Reproductive Science Center

Evidence from multicenter studies in Chinese populations on prenatal per- and polyfluoroalkyl substance (PFAS) exposure and preterm birth (PTB), and related metabolic mechanisms, remains limited. We conducted a multicenter case-control study including 1990 mother-infant pairs from northern, northwestern, and southern China (2015-2021) to examine associations between umbilical cord serum PFAS levels and PTB risk. In a subcohort (n = 134), maternal venous blood was analyzed using untargeted metabolomics. Higher levels of most PFAS were associated with an increased PTB risk. Pentacosafluorotridecanoic acid (PFTrDA) showed the strongest association, with a 51% higher PTB risk per interquartile range increase (OR = 1.51; 95% CI: 1.29-1.76), and elevated risks for moderate PTB (OR = 1.66; 95% CI: 1.22-2.25) and late PTB (OR = 1.45; 95% CI: 1.21-1.74). PFAS mixture analyses indicated a positive joint effect (OR = 1.03; 95% CI: 1.01-1.06 per decile increase). Metabolomics identified PFTrDA as the PFAS linked to the most metabolic perturbations (four metabolites). Glycodeoxycholic acid (GDCA) was consistently associated with PFAS exposure and mediated 21-44% of associations between selected PFAS and PTB, suggesting disruptions in bile acid and lipid metabolism.

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Gestational diabetes mellitus (GDM) affects 14% of pregnancies worldwide with adverse maternal and offspring outcomes. Fetal sex is known to influence pregnancy outcomes and shape placental function. Although the placenta plays a central role in regulating maternal glucose levels, the molecular mechanisms driving GDM pathophysiology—and how they vary by fetal sex—are incompletely understood. We examined fetal sex impact on placental gene programs in GDM using two independent cohorts. In a case-control study (N = 101, 42 with GDM), we assessed expression of eight glycemic/immune regulation genes via qPCR in GDM placentas versus sex-matched controls. In a second prospective cohort of 433 individuals (N = 35 with GDM), we performed sex-stratified transcriptomic analyses of placental RNA-Seq data. Placental expression of genes implicated in glucose metabolism (IGFBP1, RBP4, EPYC, and PRL) was sexually dimorphic in GDM versus sex-matched controls. Transcriptomic analyses revealed enrichment in proinflammatory/glycolytic pathways and dysregulated retinoic acid signaling in male GDM placentas, while female GDM placentas showed enrichment in cell growth and immunoregulatory pathways. GDM elicits sex-specific differences in placental gene programs, highlighting the importance of incorporating fetal sex in pregnancy studies. These findings may inform future sex-tailored strategies for offspring risk prediction and intervention in GDM.

To assess whether the endometrial receptivity analysis (ERA) captures receptivity changes attributed to endometrial aging and whether it may be useful for older patients undergoing fertility treatment. Retrospective cohort study of patients who underwent ERA testing at an academic center (01/2019-05/2024). The ERA inferred transcriptomic levels of canonical receptivity markers from biopsies obtained at standard timing. Demographic and treatment-related variables were analyzed by age group. The proportion of non-receptive ERA results (pre- and post-receptive combined) was compared using Fisher's exact test. Univariable and multivariable logistic regression assessed associations between predictors and non-receptive ERA. Of 210 patients, 205 were included. Age distribution was < 35 (n = 35, 17%), 35-37 (n = 58, 28.3%), 38-40 (n = 53, 25.8%), and ≥ 41 (n = 59, 28.8%). Overall, 166 (81.0%) ERAs were receptive, 33 (16.1%) pre-receptive, and 6 (2.9%) post-receptive. BMI, infertility diagnosis, and prior implantation or miscarriage history did not differ by age. Non-receptive ERA proportions were 20% (< 35), 17.2% (35-37), 17.0% (38-40), and 22.0% (≥ 41) (p = 0.52). In multivariable analysis adjusting for BMI and number of prior failed euploid transfers, age was not associated with non-receptive ERA (aOR 0.98, 95% CI 0.34-2.30, p = 0.97). Uterine age was not associated with increased odds of non-receptive ERA, suggesting that the test does not capture age-related changes in endometrial receptivity. Although endometrial aging is implicated in reduced embryo transfer success, the ERA should not be ordered solely on the basis of uterine age. The ERA may not reliably detect age-related endometrial differences in the window of implantation at a clinical level.

Abstract Ovarian cancer stem cells (CSCs) can seed recurrent drug-resistant disease. Likewise, non-CSCs can acquire CSC phenotypic properties. How this process is orchestrated is of interest to inform how it might be prevented. We tested the hypothesis that ovarian CSC and/or drug-resistant tumor cells confer stem-like properties via extracellular vesicles (EVs). We focused our investigation on how EVs might mediate EZH2 signaling to promote a phenotypic change in drug-sensitive, non-CSCs. To accomplish this, we utilized paired PARP inhibitor-sensitive and - resistant ovarian cancer (OvCa) cell lines, EZH2 knockdown lines, and patient-derived organoids (PDOs) originating from recurrent high-grade serous OvCa. Small EVs isolated from drug-sensitive, CSC and/or drug-resistant enriched cultures, PARP inhibitor (olaparib) resistant lines, or drug-treated (olaparib or carboplatin) lines were cultured with treatment naïve or sensitive lines for defined time points. The impact of small EV exposure was determined by assessing cell number, metabolic activity, viability, sphere and colony-forming capacity, ALDH activity, DNA damage, and changes in associated signaling pathways. We found that EVs from CSC or drug-resistant enriched cell fractions communicate CSC-like phenotypes to the more sensitive tumor cells via EZH2 canonical and non-canonical signaling pathways, promoting stemness. We conclude that EV-mediated activation of EZH2 signaling represents a targetable mechanism contributing to stemness-associated drug resistance in OvCa. Graphical abstract

Sacrococcygeal teratomas (SCTs) are the most common neonatal tumors, yet their cellular origins, clinical stratification, and sex bias-occurring three times more in XX than XY individuals-remain poorly understood. To address these gaps, we examined six postnatal (one male and five female) and two prenatal (both female) SCTs by single nuclei RNA-seq and spatial transcriptomics. We identified five broad cellular lineages in SCTs: stroma, epithelia, endothelia, neuroectoderm, and immune. The transcriptomes and lineage compositions showed significant heterogeneity, which offer a framework for future molecular stratification. SCTs are thought to originate from and be propagated by pluripotent cells, notably however, we did not detect these populations. Among female tumors, a subset of cells exhibited biallelic expression of X-linked genes, consistent with X-inactivation failure or reactivation of the once inactivated X-chromosome. These biallelic cells were enriched for developmental and neuronal programs, whereas cells with single-allelic X-chromosome preferentially expressed immune-related genes. Biallelic X-chromosome activation, which can occur only in female cells, may result in transcriptomic features that favor survival of tumor cells, contributing to the sex bias of SCTs. Our findings reveal a link between X-chromosome inactivation and SCT cell identity, suggesting that X-dosage dysregulation may influence SCT heterogeneity and immune landscape.

ObjectiveTo evaluate the association between prior mode of delivery (cesarean vs. vaginal) and endometrial thickness in the subsequent frozen embryo transfer (FET) cycle. The secondary aim was to evaluate FET cycle outcomes.DesignRetrospective cohort study.SubjectsThis multicenter study included patients with one previous live birth who initiated a subsequent, autologous FET cycle from January 2012 to December 2024. Patients were grouped by mode of prior delivery: cesarean or vaginal.ExposureCesarean or vaginal delivery.Main Outcome MeasuresThe primary outcome was endometrial thickness at final lining assessment. Secondary outcomes included FET cycle cancellation rate due to thin or fluid-filled endometrium, pregnancy, and live birth rates. Subgroup analyses evaluated outcomes of euploid FET cycles only.ResultsA total of 11,131 FET cycles consisting of 5,149 from patients with prior cesarean and 5,982 from patients with prior vaginal delivery were included. Endometrial thickness in the subsequent FET cycle was similar between cohorts (cesarean: 10.4 mm [10.3–10.5 mm]; vaginal: 10.4 mm [10.3–10.4 mm]). The FET cycle cancellation rate due to thin endometrium was comparable (cesarean: 1.3%, vaginal: 1.2%; adjusted relative risk [aRR] 1.02 [0.72–1.43]); cancellation due to endometrial fluid accumulation was higher in the cesarean cohort (1.0% vs. 0.5%; aRR 2.22 [1.40–3.58]). Cesarean delivery was associated with lower live birth (49.5% vs. 53.0%; aRR 0.95 [0.90–0.98]) and clinical pregnancy (60.5% vs. 64.1%; aRR 0.95 [0.90–0.99]), with similar rates of clinical pregnancy loss (cesarean: 10.6%, vaginal: 10.6%; aRR 0.95 [0.84–1.07]). Similar trends were observed in patients undergoing euploid FET, with lower live birth demonstrated in those with a prior cesarean (55.3% vs. 60.3%; aRR 0.91 [0.84–0.98]), but similar chance of clinical pregnancy loss (cesarean: 9.1%, vaginal: 9.4%; aRR 0.95 [0.77–1.17]).ConclusionAlthough patients can be reassured that a prior cesarean does not appear to be associated with reduced endometrial thickness, receptivity in FET cycles may be diminished, as reflected by lower subsequent live birth rates. One possible explanation is an altered endometrial environment, given the increased risk of cycle cancellation due to endometrial fluid accumulation in patients with prior cesarean delivery.

Intrauterine adhesion often leads to complications such as miscarriage and infertility. Owing to the limitations of current mechanical/hormonal interventions, such as risk of retrograde infection and rapid barrier degradation, intrauterine adhesion remains a therapeutic challenge. In this study, a degradable hydrogel film composed of chondroitin sulfate (CS) and chitosan (CHT) was developed. CS has anti-inflammatory functions, while CHT provides antibacterial activity and inhibits cellular fibrosis. The optimized CS/CHT hydrogel, designed to degrade over 7–14 d, exhibited mechanical stability matching the window for endometrial repair. In rat curettage models, the proposed hydrogel significantly reduced endometrial fibrosis, increased endometrial thickness, suppressed pro-inflammatory cytokines (IL-6 and TNF-α), and restored fertility. Its broad-spectrum antibacterial activity further validates its clinical potential. This dual-functional barrier works in synergy with mechanical support and biological activity regulation, providing an innovative solution for intrauterine prevention.