This special issue comprises one review and seven original articles covering diverse topics in reproductive medicine,including the microbiota-metabolite axis in endometriosis,BDE47-induced ferroptosis in spermatocytes,human papillomavirus (HPV) and fertility outcomes in endometriosis,metabolomic biomarkers for azoospermia stratification,gene function validation in male reproduction,endometrial preparation protocols and the vaginal microbiota,bisphenol A (BPA)-induced developmental cardiotoxicity,and diagnostic criteria for gestational diabetes.
The four original articles in this special section explore diverse aspects of cancer biology,ranging from molecular mechanisms and tumor heterogeneity to behavioral risk prediction,thereby highlighting the power of integrating experimental biology with computational approaches.
Cytochrome P450 CYP3A (CYP3A) is among the most abundant hepatic cytochrome P450 subfamilies and also mediates the metabolism and toxicity of xenobiotics. Previous studies have reported that CYP3A is also expressed in the testis; however, its role and molecular mechanism in mediating male reproductive damage remain unclear. In this study, through in vitro and in vivo experiments, we demonstrated the role of CYP3A in 2,2',4,4'-tetrabromodiphenyl ether (BDE47)-induced reproductive toxicity. The results showed that BDE47 induced CYP3A expression in mouse testes, leading to oxidative stress and ferroptosis through excessive reactive oxygen species (ROS) and ferrous iron (Fe 2+) overload, which was demonstrated by CYP3A overexpression or knockdown experiments in GC-2 cells. Mechanistically, in addition to direct ROS generation during metabolic processing, ferritinophagy contributed to intracellular Fe 2+ accumulation. Specifically, BDE47-induced ROS was associated with reduced N6-methyladenosine (m 6A) modification of Atg12 mRNA and increased autophagy-related (ATG12) expression, thereby promoting ferritin heavy chain 1 (FTH1) degradation and subsequent Fe 2+ overload. These results were further validated by experiments using hydrogen peroxide or antioxidants in GC-2 cells, as well as by Atg12 haploinsufficiency in mice. Our findings demonstrate that CYP3A plays a critical role in male reproductive toxicity induced by BDE47.
Growing evidence highlights the gut, reproductive tract, and endometrial microbiota as important functional contributors in the pathogenesis of endometriosis (EM). Studies have revealed a characteristic microbial imbalance in patients with EM, marked by a reduced abundance of beneficial bacteria and an enrichment of opportunistic pathogens. These microbial communities are thought to influence disease progression primarily through metabolic activity, as demonstrated by metabolomic studies showing their capacity to modulate host immune and endocrine responses. This imbalance may contribute to several key metabolic disturbances, including decreased levels of short-chain fatty acids, particularly butyrate; a shift in tryptophan metabolism toward the kynurenine pathway; elevated β-glucuronidase activity; increased lipopolysaccharide production; and altered secondary bile acid profiles. Functionally, these metabolic alterations are thought to contribute to EM by disrupting immune homeostasis, enhancing estrogen signaling, and driving systemic inflammation, thereby creating a permissive microenvironment for ectopic lesion growth and invasion. Targeted interventions, such as probiotics, high-fiber dietary strategies, fecal microbiota transplantation, and selective modulation of microbial or host metabolic enzymes, are emerging as promising non-hormonal therapeutic approaches. Nonetheless, further studies incorporating longitudinal cohort designs and integrative multi-omics approaches are essential to establish causality and facilitate the development of precise diagnostic and personalized treatment strategies.
Bisphenol A (BPA), a widely encountered environmental endocrine-disrupting chemical, has been linked to an increased risk of congenital heart defects in epidemiological and experimental studies. To investigate its impact in a human-relevant system, we used a human cardiac organoid (hCO) model derived from human embryonic stem cells and exposed hCOs to BPA concentrations ranging from environmentally relevant to higher experimental levels (0.1-10 μmol/L) throughout differentiation. BPA exposure impaired cardiac contractile function and disrupted endothelial network formation, with more pronounced functional effects at higher concentrations. BPA exposure also induced apoptosis in hCOs. Subsequently, transcriptomic profiling revealed dysregulation of genes associated with cardiac rhythm and developmental signaling in BPA-treated hCOs. Among the concentrations tested, 0.5 μmol/L was the lowest concentration associated with a significant reduction in CD31 fluorescence intensity. This research provides in vitro evidence that BPA can perturb key processes in early human heart development, highlighting the necessity for further mechanistic and in vivo studies to clarify exposure relevance and its potential implications for fetal heart health.
