Development Of Reproductive System Research Articles

Arsenic exposure during juvenile and puberty significantly affected reproductive system development of female SD rats

Infertility affects about 10–15% couples over the world, among which a large number of cases the underlying causes are still unclear. Recent studies suggest that environmental factors may play an important role in these idiopathic infertilities. Arsenic is a heavy metal found in drinking water over the world. Its effect on the development of female reproductive system at the environmental-relevant levels is still largely unknown. To test the hypothesis that arsenic exposure during juvenile and puberty may affect sex maturation and female reproductive system development, SD rats of 3 weeks of age were exposed to arsenic with environmental-relevant levels (0, 0.02, 0.2, or 2 mg/L, n = 16/group) through drinking water for about 44 days until the rats reached adulthood (65 days of age). Arsenic exposure significantly reduced the weights of both ovary and uterus without affecting the body weight. Also, arsenic exposure disturbed estrus cycles and reduced the numbers of primordial follicles and corpora lutea while increased atretic follicles. In addition, arsenic reduced serum levels of estradiol, progesterone and testosterone but increased LH and FSH levels in dose-dependent manners. QPCR and Western blot experiments indicated arsenic selectively down-regulated ovarian steroidogenic-related proteins FSHR, STAR, CYP17A1, HSD3B1 and CYP19A1 and signaling molecules PKA-ERK-JNK-cJUN, without affecting AKT and CREB. As about reproductive capacity, arsenic-exposed dams had smaller pups, reduced litter size and lower number of male pups without a change in female pups. In conclusion, juvenile and pubertal arsenic exposures at environmental-relevant levels significantly reduced reproductive functions and capacity by adult. Since the lowest effective dose is very close to the government safety standards, the relevancy of arsenic over exposure to reproductive defects in human deserves further study.

P-654 Arsenic Exposure During Puberty Significantly Affected Sex Maturation and Reproductive System Development of Female SD Rats

Abstract Study question Can sex maturation and reproductive hormones affected by Arsenic exposure during puberty in female rats. Summary answer Pubertal AS exposure at environmental-relevant levels significantly enhanced sexual precocity but reduced reproductive functions and capacity by adult. What is known already Arsenic (AS) is widely distributed in the earth’s surface and its toxic effects have been known for a long time. About 130 million people, mainly in the developing countries, are overly exposed to the chemical of AS through the drinking water. AS contaminations in drinking water (10 - 50 ug/L) were associated with human reproductive defects, such as spontaneous abortion, stillbirth, lower birth weight, and smaller birth size. As exposures in adult rats were have been related to inhibition of steroidogenic enzymes and decreased estradiol levels. Study design, size, duration Forty female rats of 21 days of age were exposed to AS at different doses (0, 0.02, 0.2, or 2 mg/L, n = 10/group) through drinking water for about 44 days until the rats reached adulthood. In a second experiment, 24 rats were exposed to AS with a similar protocol and doses, in order to examine the effects of AS on the pregnancy and reproductive capacity. Participants/materials, setting, methods Sex maturation day and estrus cycles were recorded. When rats reached adult, serum pituitary and ovarian sex hormones were assayed. Ovarian steroidogenic pathway and its regulatory signaling molecules were analyzed by qPCR and/or Western blots. The parameters compared include Mating Index, Days with Copulatory Vaginal Sperm Plug, Pregnancy Rate, Fertility Index, Weight of Pups, Litter Size and Ratio of Male/Female Pups. Main results and the role of chance AS exposure significantly reduced the weights of both ovary and uterus without affecting the overall body weight. AS promoted sexual precocity, disturbed estrus cycles, significantly reduced the numbers of primordial follicles while increased atretic follicles. AS also reduced serum levels of estradiol, progesterone and testosterone but increased the LH and FSH levels in dose-dependent manners. In addition, AS selectively down-regulated steroidogenic-related proteins FSHR, STAR, CYP17A1, HSD3B1 and CYP19A1 and signaling molecules PKA-ERK/JNK-cJUN, without affecting AKT and CREB. As about reproductive capacity, AS significantly reduced pup weights, litter size and the number of male pups. Limitations, reasons for caution Future works are need to examined how AS may affect the hypothalamic-pituitary functions during the prepubertal period. Further studies are required to address how AS may affect the environment of female reproductive tract and the egg qualities. Wider implications of the findings AS exposure at environmental-relevant level during puberty significantly affected female reproductive system development. Since the concentrations tested overlaps the environmental levels recorded, the results may have important public health significance. Trial registration number NA

P-793 The effect of Nuclear Receptor Subfamily 5 Group A Member 1 (NR5A1) in human ovarian somatic cell development

Abstract Study question Can an inducible NR5A1 (encoding Steroidogenic Factor 1) cell line be used to study the functional role of NR5A1 in human female gonadal differentiation? Summary answer Conditional induction of NR5A1 in a human pluripotent stem cell (hPSC)-based model of gonadal differentiation allows us to study its effect on the differentiating cells. What is known already According to animal studies, NR5A1 is a critical factor in gonadal development. Previous research in our lab showed that CRISPR/Cas9 induced upregulation of NR5A1 during gonadal differentiation in male (XY) hPSCs increases expression of early Sertoli cell markers such as Inhibin A and Anti-Müllerian hormone (AMH) and thus pushes the cells into a more mature gonadal cell type. However, the role of NR5A1 in female gonadal differentiation has yet to be determined. Study design, size, duration The female (XX) human embryonic stem cell (hESC) line, H9, was edited using CRISPR/Cas9 to conditionally induce NR5A1. These cells were subjected to a 10/20-day gonadal differentiation protocol where NR5A1 was induced through addition of Doxycycline (DOX) and Trimethoprim (TMP) from day 4 until day 10/20. Starting from day 4 technical duplicates/triplicates from every second day were subjected to qRT-PCR. Technical triplicates from day 4, 6, 8 and 10 were subjected to bulk RNA-sequencing. Participants/materials, setting, methods The cell line that was used in this project is a female hESC line, H9 (WiCell). A previously established protocol for gonadal differentiation (Sepponen et al., 2017) was followed wherein different cell culture media and matrices were supplemented with small molecules, inhibitors and growth factors. The CRISPR/Cas9 genome-editing system was used to generate the NR5A1 inducible cell line. Cell characterisation was performed using qRT-PCR and bulk RNA sequencing (NovaSeq S4) methods. Main results and the role of chance qRT-PCR results showed that without NR5A1 induction there was almost no expression of this gene, but its expression increased drastically upon addition of DOX and TMP to the culture media. NR5A1 induction seemed to upregulate FOXL2 and WNT4, which are crucial genes for female gonadal differentiation, although the increase was not statistically significant. AMH showed a significant increase on day 8 of differentiation after NR5A1 induction. We also saw an increase in the expression of steroidogenic genes such as STAR, CYP11A1, CYP17A1 and CYP19A1 after NR5A1 induction. Subjecting the cells to NR5A1 induction for an additional 10 days resulted in the upregulation of bipotential gonadal markers GATA4, WT1 and EMX2 after NR5A1 induction. Similarly, the female gonadal markers RSPO1 and WNT4 were upregulated over time and WNT4 expression further increased upon NR5A1 induction. NovaSeq S4 data showed that on day 8, after induction of NR5A1, genes related to reproductive system development and female pregnancy were upregulated. These included DHH, NR5A1, CYP19A1, AR, INHA and NR0B1. On day 10 genes related to reproductive system development such as FOXL2, NR5A1, INHA, LHCGR, and NR0B1 were also upregulated after NR5A1 induction. Limitations, reasons for caution The effect of NR5A1 induction on expression levels of bipotential gonadal markers GATA4, LHX9, WT1, EMX2 and female gonadal markers FOXL2, RSPO1, WNT4 was small in comparison to differentiation without additional NR5A1 induction. Moreover, we lack a protocol to generate bipotential gonadal cells expressing NR5A1 without inducing NR5A1 through CRISPR/Cas9. Wider implications of the findings Taken together the results will provide valuable insight and novel information on the function of NR5A1 in early female gonadal development and more in general on human ovarian development and sex determination. This knowledge will increase our understanding of pathological gonadal development, which often underlies disorders of sex development. Trial registration number Not applicable

Sub-chronic and developmental toxicity of transdermal delivery of Renzhu ointment in young SD rats

Purpose: Renzhu ointment (Renzhuqigao, RZQG) is a patented herbal drug derived from Chinese traditional medicine formula and modern clinical experience for the transdermal treatment of non-infectious infantile diarrhoea. The safety of RZQG in preclinical studies has not been reported. Materials and methods: In this study, the pups of parent rats were examined for sub-chronic toxicity and developmental toxicity. After 21 days of birth, they were exposed to RZQG through their abdominal skin at doses of 0.1, 0.3, and 0.9 g/kg/day for 4 weeks and then were observed for another four weeks during their recovery period. Results: During the administration period, RZQG had no significant toxicological effect on body weight, food consumption, external eye examination, urinalysis, bone marrow examination, histopathology, central nervous system, reproductive system, or skeletal development. However, in the 0.9 g/kg/day group, the skin of some rats became dry and cracked, red and swollen, forming a white scab, while the white blood cells (WBC) count in female rats was lower and cholesterol (CHOL), triglycerides (TG), and glutamyl-transferase (GGT) were higher (p < 0.05). Conclusions: Rats receiving 0.9 g/kg/day exhibited skin irritation and were suspected to have a mild liver injury. There was no evidence of delayed toxicity four weeks after withdrawal. Therefore, the no-observed adverse effect level of RZQG was 0.3 g/kg/day (30 times the clinical dose planned and 4.92 times the human equivalent dose).

Construction of Copy Number Variation Map Identifies Small Regions of Overlap and Candidate Genes for Atypical Female Genitalia Development

Copy number variations (CNVs) have been implicated in various conditions of differences of sexual development (DSD). Generally, larger genomic aberrations are more often considered disease-causing or clinically relevant, but over time, smaller CNVs have been associated with various forms of DSD. The main objective of this study is to identify small CNVs and the smallest regions of overlap (SROs) in patients with atypical female genitalia (AFG) and build a CNV map of AFG. We queried the DECIPHER database for recurrent duplications and/or deletions detected across the genome of AFG individuals. From these data, we constructed a chromosome map consisting of SROs and investigated such regions for genes that may be associated with the development of atypical female genitalia. Our study identified 180 unique SROs (7.95 kb to 45.34 Mb) distributed among 22 chromosomes. The most SROs were found in chromosomes X, 17, 11, and 22. None were found in chromosome 3. From these SROs, we identified 22 genes as potential candidates. Although none of these genes are currently associated with AFG, a literature review indicated that almost half were potentially involved in the development and/or function of the reproductive system, and only one gene was associated with a disorder that reported an individual patient with ambiguous genitalia. Our data regarding novel SROs requires further functional investigation to determine the role of the identified candidate genes in the development of atypical female genitalia, and this paper should serve as a catalyst for downstream molecular studies that may eventually affect the genetic counseling, diagnosis, and management of these DSD patients.

Reference Values for and Correlation Analysis of the Anogenital Distance of Chinese Han Full-Term Singleton Neonates.

BackgroundAnogenital distance (AGD) is a biomarker used for the evaluation of fetal androgen action. The disruption of fetal androgen action can affect the development of the reproductive system and adversely affect future reproductive functions. However, AGD may differ by race. Currently, there is a lack of data regarding the evaluation of AGD in large Han Chinese samples.ObjectiveAGD for neonates in Shanghai, China, was measured, and relevant factors that influenced AGD were analyzed.MethodsThe AGD of full-term singleton neonates was measured within 3 days of birth, and the results were grouped according to gestational age and body weight at birth. In addition, relevant factors that influenced AGD were investigated.ResultsA total of 1,867 full-term singleton neonates were enrolled in this study. All the neonates were Han Chinese; among them, 986 were male, and 881 were female. Male AGD was 23.18 ± 3.17 mm, and female AGD was 11.65 ± 1.53 mm. Male AGD was 1.99 times longer than female AGD. With the increase in gestational age and body weight, AGD gradually increased. AGD was correlated with gestational age, body weight, and head circumference. The correlation between body weight at birth and AGD was highly significant.ConclusionThis study, for the first time, reported AGD measurement data for Chinese Han neonates. The results indicated that AGD was correlated with gestational age, body weight, and head circumference. The correlation between body weight at birth and AGD was highly significant.

Phenotype expansion of variants affecting p38 MAPK signaling in hypospadias patients

BackgroundHypospadias is a congenital anomaly of the male urogenital system. Genetics factors play an important role in its pathogenesis. To search for potential causal genes/variants for hypospadias, we performed exome sequencing in a pedigree with three patients across two generations and a cohort of 49 sporadic patients with hypospadias.ResultsA novel BRAF variant (NM_004333.6: c.362C > A) was found to co-segregate with the hypospadias phenotype in the disease pedigree. In cells overexpressing the BRAF mutant, the phosphorylation level of p38 MAPK was significantly increased as compared with the cells overexpressing the wild-type BRAF or RASopathy-related BRAF mutant. This variant further led to a reduced transcription level of the SRY gene, which is essential for the normal development of the male reproductive system. In the cohort of sporadic patients, we identified two additional variants in p38 MAPK signaling-related genes (TRIM67 and DAB2IP) potentially associated with hypospadias.ConclusionOur study expands the phenotypic spectrum of variants affecting p38 MAPK signaling toward the involvement of hypospadias.

Evaluation of the effects of temperature conditions on spermatogenesis and production characteristics of Siberian sturgeon at different types of fish farms

Issues related to temperature conditions of housing on spermatogenesis and production characteristics of newly developing males of Siberian sturgeon at different types of fish farms. Histological pattern of spermatozoa development at the stage of spermatogenesis has been evaluated. The study was performed at the Konakovo Division Industrial Site of the Branch for the freshwater fisheries of “VNIRO” (VNIIPRKH). At the initial phase of the study the assessment of sexual maturity of genital glands of male Siberian sturgeon in the autumn season was performed by ultrasound on the Samsung Medison SonoAce R3 apparatus. Subsequently, reference biopsy samples of reproductive products for histology tests were obtained. Selected and electronically tagged males were assigned into two study groups and kept in two fish farming pools with different temperature conditions. Histology of testes has shown that the reproductive system is at the prespawning condition. The quality of reproductive products (ejaculate) was evaluated by total volume, relative fertility, sperm concentration, by motility and also by score. It was established that the interval for potential production of qualitative reproductive products may range from 213 days at low temperatures with the total sum of the warmth of 1168.6 degree-days in direct flow pools to 136 days with the total sum of the warmth of 1480.0 degree-days. Keeping fish at low temperatures (4–6 °С) helps to prolong the process of spermatogenesis by 77 days. Therefore, at industrial fishery setting, particularly in RAS, with water temperatures durably kept optimal for spawning, it is possible to grow sturgeon males to spawning condition within the required time period. Obtained knowledge on the peculiarities of reproductive system development in male Siberian sturgeon will allow to improve the technology of spermatogenesis management at the industrial fishery setting, which will enable obtaining reproductive products of high fish quality at the required timeframes.

Juvenile Hormone Is an Important Factor in Regulating Aspongopus chinensis Dallas Diapause.

Aspongopus chinensis is a Chinese traditional edible and medicinal insect, which is in great demand in the society. This insect reproduces once a year which is caused by reproductive diapause resulting in insufficient production in wild resources. However, the mechanism of diapause in A. chinensis is still unclear. In this study, we focus on the relationship between juvenile hormones (JHs) and A. chinensis diapause. The results showed that JHIII concentration in diapause adult individuals was significantly lower than that in diapause termination adult individuals. When exogenous JHⅢ was injected into diapause adults, the rate of mating was increased significantly, development of the reproductive systems was accelerated, consumption of fat intensified, the expression of juvenile hormone acid o-methyl-transferase (JHAMT) was upregulated, and juvenile hormone epoxide hydrolase (JHEH) and fatty acid synthase (FAS) gene expressions were downregulated. In addition, RNAi of JHAMT decreased JH concentration, delayed the development of reproductive systems, slowed down fat consumption, and delayed the mean mating occurrence time significantly. Conversely, RNAi of JHEH resulted in an increased concentration of JH, development of reproductive systems was accelerated, consumption of fat was intensified, and mean mating occurrence time advanced significantly. Taken together, these findings uncovered that JH plays an important role in regulating reproductive diapause in A. chinensis and, thus, could provide a theoretical basis for further research on the diapause of A. chinensis.

Zinc transporters ZIPT-2.4 and ZIPT-15 are required for normal C. elegans fecundity.

The requirement of zinc for the development and maturation of germ lines and reproductive systems is deeply conserved across evolution. The nematode Caenorhabditis elegans offers a tractable platform to study the complex system of distributing zinc to the germ line. We investigated several zinc importers to investigate how zinc transporters play a role in the reproductive system in nematodes, as well as establish a platform to study zinc transporter biology in germline and reproductive development. Previous high throughput transcriptional datasets as well as phylogenetic analysis identified several putative zinc transporters that have a function in reproduction in worms. Phenotypic analysis of CRISPR-generated knockouts and tags included characterization of offspring output, gonad development, and protein localization. Light and immunofluorescence microscopy allowed for visualization of physiological and molecular effects of zinc transporter mutations. Disruption of two zinc transporters, ZIPT-2.4 and ZIPT-15, was shown to lead to defects in reproductive output. A mutation in zipt-2.4 has subtle effects on reproduction, while a mutation in zipt-15 has a clear impact on gonad and germline development that translates into a more pronounced defect in fecundity. Both transporters have germline expression, as well as additional expression in other cell types. Two ZIP-family zinc transporter orthologs of human ZIP6/10 and ZIP1/2/3 proteins are important for full reproductive fecundity and participate in development of the gonad. Notably, these zinc transporters are present in gut and reproductive tissues in addition to the germ line, consistent with a complex zinc trafficking network important for reproductive success.

46, XY 5-Alpha Reductase Deficiency in a 36-Year-Old Phenotypic Female Patient

46, XY 5-Alpha Reductase Deficiency in a 36-Year-Old Phenotypic Female Patient

SRY-GENE IN THE PATHOGENESIS OF GONADAL DYSGENESIS. SWIER’S SYNDROME

Annotation: Swier's syndrome is a genetic disorder, a variant of hypogonadism with a 46 XY karyotype, in which complete or "pure" dysgenesis of the testicles is observed, a female phenotype is formed with a male genotype. It is a congenital disorder associated with the Y chromosome. Swier's syndrome is usually associated with a genetic variant of testicular dysgenesis associated with mutations in the SRY gene (Sex-determining Region Y) located on the Y-chromosome of most mammals, and is involved in the development of the male-type organism (locus Yp11.3). The SRY gene, localized on the short arm of the Y chromosome, is usually expressed by 7-8 weeks of embryogenesis, triggering a signal for the differentiation of Sertoli cells, germinal epithelium of the seminiferous tubules, and Leydig cells. During physiological embryogenesis, AMH (anti-Müllerian hormone) is released in Sertoli cells, leading to regression of the Müllerian ducts, and in Leydig cells stimulated by placental chorionic gonadotropin (CG), and then by their own luteinizing hormone (LH), an increasing amount of testosterone is secreted. The SRY gene encodes the protein TDF (testisdeterminingfactor), a transcription factor that regulates the expression of other genes, which in turn encodes transcription factors that initiate the development of the male reproductive system in the embryonic period. During spermatogenesis during meiosis, the Y chromosome can lose SRY by transferring this gene to the X chromosome. In the absence of full-fledged genetic material (in particular, the expression of the SRY gene), the formation of functionally active testicular tissue is impossible. The lack of secretion of anti-Müllerian hormone leads to the development of Müllerian ducts, from which the uterus, upper vagina and fallopian tubes are formed. Thus, despite the male 46 XY karyotype, the external and internal reproductive organs of the fetus are formed by the female. In this literature review, the defects of the genes responsible for the varieties and clinical manifestations of Swier's syndrome are analyzed.

85 What Does the Vaginal Lipidome Tell Us?

Abstract Increasing reproductive efficiency in the breeding herd is a fundamental goal of modern swine production systems that depends on a multitude of factors, some of which begin at or before birth. Of particular interest, previous research has identified a link between colostrum consumption in the first 24h of the piglet’s life with survival, growth, and fertility through adulthood. Thus, the ingestion of colostrum appears to set the developmental trajectory of health and fertility in swine. However, the mechanism that link colostrum to long-term growth, health and fertility are not fully understood. Exploratory analysis of vaginal lipidome collected from three-week-old neonates that were followed prospectively to determine fertility found infertile sows had lower levels of arachidonic acid (AHA) and docosahexaenoic acid (DHA), and a greater abundance of two very long chain fatty acids (VLCFA: cerotic and ximenic). We surmise that AHA and DHA are markers of colostrum intake as additional studies found that AHA was increased in vaginal lipidome of gilts that consumed colostrum versus being fed milk replacer. We also surmise that high levels of VLCFA in the infertile animals was indicative of a buildup of these fatty acids in the tissue, similar to individuals with peroxisomal disorders with resulting alterations in lipid homeostasis linked to infertility. Taken together, our hypothesis is that differing levels of colostrum intake stimulate differing rates of peroxisomal biogenesis in neonates which in turn affects the development of the reproductive system and long-term fertility.

Population Genomic Sequencing Delineates Global Landscape of Copy Number Variations that Drive Domestication and Breed Formation of in Chicken.

Copy number variation (CNV) is an important genetic mechanism that drives evolution and generates new phenotypic variations. To explore the impact of CNV on chicken domestication and breed shaping, the whole-genome CNVs were detected via multiple methods. Using the whole-genome sequencing data from 51 individuals, corresponding to six domestic breeds and wild red jungle fowl (RJF), we determined 19,329 duplications and 98,736 deletions, which covered 11,123 copy number variation regions (CNVRs) and 2,636 protein-coding genes. The principal component analysis (PCA) showed that these individuals could be divided into four populations according to their domestication and selection purpose. Seventy-two highly duplicated CNVRs were detected across all individuals, revealing pivotal roles of nervous system (NRG3, NCAM2), sensory (OR), and follicle development (VTG2) in chicken genome. When contrasting the CNVs of domestic breeds to those of RJFs, 235 CNVRs harboring 255 protein-coding genes, which were predominantly involved in pathways of nervous, immunity, and reproductive system development, were discovered. In breed-specific CNVRs, some valuable genes were identified, including HOXB7 for beard trait in Beijing You chicken; EDN3, SLMO2, TUBB1, and GFPT1 for melanin deposition in Silkie chicken; and SORCS2 for aggressiveness in Luxi Game fowl. Moreover, CSMD1 and NTRK3 with high duplications found exclusively in White Leghorn chicken, and POLR3H, MCM9, DOCK3, and AKR1B1L found in Recessive White Rock chicken may contribute to high egg production and fast-growing traits, respectively. The candidate genes of breed characteristics are valuable resources for further studies on phenotypic variation and the artificial breeding of chickens.

Оцінка репродуктивного потенціалу дівчаток-підлітків із гінекологічною патологією, народжених із дефіцитом маси тіла

The timing of puberty depends on many genetic factors and external conditions: race and ethnicity, environmental characteristics, geographical location and even the nature of nutrition. Often the cause of functional delayed puberty is the syndrome of delayed fetal development. Purpose - to study the main indicators of development and formation of the reproductive system of adolescent girls with gynecological pathology, born with a deficit of body weight. Materials and methods. We examined 53 adolescent girls aged 13-18 years, who were divided into groups according to body weight at birth. Group 1 (main) - 26 girls born weighing less than 3000.0 grams. The second group (comparison) included 27 girls born with a body weight of 3000-3700.0 grams. The survey included analysis of anamnesis data, assessment of levels of physical and sexual development. Results. The mean age of the subjects was 14.5±1.8 years [12.7; 16.3]. For girls who were born with low body weight, during puberty there was a lower dynamics of annual weight gain and average body weight compared to girls in group 2. In all age periods there was a significant lag in growth in the 1st group compared to the 2nd group. The growth deficit in 13-14 years was 3.5 cm, in 15-16 years - 3.7 cm, and in 17-18 years - 4.2 cm. The largest increase in the external size of the pelvis compared to the previous age period is observed in 15-16 years. In the 1st and 2nd groups of the transverse dimensions of the pelvis d.cristarum increases most intensively, slightly less - d.trochanterica. Analyzing the indicators of the main external dimensions of the pelvis, we can conclude that at the age of 13-14 and 15-16 years in girls of the 1st group, the size of the pelvis did not differ from the parameters in the 2nd group. However, in 17-18 years, all the external dimensions of the pelvis lagged behind the data in the 2nd group by an average of 1 cm, which indicates a tendency to form a narrow pelvis in girls born with low body weight. The average total score of sexual development in the 1st group in all studied age periods was significantly lower than in the 2nd. Conclusions. For girls born with low body weight, there is a tendency to delay sexual development by the nature of pubic hair, but by the end of puberty, this feature is close to the parameters of peers born with normal body weight. Thus, by the age of 18, almost all girls born with normal body weight have a complete degree of secondary sexual characteristics, typical of women of childbearing age. While girls born with low body weight, there was a slowdown in the formation of secondary sexual characteristics in adolescence. The research was carried out in accordance with the principles of the Helsinki declaration. The study protocol was approved by the Local ethics committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interest was declared by the authors. Key words: puberty, reproductive potential, low birth weight, menarche.

Comparative transcriptome analysis identifies crucial candidate genes and pathways in the hypothalamic-pituitary-gonadal axis during external genitalia development of male geese

BackgroundAll birds reproduce via internal fertilization, but only ~3% of male birds possess the external genitalia that allows for intromission. Waterfowl (e.g., duck and goose) are representatives of them, and the external genitalia development of male geese is directly related to mating ability. Notably, some male geese show abnormal external genitalia development during ontogenesis. However, until now little is known about the molecular mechanisms of the external genitalia development in goose. In the present study, comparative transcriptomic analyses were performed on the hypothalamus, pituitary gland, testis, and external genitalia isolated from the 245-day-old male Tianfu meat geese showing normal (NEGG, n = 3) and abnormal (AEGG, n = 3) external genitals in order to provide a better understanding of the mechanisms controlling the development of the external genitalia in aquatic bird species.ResultsThere were 107, 284, 2192, and 1005 differentially expressed genes (DEGs) identified in the hypothalamus, pituitary gland, testis and external genitalia between NEGG and AEGG. Functional enrichment analysis indicated that the DEGs identified in the hypothalamus were mainly enriched in the ECM-receptor interaction pathway. The ECM-receptor interaction, focal adhesion, and neuroactive ligand-receptor interaction pathways were significantly enriched by the DEGs in the pituitary gland. In the testis, the DEGs were enriched in the neuroactive ligand-receptor interaction, cell cycle, oocyte meiosis, and purine metabolism. In the external genitalia, the DEGs were enriched in the metabolic, neuroactive ligand-receptor interaction, and WNT signaling pathways. Furthermore, through integrated analysis of protein-protein interaction (PPI) network and co-expression network, fifteen genes involved in the neuroactive ligand-receptor interaction and WNT signaling pathways were identified, including KNG1, LPAR2, LPAR3, NPY, PLCB1, AVPR1B, GHSR, GRM3, HTR5A, FSHB, FSHR, WNT11, WNT5A, WIF1, and WNT7B, which could play crucial roles in the development of goose external genitalia.ConclusionsThis study is the first systematically comparing the hypothalamus, pituitary gland, testis, and external genitalia transcriptomes of male geese exhibiting normal and abnormal external genitals. Both bioinformatic analysis and validation experiments indicated that the neuroactive ligand-receptor interaction pathway could regulate the WNT signaling pathway through PLCB1 to control male goose external genitalia development.

The Impact of Estrogens and Their Receptors on Immunity and Inflammation during Infection.

Simple SummaryHuman health is significantly affected by microbial infections. One of the largest determinants of the outcomes of such infections is the host immune response. Too weak of a response can lead to enhanced spread by the pathogen, while an overstimulated response can lead to immune-induced tissue damage. Thus, to effectively treat infected individuals, it is critical to understand the regulators that control inflammatory responses. Recently, it has become widely accepted that estrogens, a class of sex hormones, are capable of dramatically altering the responses of host cells to microbes. In this review, we discuss how estrogens change the host immune response, as well as how these changes can alter the outcome of the infection for the individual.Sex hormones, such as estrogen and testosterone, are steroid compounds with well-characterized effects on the coordination and development of vertebrate reproductive systems. Since their discovery, however, it has become clear that these “sex hormones” also regulate/influence a broad range of biological functions. In this review, we will summarize some current findings on how estrogens interact with and regulate inflammation and immunity. Specifically, we will focus on describing the mechanisms by which estrogens alter immune pathway activation, the impact of these changes during infection and the development of long-term immunity, and how different types of estrogens and their respective concentrations mediate these outcomes.

Ambulatory Blood Pressure Monitoring in Children and Adults Prenatally Exposed to Dexamethasone Treatment.

ContextThe clinical use of dexamethasone (DEX) prenatally to reduce virilization of external genitalia in female fetuses with congenital adrenal hyperplasia (CAH) is efficient but still controversial. It remains challenging to prevent the excessive exposure of DEX in unborn healthy babies during the first trimester of pregnancy.ObjectiveSince endogenous glucocorticoids contribute to the maintenance of blood pressure (BP) and since events during fetal life may program the fetus and affect future metabolic health, the aim of this study was to analyze ambulatory BP measurements in CAH-unaffected children and adults that were prenatally exposed to DEX treatment.MethodsAmbulatory BP measurements were analyzed in 33 (16 female) DEX-treated participants aged 5.1 to 26.3 years (19 participants aged ≤ 18 years) and in 54 (28 female) age- and sex-matched apparently healthy controls aged 5.5 to 25.3 years (27 participants aged ≤ 18 years) with ambulatory normotension.ResultsParticipants’ age, height, weight, and body mass index were similar between the DEX-treated group and the control group. Heart rate, 24-hour BP, pulse pressure, and nighttime dipping did not statistically significantly differ between DEX-treated participants and controls.ConclusionOur study suggests that prenatal DEX treatment in CAH-unaffected children and adults does not appear to adversely affect ambulatory BP later in life. Our observations need to be confirmed in larger studies.

Molecular mechanism of ovarian toxicity of Hook.F. a study based on network pharmacology and molecular docking.

To explore the mechanism of ovarian toxicity of Hook. F. (TwHF) by network pharmacology and molecular docking. The candidate toxic compounds and targets of TwHF were collected by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and the Comparative Toxicogenomics Database (CTD). Then, the potential ovarian toxic targets were obtained from CTD, and the target genes of ovarian toxicity of TwHF were analyzed using the STRING database. The protein-protein interaction (PPI) network was established by Cytoscape and analyzed by the cytoHubba plug-in to identify hub genes. Additionally, the target genes of ovarian toxicity of TwHF were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses by using the R software. Finally, Discovery Studio software was used for molecular docking verification of the core toxic compounds and the hub genes. Nine candidate toxic compounds of TwHF and 56 potential ovarian toxic targets were identified in this study. Further network analysis showed that the core ovarian toxic compounds of TwHF were triptolide, kaempferol and tripterine, and the hub ovarian toxic genes included , , , , , , , , and . Besides, the GO and KEGG analysis indicated that TwHF caused ovarian toxicity through oxidative stress, reproductive system development and function, regulation of cell cycle, response to endogenous hormones and exogenous stimuli, apoptosis regulation and aging. The docking studies suggested that 3 core ovarian toxic compounds of TwHF were able to fit in the binding pocket of the 10 hub genes. TwHF may cause ovarian toxicity by acting on 10 hub genes and 140 signaling pathways.

Mouse Cre drivers: tools for studying disorders of the human female neuroendocrine-reproductive axis†.

Benign disorders of the human female reproductive system, such primary ovarian insufficiency and polycystic ovary syndrome are associated with infertility and recurrent miscarriage, as well as increased risk of adverse health outcomes, including cardiovascular disease and type 2 diabetes. For many of these conditions, the contributing molecular and cellular processes are poorly understood. The overarching similarities between mice and humans have rendered mouse models irreplaceable in understanding normal physiology and elucidating pathological processes that underlie disorders of the female reproductive system. The utilization of Cre-LoxP recombination technology, which allows for spatial and temporal control of gene expression, has identified the role of numerous genes in development of the female reproductive system and in processes, such as ovulation and endometrial decidualization, that are required for the establishment and maintenance of pregnancy in mammals. In this comprehensive review, we provide a detailed overview of Cre drivers with activity in the neuroendocrine-reproductive axis that have been used to study disruptions in key intracellular signaling pathways. We first summarize normal development of the hypothalamus, pituitary, ovary, and uterus, highlighting similarities and differences between mice and humans. We then describe human conditions resulting from abnormal development and/or function of the organ. Finally, we describe loss-of-function models for each Cre driver that elegantly recapitulate some key features of the human condition and are associated with impaired fertility. The examples we provide illustrate use of each Cre driver as a tool for elucidating genetic and molecular underpinnings of reproductive dysfunction.