression in control females, and the highest RXR gene expression was found in the penis-forming area or penis. Moreover, RXR gene expression in the penis-forming area or penis of each female exposed to TPT seemed to be associated with an increase in penis length. In males, the ratio of penis length to shell height was significantly larger in the exposed groups than in the controls. Although RXR gene expression in males exposed for 3 months was not significantly higher than expression in control males in any tissues, the highest gene expression was observed in the penis of exposed males. These results suggest that RXR plays an important role in the development of male genitalia (i.e., penis and vas deferens) in gastropods, although RXR might also have other physiological functions.

Mutations of CXorf6 are associated with a range of severities of hypospadias

Mutations in chromosome X open reading frame 6 (CXorf6), a recently described candidate gene involved in the development of male genitalia, have been found in patients with complex 46,XY disorders of sexual development (46,XY DSD) including micropenis, bifid scrotum, and penoscrotal hypospadias. The objective of this work was to identify genomic variants of CXorf6 in patients with isolated hypospadias, severe or non-severe. Forty-one patients with glandular to perineal hypospadias and thirty controls were studied. Direct sequencing for coding exons 3-6 of CXorf6 and their flanking splice sites was performed on DNA extracted from foreskin collected from surgery. Secondary and tertiary structures of the protein were predicted using NNpredict and Protein Homology/analogY Recognition Engine engines. Four mutations (9.7% of cases) were identified. One missense mutation (1295T>C, V432A) and two deletions (325delG, predicted to cause a stop codon L121X) occurred in patients with penoscrotal and proximal hypospadias. One patient with subcoronal hypospadias had CAG-repeat amplification in the second polyglutamine domain of CXorf6. Secondary structure prediction indicated that this insertion occurred in a helix element of the protein. The tertiary structure prediction showed an alteration of the shape of the protein and crowding between domains. CXorf6 mutations are associated with isolated hypospadias of varying severity. However, the pathophysiology of these mutations and the function of the CXorf6 gene product remain to be investigated.

Mutations of Cxorf6 Cause a Range of Severities of Hypospadias

PURPOSE Mutations in CXorf6, a recently-described candidate gene involved in the development of male genitalia, have been found in patients with 46, XY disorders-of-sexual-development (46, XY DSD) and severe hypospadias. To date, there has been no data regarding CXorf6 in isolated hypospadias without DSD. This study aimed to characterize the potential role of CXorf6 in such patients. MATERIAL AND METHODS Forty-one patients with isolated hypospadias of various severity, and 30 controls were included. DNA was extracted from excess foreskin collected during surgery. Direct sequencing for coding exons 3-6 of CXorf6 and their flanking splice sites was performed. Secondary and tertiary structures of the protein were predicted using NNpredict and PHYRE engines. RESULTS Four mutations (9.7%) were identified. One missense mutation (V432A) and two deletions (del324G, predicted to cause a stop codon L121X) occurred in patients with penoscrotal and proximal hypospadias. One patient with subcoronal hypospadias had a CAG repeat amplification in the second polyglutamine domain of CXorf6. Secondary structure prediction indicated that this insertion occurred in a helix element of the protein. The tertiary structure prediction showed an alteration of the shape of the protein and crowding between domains. We also found a high incidence of polymorphisms (12.2%) in hypospadiac patients, (haplotype N589S/P286S in 4 cases). CONCLUSIONS CXorf6 mutations occur not only in 46 XY DSD but also in isolated hypospadias of varying severity. We also describe the first CAG repeat amplification of CXorf6. However, the specific events associated with these mutations and the precise function of CXorf6 remain to be investigated.

Californian hybrid zone between Culex pipiens pipiens and Cx. p. quinquefasciatus revisited (Diptera:Culicidae).

Phallosome morphology (DV/D ratio) and allozyme variation were used to reexamine the transition from Culex pipiens pipiens L. to Cx. p. quinquefasciatus Say, detected in California from the northern Central Valley to the Mexican border of the United States of America. Significant deficiency of heterozygotes was observed at the diagnostic locus Mdhp-2 in populations from the central part of the hybrid zone. Long tails of introgression were detected: populations from both north and south ends of the transect were not genetically pure Cx. p. pipiens or Cx. p. quinquefasciatus, respectively, as previously considered, but included approximately 5% introgressed individuals. A narrow reversed cline from the Delta area into the Sacramento Valley, characterized by increasing frequencies of Cx. p. quinquefasciatus alleles proceeding to the north, was confirmed. Both these cline appear to be related mainly to temperature gradients. Over the last 50 yr, an increase in the proportion of Cx. p. pipiens DV/D phenotypes was detected proceeding north to south along the main latitudinal cline, as well as in the narrow reversed cline. Accordingly, the center of the main latitudinal hybrid zone has apparently moved approximately 100 km to the south. This phenomenon is only partially paralleled by the differentiated locus Pgm of the 3 for which comparison was possible. Similarities to and differences from previous studies are discussed, also in relation with comparable data from another hybrid zone between Cx. p. pipiens and Cx. p. quinquefasciatus recently detected in Madagascar. Hybrid index scores based on differentiated allozymes and the diagnostic locus Mdhp-2 prove to be better descriptors than the DV/D ratio of hybridization and introgression occurring between Cx. p. pipiens and Cx. p. quinquefasciatus. This seems to be caused mainly by the influence of temperature on male genitalia development, and the weaker association found between genetic markers and DV/D phenotypes in hybrid populations.

Increased incidence of preeclampsia in pregnancies complicated by fetal malformation.

There seems to be a correlation between preeclampsia and congenital abnormalities, but whether it is positive or negative is a matter of controversy. Since it has been demonstrated that reduced perfusion of the trophoblast, which is an early feature of preeclampsia, can also represent a cause of fetal malformation, a positive correlation between the two conditions should be found. In the search for such a correlation we retrospectively examined 8,894 cases collected until 1994 by the IMER group (Indagine Malformazioni Emilia-Romagna). In the presence of malformation a higher incidence of preeclampsia was found (4.60 versus 3.47) with an odds ratio of 1.34 (95% CI = 1.08-1.67). Furthermore multivariate analysis showed that malformations of the male genital apparatus and those named 'multiple congenital abnormalities' can be considered as risk factors for preeclampsia. Since it is known that the development of male genitalia occurs under the influence of androgens, it can be hypothesized that hypoxia could act by favoring low end organ responsiveness. In our opinion the positive correlation with fetal malformations should be interpreted as clinical evidence of the early onset of the physiopathologic mechanism of preeclampsia.

Development of the external male and female genitalia in the immature stages of Cicadellidae (Homoptera)

Up to date studies on the development of the external male and female genitalia in Cicadellidae are somewhat limited. Hackman (1922) described the male and female genitalia in Cicadella. hieroglyphica Say, and Singh Puthri (19241 has given a brief description of the development of the male genitalia of Idiocerus. This paper presents a detailed study of the development of the various parts of the external male and female genitalia in fivespecies of Cicadellidae: Ulopa reticulata (F.), Doratura stylata (Boheman), Cicadula persimilis (Edwards), Mocydiopsis parvicauda Ribaut, Balclutha punctata (Thunberg), and Zygina scutellaris (Herrich-Schaeffer). The various instars were reared in the laboratory and specimens were fixed and mounted unstained for microscopic examination.

The development of male genitalia in an abnormal calf foetus

The development of male genitalia in an abnormal calf foetus