BACKGROUND: Reducing cardiovascular disease burden among women remains challenging. Epidemiologic studies have indicated that polycystic ovary syndrome (PCOS), the most common endocrine disease in women of reproductive age, is associated with an increased prevalence and extent of coronary artery disease. However, the mechanism through which PCOS affects cardiac health in women remains unclear. METHODS: Prenatal anti-Müllerian hormone treatment or peripubertal letrozole infusion was used to establish mouse models of PCOS. RNA sequencing was performed to determine global transcriptomic changes in the hearts of PCOS mice. Flow cytometry and immunofluorescence staining were performed to detect myocardial macrophage accumulation in multiple PCOS models. Parabiosis models, cell-tracking experiments, and in vivo gene silencing approaches were used to explore the mechanisms underlying increased macrophage infiltration in PCOS mouse hearts. Permanent coronary ligation was performed to establish myocardial infarction (MI). Histologic analysis and small-animal imaging modalities (eg, magnetic resonance imaging and echocardiography) were performed to evaluate the effects of PCOS on injury after MI. Women with PCOS and control participants (n=200) were recruited to confirm findings observed in animal models. RESULTS: Transcriptomic profiling and immunostaining revealed that hearts from PCOS mice were characterized by increased macrophage accumulation. Parabiosis studies revealed that monocyte-derived macrophages were significantly increased in the hearts of PCOS mice because of enhanced circulating Ly6C ⁺ monocyte supply. Compared with control mice, PCOS mice showed a significant increase in splenic Ly6C ⁺ monocyte output, associated with elevated hematopoietic progenitors in the spleen and sympathetic tone. Plasma norepinephrine (a sympathetic neurotransmitter) levels and spleen size were consistently increased in women with PCOS when compared with those in control participants, and norepinephrine levels were significantly correlated with circulating CD14 ⁺⁺ CD16 ⁻ monocyte counts. Compared with animals without PCOS, PCOS animals showed significantly exacerbated atherosclerotic plaque development and post-MI cardiac remodeling. Conditional Vcam1 silencing in PCOS mice significantly suppressed cardiac inflammation and improved cardiac injury after MI. CONCLUSIONS: Our data documented previously unrecognized mechanisms through which PCOS could affect cardiovascular health in women. PCOS may promote myocardial macrophage accumulation and post-MI cardiac remodeling because of augmented splenic myelopoiesis.

Background: Women are particularly vulnerable to depression during pregnancy, which is one of the strongest risk factors for developing postpartum depression (PPD). Addressing antenatal depressive symptoms in these women is crucial for preventing PPD. However, little is known about the effectiveness of internet-based cognitive behavioral therapy (ICBT) in preventing PPD in this high-risk group. Objective: This study aims to evaluate the short- and long-term effects of ICBT in preventing PPD among women with antenatal depressive symptoms. Methods: Participants were screened for antenatal depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS) and randomly allocated (1:1) to either the ICBT group (receiving weekly online modules starting antenatally and continuing into early postpartum) or the control group (observed without treatment). Follow-up assessments were conducted up to 12 months postpartum, and data were analyzed using generalized estimating equations. The primary outcome was the prevalence of depressive symptoms at 6 weeks postpartum. A subgroup analysis based on the severity of antenatal depressive symptoms was also performed. The secondary outcomes included the long-term effects of ICBT on maternal depression, as well as its impact on anxiety, sleep quality, social support, parenting stress, co-parenting relationships, and infant development. Results: Between August 2020 and September 2021, 300 pregnant individuals were recruited from 5 centers across China. No significant differences were observed in depressive symptoms at 6 weeks postpartum (P=.18) or at any longer-term follow-up time points (P=.18). However, a post hoc subgroup analysis showed that participants with antenatal EPDS scores of 10-12 in the ICBT group had a lower risk of developing depression during the first year postpartum (odds ratio 0.534, 95% CI 0.313-0.912; P=.02), but this was not observed for participants with more severe depression. Additionally, this subgroup demonstrated higher levels of co-parenting relationships (P=.02). Conclusions: Among individuals with antenatal depression, ICBT did not prevent the development of PPD. However, ICBT may be a preferable option for those with mild to moderate antenatal depressive symptoms. Future research is needed to explore modifications to ICBT to address more severe depressive symptoms. Trial Registration: Chinese Clinical Trial Registry ChiCTR2000033433; https://www.chictr.org.cn/showproj.html?proj=54482 International Registered Report Identifier (IRRID): RR2-10.1186/s13063-022-06728-5

The alarming prevalence of environmental microplastics has raised global concerns about fertility. However, the detriment of polytetrafluoroethylene (PTFE, Teflon), a widely used microplastic in non‐stick cookware, to sperm quality remains unclear. Here, a high detection rate (46.62%) and bioaccumulation of PTFE in the male urogenital system are reported and the mechanisms of PTFE exposure on male fertility are investigated in both humans and mice and potential therapeutic strategies are explored. These findings reveal that PTFE exposure delays the development of spermatogonia and spermatocytes, disrupts chromosomal synapsis and the DNA damage response, and promotes the apoptosis of spermatocytes. Interestingly, PTFE exposure specifically targets SKAP2 in the haploid spermatid, leading to disruption of the sperm cytoskeleton, abnormal sperm morphology, and decreased sperm motility. Strikingly, therapy targeting SKAP2 remodels sperm cytoskeleton and morphology and restores sperm motility and male fertility in humans and mice. Collectively, these works illustrate the mechanisms of PTFE exposure impairing spermatogenesis and highlight SKAP2 targeting as a promising therapeutic strategy for treating asthenoteratozoospermia in humans.

Huang X, et al. J Gynecol Oncol. 2024 Mar;35:e74. https://doi.org/10.3802/jgo.2024.35.e74

Sperm motility and morphology are indispensable for sperm-egg interaction and successful fertilization. However, the RNA splicing mechanisms in an m6A-dependent manner regulating spermiogenesis-related genes remain poorly defined, and targeted therapy strategies to restore impaired sperm motility and morphology are lacking. In this study, we identify heterogeneous nuclear ribonucleoprotein R (hnRNPR) as a critical m6A-dependent splicing mediator. Pathogenic mutations in HNRNPR cause sperm motility decline, morphological abnormality, and male infertility in both humans and mice. Mechanistically, Hnrnpr mutation disrupts m6A-dependent splicing of Skap2 pre-mRNA, thus impairing cytoskeletal structure and mitochondrial organization in sperm. Consistently, specific knockout of Skap2 in male germ cells displays sperm abnormalities, which phenocopy those observed in humans and mice with Hnrnpr mutants, unveiling a functional hnRNPR-SKAP2 axis. Leveraging these insights, we developed a therapeutic strategy to restore sperm motility and morphology, relying on extracellular vesicle-mediated SKAP2 delivery to enter the efferent ductules of the testicles, which could promote sperm cytoskeletal remodeling and mitochondrial organization. Notably, the co-culture of extracellular vesicle SKAP2 with human and mouse sperms also significantly enhanced the sperm motility. Altogether, these findings identify hnRNPR as a pivotal regulator of m6A-mediated Skap2 splicing during spermiogenesis and highlight extracellular vesicle SKAP2 as a promising therapeutic target for poor sperm quality and male infertility.