Reproductive and Developmental Medicine最新文献

The Ras homolog gene family member A (RhoA) is a small GTPase. RhoA plays major roles in cytoskeletal regulation, transcriptional control, and cell cycle maintenance. RhoA is widely expressed in the female reproductive system (FRS). In vitro studies have implicated RhoA in several FRS functions and studies defining the in vivo functions of RhoA in the FRS are emerging. In the ovary, RhoA is essential for corpus luteum development and progesterone synthesis and is implicated in ovarian cancer. Some studies on the oviduct/fallopian tube suggest potential functions of RhoA in post-ovulation cumulus cells and embryo transport. In the uterus (corpus uterus), RhoA may be involved in embryo implantation (eg, decidualization) and parturition (eg, uterine contraction) and is also implicated in uterine disorders (eg, endometriosis and leiomyoma). Downregulation of RhoA in the cervix is correlated with cervical ripening during parturition, and numerous studies have implicated RhoA in cervical cancer. In the placenta, RhoA is implicated in preeclampsia and placenta accreta. In the vagina, RhoA downregulation correlates with vaginal smooth muscle relaxation and sexual response. RhoA in the mammary glands has been implicated in development and lactation as well as breast cancer. RhoA signaling is a potential therapeutic target for managing pathological conditions of the FRS. This review provides a comprehensive coverage of the current understanding of the spatiotemporal functions of RhoA in the FRS. Extensive knowledge regarding the in vivo cell type- and stage-specific functions of RhoA in FRS remains to be elucidated.

Objective: Although numerous observational studies have revealed a correlation between leukocyte telomere length (LTL) and female reproductive system diseases (RSDs), the findings of these studies have tended to be consistent. In this study, we accordingly sought to clarify the causal relationships between LTL and RSDs.

Methods: We performed a bidirectional two-sample Mendelian randomization (MR) analysis using pooled statistics from genome-wide association studies of LTL and nine female RSDs. The final results were analyzed using five MR methods, with the inverse variance weighted (IVW) method used as the primary outcome. We applied MR-PRESSO to exclude outliers. Sensitivity analyses were also conducted to assess heterogeneity and pleiotropy.

Results: In the forward MR analysis, a genetic prediction of longer LTLs was found to be causally associated with higher risks of endometriosis (IVW: odds ratio [OR] = 1.25, 95% confidence interval [CI] = 1.06-1.46, P = 0.008), leiomyoma of the uterus (IVW: OR = 1.73, 95% CI = 1.52-1.98, P = 4.9E-16), and ovarian cysts (IVW: OR = 1.31, 95% CI:1.19-1.45, P = 1.5E-07). In the reverse MR results, female RSDs were shown to have no significant effect on LTLs (all P values >0.05). Sensitivity analysis confirmed the robustness of these results.

Conclusions: Our findings substantiate the assumption that a genetically predicted longer LTL elevates the risk of endometriosis, leiomyoma of the uterus, and ovarian cysts, with no influence of RSDs on LTL. These findings contribute to establishing a causal link between LTL and RSDs, overcoming the constraints of earlier observational studies. They also imply that LTL could potentially serve as a biomarker for the occurrence of endometriosis, leiomyoma of the uterus, and ovarian cysts.

Objective: This study aimed to investigate the influence of lung function on the relationship between allergies and hypertension, thereby elucidating significant potential mechanisms from a genetic standpoint. We investigated the causal relationship between childhood allergies (age <16 years) and essential hypertension and identified and quantified the role of lung function (forced vital capacity [FVC] and forced expiratory volume in the first second/forced vital capacity [FEV1/FVC]) as potential mediators.

Methods: Using data from a genome-wide association study and the Fenn Genn consortium, a two-sample Mendelian randomization (MR) analysis of genetically predicted childhood allergies (7128 cases and 211,703 controls) and essential hypertension (116,714 cases and 1,032,659 controls) was performed. Furthermore, we used two-step MR to quantify the effect of lung function-mediated childhood allergies on essential hypertension. The FVC and FEV1/FV sample size was 371,898.

Results: Childhood allergies were associated with increased odds of developing essential hypertension (odds ratio [OR] = 1.0900, 95% confidence interval [CI] =   1.0034-1.1842, P = 0.0414). No strong evidence that genetically predicted essential hypertension affected childhood allergy risk was identified (OR = 1.0631, 95% CI = 0.9829-1.1498, P = 0.1264). The proportion of genetically predicted childhood allergies mediated only by FVC was 5.67% (95% CI, 5.13%-5.73%).

Conclusion: A causal relationship between childhood allergies and essential hypertension was identified, with a proportion of the effect mediated by FVC. Therefore, implementing early interventions in children with allergies is imperative to mitigate the long-term risk of developing hypertension. Further research is required to identify additional risk factors as potential mediators.

Objective: Female Mcoln1 ^-/- mice exhibit progressive progesterone (P4) deficiency, luteal cell degeneration, and premature embryo implantation failure at 5 months old. We attempted to rescue embryo implantation in non-virgin Mcoln1 ^-/- mice (5-6 months old) with exogenous P4 treatment on days 1.5 post-coitum (D1.5), D2.5, and D3.5, and observed partially restored luteal cell morphology on D4.5, but unexpectedly found 17β-estradiol (E₂) contamination in the P4 working solution. In this study, we aim to investigate exogenous P4 and/or E₂ for the partial recovery of luteal cell morphology in infertile Mcoln1 ^-/- mice.

Methods: Control and non-virgin Mcoln1 ^-/- mice (5-6 months old) were treated with newly ordered vehicle, P4, E₂, or P4 + E₂ on D1.5 and D2.5 and dissected on D3.5 for P4 and E₂ measurements, ovary histology, immunofluorescence, lipid droplet staining, and transmission electron microscopy.

Results: E₂ treatment significantly increased serum P4 levels in D3.5 Mcoln1 ^-/- mice. E₂ and P4 + E₂ treatments, but not P4 treatment alone, largely improved the morphology of D3.5 Mcoln1 ^-/- corpora lutea, indicated by a more contiguous web-like collagen IV expression pattern, increased heat shock protein 60 expression, and reduced accumulation of large lipid droplets. Transmission electron microscopy revealed extremely enlarged autophagosomes and lipid droplets, lysosomes with lamellar structures, and mitochondria with reduced cristae in vehicle-treated D3.5 Mcoln1 ^-/- luteal cells, while in E₂-treated D3.5 Mcoln1 ^-/- luteal cells, extremely enlarged autophagosomes and lipid droplets were reduced, indicating improved luteal cell ultrastructure.

Conclusion: These findings reveal protective effects of high levels of exogenous E₂ on P4 production and lysosomal function in Mcoln1 ^-/- luteal cells.