Single-nucleotide polymorphisms in <i>FLT3</i>, <i>NLRP5</i>, and <i>TGIF1</i> are associated with litter size in Small-tailed Han sheep

Previous studies have indicated that FLT3, NLRP5, and TGIF1 play a pivotal role in sheep fecundity. Nevertheless, little is known about the association of the polymorphisms of these genes with litter size (LS). In this study, the selected single-nucleotide polymorphisms (SNPs) were genotyped using a Sequenom MassARRAY® platform, and the distribution of different genotypes of the SNPs in the seven sheep breeds (Small-tailed Han, Hu, Cele Black, Suffolk, Tan, Prairie Tibetan, and Sunite sheep) were analyzed. The reliability of the estimated allele frequency for all seven SNPs was at least 0.9545. Given the association of the TGIF1 g.37866222C > T polymorphism with LS in Small-tailed Han sheep (p<0.05), fecundity differences might be caused by the change in amino acid from proline (Pro) to serine (Ser), which has an impact on secondary, tertiary protein structures with concomitant TGIF1 functionality changes. The FLT3 rs421947730 locus has a great effect on the LS (p<0.05), indicating that the locus of FLT3 in synergy with KILTG is likely to facilitate ovarian follicle maturation and ovulation. Moreover, NLRP5 rs426897754 is associated with the LS of the second and third parities (p<0.05). We speculate that a synonymous variant of NLRP5 may be involved in folliculogenesis accompanied by BMP15, FSHR, BMPR1B, AMH, and GDF9, resulting in the different fecundity of Small-tailed Han sheep. Our studies provide valuable genetic markers for sheep breeding.

Endocrine Disruption of the Follicle-Stimulating Hormone Receptor Signaling During the Human Antral Follicle Growth

An increasing number of pollutants with endocrine disrupting potential are accumulating in the environment, increasing the exposure risk for humans. Several of them are known or suspected to interfere with endocrine signals, impairing reproductive functions. Follicle-stimulating hormone (FSH) is a glycoprotein playing an essential role in supporting antral follicle maturation and may be a target of disrupting chemicals (EDs) likely impacting female fertility. EDs may interfere with FSH-mediated signals at different levels, since they may modulate the mRNA or protein levels of both the hormone and its receptor (FSHR), perturb the functioning of partner membrane molecules, modify intracellular signal transduction pathways and gene expression. In vitro studies and animal models provided results helpful to understand ED modes of action and suggest that they could effectively play a role as molecules interfering with the female reproductive system. However, most of these data are potentially subjected to experimental limitations and need to be confirmed by long-term observations in human.

Expression of the apoptosis regulatory gene family in the long-term in vitro cultured human cumulus cells

Human cumulus cells (CCs) play a key role in the regulation of ovarian follicle maturation and oocyte fertilization. They influence the oocyte development by transferring the various molecules via the specific gap junction proteins, also known as the connexins, which provide a direct transmembrane connection between the oocyte and CCs. The human CCs were obtained in the patients diagnosed with infertility, who underwent the procedure of the controlled ovarian stimulation, and the following in vitro fertilization to elucidate the possible involvement of the CCs in the regulation of the fertilization and oocyte aging. Collected samples were long-term cultured and harvested after 7, 15, and 30 days of cultivation. Afterward, we assessed the relative expression of the following apoptosis regulatory genes - BAX, CASP9, and TP53 - using the RT-qPCR method. We noted a decrease in the expression of all above-mentioned genes in the samples harvested after 15 and 30 days, in reference to 7 days in vitro cultured CCs. In summary, our results provide precious insight into the dynamics of changes and confirm the continuous expression of the proapoptotic genes – BAX, CASP9, and TP53 in the long-term cultured CCs. Running title: Apoptotic gene expression in the human cumulus cells

The Effect of Unripe Dates (Phoenix dactylifera) on Rat Ovarian Follicle Maturation and Ovulation

Unripe dates are believed by Indonesian citizens to increase fertility. This study aimed to assess the effect of unripe dates in the ovary of rats. Fresh yellow-colored dates were dried in an oven and crushed into powder. Eighteen rats aged three months and had given birth once were randomly divided into three groups. The treatment groups were given unripe dates at doses of 160mg/kgBW and 320mg/kgBW through a feeding tube for 28 days, and the control group was only given distilled water. Histopathological examination was carried out by the pathology expert using Hematoxylin-Eosin staining to observe the number of ovarian follicles according to their maturation stage. The results showed that the administration of unripe dates powder 320mg/kgBW increased corpus luteum number (21.50±4.72) and was statistically significant compared to the control group (15.16±3.71). Similar differences were also found in other stages of the follicle although not statistically significant. Administration of unripe date powder can increase ovulation induction among fertile rats.

Granulosa cell genes that regulate ovarian follicle development beyond the antral stage: the role of estrogen receptor β

ABSTRACTFollicle development beyond the preantral stage is dependent on gonadotropins. FSH signaling is crucial for the advancement of preantral follicles to the antral stage, and LH signaling is essential for further maturation of preovulatory follicles. Estrogen is intricately tied to gonadotropin signaling during the advanced stages of folliculogenesis. We observed that Erβnull ovarian follicles fail to develop beyond the antral stage, even after exogenous gonadotropin stimulation. As ERβ is primarily expressed in the granulosa cells (GCs), we explored the gonadotropin-regulated GC genes that induce maturation of antral follicles. Synchronized follicle development was induced by administration of exogenous gonadotropins to wildtype 4-wk-old female rats. The GC transcriptome was analyzed via RNA-sequencing before and after gonadotropin stimulation. An Erβnull mutant model that fails to show follicle maturation was also included in order to identify the ERβ-regulated genes involved at this step. We observed that specific groups of genes were differentially expressed in response to PMSG or hCG administration in wildtype rats. While some of the PMSG or hCG-induced genes showed a similar expression pattern in Erβnull GCs, a subset of PMSG- or hCG-induced genes showed a differential expression in Erβnull GCs. These latter ERβ-regulated genes included previously known FSH or LH target genes including Lhcgr, Cyp11a1, Cyp19a1, Pgr, Runx2, Egfr, Kiss1, and Ptgs2, which are involved in follicle development, oocyte maturation, and ovulation. We also identified novel ERβ-regulated genes including Jaml, Galnt6, Znf750, Dusp9, Wnt16, and Mageb16 that failed to respond to gonadotropin stimulation in Erβnull GCs. Our findings indicate that the gonadotropin-induced spatiotemporal pattern of gene expression is essential for ovarian follicle maturation beyond the antral stage. However, expression of a subset of those gonadotropin-induced genes is dependent on transcriptional regulation by ERβ.

Adverse Effects of some of the Most Widely used Metal Nanoparticles on the Reproductive System

Nanotechnology, which allows the manipulation of molecular dimensions, is used in many aspects of human life, from industrial to medical and therapeutic aspects. Features of nanoparticles and their unique capabilities have attracted a lot of attention. Among nanotechnology structures, metal nanoparticles have been widely used in many aspects of industry and medicine. The unique properties of these nanoparticles make possible to produce and expand them on a large scale, thus making the possibility of exposure to these nanoparticles more likely. Nanotechnology and nanoparticles like a double-edged sword despite its many benefits, it also has a number of disadvantages. One of the most important of these disadvantages is their toxicity. This toxicity may have adverse effects on the environment and humans. One of the most important adverse effects of nanoparticles is adverse effects on the reproductive system. In this paper, the adverse effects of some of the most widely used metal nanoparticles on the reproductive system are described. These adverse effects can be on: sexual behaviors, sexual organs, sperm count, sperm motility, sperm shape, sperm maturity, ovarian and follicle maturation, their fertility rate and also the level of sex hormones in men and women. The adverse effects of these nanoparticles and their toxicity on a variety of tissues and organs lead us to use safer nanoparticles.

Validity of the association between periodontitis and female infertility conditions: a concise review

Hormones and inflammatory mechanisms are implicated with female reproductive function, including follicle maturation, ovulation, embryo implantation, and pregnancy. Periodontitis is a chronic inflammatory disease due to a polymicrobial disruption of the homeostasis and may be considered as a potential risk factor that affect female fertility. The role of periodontitis is becoming meaningful, with significant associations with polycystic ovary syndrome, endometriosis and bacterial vaginosis. Further, periodontitis is linked with known risk factors towards female infertility, such as age, obesity, and chronic kidney disease. This review aims to summarize the available evidence on the association between periodontitis and female infertility-associated conditions, and to discuss warranting steps in future research.

Nuclear receptor Ftz-f1 promotes follicle maturation and ovulation partly via bHLH/PAS transcription factor Sim

The NR5A-family nuclear receptors are highly conserved and function within the somatic follicle cells of the ovary to regulate folliculogenesis and ovulation in mammals; however, their roles in Drosophila ovaries are largely unknown. Here, we discover that Ftz-f1, one of the NR5A nuclear receptors in Drosophila, is transiently induced in follicle cells in late stages of oogenesis via ecdysteroid signaling. Genetic disruption of Ftz-f1 expression prevents follicle cell differentiation into the final maturation stage, which leads to anovulation. In addition, we demonstrate that the bHLH/PAS transcription factor Single-minded (Sim) acts as a direct target of Ftz-f1 to promote follicle cell differentiation/maturation and that Ftz-f1’s role in regulating Sim expression and follicle cell differentiation can be replaced by its mouse homolog steroidogenic factor 1 (mSF-1). Our work provides new insight into the regulation of follicle maturation in Drosophila and the conserved role of NR5A nuclear receptors in regulating folliculogenesis and ovulation.