Benzo(a)pyrene (BaP), a ubiquitous environmental pollutant, exerts reproductive toxicity by disrupting endometrial decidualization, yet the underlying mechanisms remain unclear. This study aimed to dissect the molecular cascade linking BaP-induced oxidative stress to abnormal endometrial stromal cell (ESC) proliferation and decidualization injury. Pregnant mice were gavaged with 0.2 mg kg-1·day-1 BaP from gestational Day 1 to 7, and primary ESCs were treated with BaP, H2O2, NAC and different inhibitor/agonist in vitro. BaP exposure reduced embryo implantation sites, induced asymmetric embryo distribution in bilateral uterine horns, and down-regulated decidualization markers (FOXO1, BMP2, HOXA10) in vivo and in vitro. Concurrently, BaP up-regulated proliferation markers (PHH3, PCNA, Ki67) and EdU incorporation in ESCs. Mechanistically, BaP induced uterine oxidative stress by down-regulating antioxidant enzymes (GPx4, CAT, SOD2) and accumulating intracellular ROS. H2O2 recapitulated BaP-induced phenotypes, while NAC reversed these effects. BaP-induced oxidative stress activated the PKCα/KEAP1 pathway, promoting Nrf2 phosphorylation and nuclear translocation. Inhibition of PKCα by PKC-IN-6 alleviated BaP-induced Nrf2 activation. Activated Nrf2 up-regulated transketolase (TKT) and glucose-6-phosphate dehydrogenase (G6PD), key enzymes of the pentose phosphate pathway (PPP), to drive abnormal ESC proliferation. ML385 inhibited Nrf2 to rescued BaP-induced ESC hyperproliferation and decidualization injury, while SFN activated Nrf2 mimicked BaP's toxic effects. Collectively, BaP induces oxidative stress in early pregnancy uteri, sequentially activating the PKCα/KEAP1/Nrf2 pathway and G6PD and TKT, leading to ESC proliferation-differentiation imbalance and decidualization impairment. This study uncovers a novel oxidative stress-mediated mechanism of BaP reproductive toxicity, identifying Nrf2 and PPP enzymes as potential therapeutic targets for pollutant-related pregnancy disorders.

Processing-bodies (PBs) are cytoplasmic membraneless condensates essential for RNA regulation. They share structural and functional similarities with germ granules and are critical for primordial folliculogenesis, a developmental process highly susceptible to exogenous insults. Aristolochic acid I (AAⅠ), a pervasive environmental toxin from Aristolochiaceae plants, is known to cross the placental barrier and induce fetal ovarian oxidative stress. Here, using a mouse model of maternal AAⅠ exposure (16.5 to 18.5 days post-coitus), we demonstrate that this prenatal insult causes profound defects in offspring folliculogenesis. AAⅠ induces PB enlargement and protein accumulation, causing these condensates to acquire germ granule-like properties. Specifically, AAⅠ upregulates the germ granule component NANOS3 to drive condensate enlargement. Multi-omic profiling further revealed that these aberrant condensates recruit germ granule-associated proteins and exhibit altered RNA profiles. Concurrently, neonatal oocytes exhibited enlarged Balbiani body-like structures alongside intermitochondrial cement, a feature not previously reported in oocytes. Furthermore, AAⅠ promotes the recruitment of N6-methyladenosine (m6A)-related factors into PBs, accompanied by elevated global m6A levels and the upregulation of YTHDF2. We show that YTHDF2 is essential for recruiting NANOS3 to PBs; truncating the intrinsically disordered regions (IDRs) or RNA-binding domains of either protein impairs their interaction. These perinatal perturbations manifest in adulthood as primary ovarian insufficiency (POI)-like dysfunction, including reduced ovarian reserve, compromised oocyte quality, and hormonal deficits. Overall, our work uncovers a NANOS3-YTHDF2 axis that drives germ granule-like PB adaptations, illustrating how fetal environmental insults disrupt folliculogenesis and serve as an etiological driver for adult-onset POI. Female reproductive health depends on the establishment of the ovarian follicle pool before birth, a delicate process highly vulnerable to environmental toxins. This study investigates how Aristolochic acid I (AAⅠ), a widespread, plant-derived toxin that accumulates in the food chain, disrupts folliculogenesis in mice. We found that maternal AAⅠ exposure delayed primordial folliculogenesis in neonatal mouse ovaries. Specifically, AAⅠ abnormally upregulates germline factor NANOS3 and drives the enlargement of processing-bodies (PBs), which regulate RNA metabolism. AAⅠ causes these PBs to recruit germ granule-associated proteins and alters the profiles of PB-associated RNAs. Furthermore, AAⅠ elevates m6A RNA modifications and upregulates the m6A reader YTHDF2. Our cellular assays reveal that YTHDF2 is essential for recruiting NANOS3 into PBs. Most importantly, this neonatal ovarian damage has long-lasting consequences. Female offspring maternally exposed to AAⅠ develop primary ovarian insufficiency (POI)-like dysfunction in early adulthood, characterized by a severely reduced ovarian reserve, poor oocyte quality, and hormonal deficits. Ultimately, our findings illustrate how environmental insults during fetal development can impair female fertility and trigger adult-onset ovarian dysfunction.

Dibutyl phthalate (DBP), a common environmental endocrine-disrupting chemical, is known to impair female reproduction, yet its specific effects on ovarian reserve and underlying epigenetic mechanisms are not fully understood. Here, using gestational exposure models (in vivo) and fetal ovarian culture models (in vitro), we show that gestational DBP exposure disrupts the ovarian reserve through a dual assault: impairing primordial follicle formation ("input") and, more critically, driving primordial follicle premature activation ("output"). Mechanistically, DBP induces METTL14-dependent m⁶A hypermethylation, which activates the PI3K-AKT-FOXO3a signaling axis to promote aberrant follicular activation. Knockdown of Mettl14 rescues this pathway activation and the follicular disruption. Long‑term follow‑up revealed that such precocious activation leads to progressive ovarian reserve depletion, culminating in a premature ovarian insufficiency (POI)-like phenotype with hormonal dysfunction, reduced oocyte quality, and compromised fertility in adult offspring. Collectively, these findings indicate that gestational DBP exposure activates the PI3K-AKT-FOXO3a signaling pathway via METTL14-mediated m⁶A modification, causing impaired follicle formation, follicular over-activation, and ultimately ovarian reserve depletion and a POI-like phenotype in offspring. This study reveals a novel m⁶A‑mediated epigenetic mechanism in plasticizer-induced ovarian toxicity, advancing our understanding of POI etiology and highlighting a significant environmental risk to female fertility.

Lipid disorder is an independent risk factor of diabetic kidney disease (DKD). Excess accumulation of lipid in podocytes can cause cell dysfunction and cell death. Chaperone-mediated autophagy (CMA) serves as a critical role in regulating lipid metabolism. However, the exact role of CMA in the podocytes of DKD with dyslipidemia is still uncertain. Herein, we aimed to explore the role of CMA in hyperlipidemia-induced lipid accumulation and apoptosis in podocytes. In the present study, we showed that palmitic acid (PA) treatment induced the activation of CMA, increased lipid accumulation and apoptosis in podocytes. We further found that blocking CMA with inhibitor VER155008 or LAMP-2 A siRNA significantly upregulated PA-induced increased expression of PLIN2, exacerbated PA-induced lipid accumulation and apoptosis, whereas promoting CMA with Torin1 downregulated the expression of PLIN2, ameliorated lipid accumulation and apoptosis in PA-induced podocytes. Moreover, we also observed the activation of CMA and increased lipid accumulation in the kidney tissue of DKD mice. Taken together, these results suggest that CMA plays a protective role in PA-induced podocytes apoptosis and that the potential protective mechanism of CMA is involved in reducing cellular lipid accumulation through mediating the degradation of PLIN2.

BackgroundChronic Rhinosinusitis with Nasal Polyps (CRSwNP) is characterized by persistent mucosal inflammation and tissue remodeling, driven by the crosstalk between epithelial and immune cells. Emerging evidence indicates that, in addition to IL-13, TSLP, and IL-33, other mediators also significantly contribute to the crosstalk. In this study, we investigate the mechanism by which epithelial cell mitochondrial dysfunction drives immune dysregulation in CRSwNP, aiming to uncover novel therapeutic targets.MethodsWe analyzed transcriptomic data from three GEO datasets (GSE194282, GSE72713, GSE36830) to identify Differentially Expressed Genes (DEGs). By integrating mitochondrial-associated genes (MitoCarta3.0), we performed functional enrichment (GO/KEGG) and PPI network analyses to identify hub genes. In vitro experiments, including western blotting, flow cytometry, and immunofluorescence, were applied to elucidated the role of COX5A in mediating M2 macrophage polarization via ROS production. A murine nasal polyp (NP) model further confirmed key findings.ResultsWe identified 110 mitochondrial-related DEGs (80 upregulated, 30 downregulated), prominently enriched in immune regulation and mitochondrial respiratory chain. Immune infiltration analysis revealed significant upregulation of M2 macrophages and resting memory CD4+T cells in CRSwNP tissues. Strikingly, IL-13-stimulated epithelial cells (ECs) drove M2 polarization via COX5A-mediated ROS production-an effect abolished by COX5A knockdown or ROS scavengers. Furthermore, a murine nasal polyps model confirmed elevated COX5A and M2 marker expression, reinforcing the clinical relevance of our findings.ConclusionOur research highlights the crucial role of mitochondrial dysfunction, particularly through COX5A-mediated reactive oxygen species (ROS) generation, in promoting the polarization of M2 macrophages and the progression of CRSwNP. These findings emphasize the potential for targeting mitochondrial-immune crosstalk as an effective therapeutic strategy, thereby opening new avenues for addressing CRSwNP.

The ovaries are crucial reproductive organs that regulate the menstrual cycle and support pregnancy through the production of steroid hormones. They are highly susceptible to various environmental pollutants, which can lead to ovarian disorders. Luteal phase defect (LPD) and premature ovarian failure (POF) are common ovarian disorders in women. In this study, we integrate network toxicology with molecular docking and molecular dynamics simulations to elucidate the toxicological mechanisms of Benzo(a)pyrene (BaP), a widespread endocrine disruptor, in LPD and POF. Through systematic data mining of the GeneCards and OMIM databases, we identified 1336 targets associated with LPD and 2066 targets related to POF, as well as 220 BaP targets. Venn diagram analysis revealed 36 potential targets for BaP-induced LPD and 43 for BaP-induced POF. GO and KEGG enrichment analyses suggest that BaP-induced LPD and POF may share toxicological mechanisms. PPI network visualization indicated that EGFR, ESR1, and STAT3 are critical common targets for BaP-induced LPD and POF. Molecular docking and molecular dynamics simulations revealed that BaP exhibits strong binding affinity with all three core genes. In KGN cells modeling LPD and POF phenotypes, cellular experiments confirmed that BaP downregulated EGFR and ESR1 expression while upregulating STAT3 expression, thereby supporting the reliability of these targets in BaP-induced ovarian dysfunction. These findings provide insights into BaP-induced reproductive toxicity and offer a foundation for targeted clinical interventions to mitigate the effects of environmental pollutants on women's reproductive health.

Maintaining normal thyroid function is crucial in pregnancy, and the thyroid hormone signaling pathway is involved in embryo implantation. However, the regulation of iodothyronine deiodinase 2 (DIO2), which is the central hub controlling thyroid hormone signaling, and the intracellular pathway activated by triiodothyronine (T3) binding to the thyroid hormone receptor (THR) in endometrial cells, remains unclear. Here, we demonstrate that DIO2 expression increases in endometrium during the establishment of endometrial receptivity and is involved in this process. Iopanoic acid inhibition of DIO2 in vivo can cause a delayed receptive state. In vitro adhesion models have consistently confirmed that knocking down DIO2 in epithelial cells inhibited receptivity establishment. Membrane lipidomics was performed to explore how DIO2 regulates the morphological transformation of endometrial epithelial cells. We found that the deletion of Dio2 inhibited the increase in the degree of lipid unsaturation, which subsequently decreased membrane fluidity. Transcriptomics analysis was employed to explore the downstream target gene of T3-THR signaling mediated by Dio2-mediated T3-THR signaling, and Scd1 is confirmed as the direct target gene of THR in endometrial epithelial cells. These data reveal that DIO2 could regulate lipid metabolism by targeting Scd1 through the T3-THR signaling pathway, thereby modifying membrane fluidity of endometrial epithelial cells and promoting cell morphological transformation to establish endometrial receptivity. These findings contribute to filling the gap in downstream pathways activated by T3-THR signaling in endometrial cells and provide insights into the new therapeutics, prediagnosis, and preventive strategies for the derailment of endometrial receptivity and subsequently adverse "ripple effect" including infertility.

DEHP is a pervasive endocrine disrupting chemical with multiple adverse effects on the female reproductive system. However, its impact on endometrial decidualization, the foundation for embryo implantation and successful pregnancy, remains poorly defined, and the underlying regulatory mechanisms have been rarely explored. In present study, we utilized several assays with DEHP-exposed mouse decidual tissues to clarify whether DEHP exposure confers adverse effects on decidualization. The results showed that 1000 mg/kg/d DEHP exposure led to a significant reduction in the weight and area of the uterine deciduoma, accompanied by a significant decrease in the expression of decidualization markers on GD6, GD8 of pregnancy, and PD8 of pseudopregnancy in mice. Moreover, the in vitro findings revealed that exposure to 12.5 μM MEHP, the primary and active metabolite of DEHP, disturbed the cytoskeletal remodeling and downregulated the marker molecules during endometrial stromal cell decidualization. Meanwhile, we detected that Mtmr6 as identified by proteomics analysis, was up-regulated after DEHP and MEHP exposure in vivo and in vitro. Knockdown of Mtmr6 alleviated the deficiencies in stromal cell decidualization induced by DEHP' metabolite MEHP. Furthermore, we also found that the active-site residue ALA-131 of Mtmr6 may be the direct binding site for MEHP by performing molecular docking. This study uncovered the adverse effects of DEHP on endometrial decidualization and revealed the possible mechanisms, providing potential strategies for minimizing their toxicological effects on female reproductive health.

Decabromodiphenyl ethane (DBDPE) is a brominated flame retardant widely used for its high flame retardancy and low bioavailability. However, DBDPE exhibits bioaccumulative potential. The placental vasculature, critical for the exchange between maternal and fetal circulation, is susceptible to environmental factors. We aimed to understand the potential toxicity of DBDPE to the placental vasculature. Gestational CD-1 mice and human umbilical vein endothelial cells (HUVECs) were exposed to 0, 0.5, 5, 50 mg/kg·bw·day or 0, 6.25, 12.5, 25, 50 μmol/L DBDPE, respectively. DBDPE exposure impaired placental angiogenesis and inhibited the proliferation and invasion of HUVECs by activating the endothelial-to-mesenchymal transition (EndMT) through the TGF-β1/Smad pathway, in vivo and in vitro. DBDPE upregulated the transcription factor TWIST2 and mRNA acetyltransferase NAT10. Knockdown or overexpression of TWIST2 reversed the vascular dysfunction and EndMT mechanism. DBDPE facilitated the recruitment of NAT10 by TWIST2, promoting N4-acetylcytidine (ac4C) RNA modifications and stabilizing the TGF-β1 mRNA. NAT10 inhibition rescued the effects caused by DBDPE. These findings uncover molecular mechanisms linking DBDPE exposure to adverse pregnancy outcomes, highlighting potential risks to pregnant women.

The extensive utilization of plastics has heightened concerns regarding microplastics exposure. However, the effects of polystyrene microplastics (PS-MPs) on early pregnancy remain inadequately investigated. This study aimed to examine the impact of PS-MPs on decidualization and embryo implantation in female mice, as well as the reproductive function of their offspring following maternal exposure to PS-MPs. We investigated the harmful effects of different PS-MPs sizes on mouse endometrial stromal cells (mESCs) during in vitro decidualization. Pregnant mice were orally given various concentrations of PS-MPs to examine their impact on decidualization. We evaluated oxidative stress and inflammation markers to understand their roles in abnormal decidualization. Additionally, we assessed potential reproductive health impacts on female offspring. Our findings indicated that 5 µm PS-MPs effectively penetrated mESCs and significantly disrupted decidualization compared to smaller or larger particles. Pregnant mice that were exposed to 5 µm PS-MPs at a dose of 1000 mg/(kg·day) exhibited substantial reductions in the decidual area and downregulation of decidualization markers such as BMP2. Inflammatory cytokines increased significantly in mESCs following 5 µm PS-MPs exposure, and the elevated malondialdehyde levels in uterine tissue were mitigated by antioxidant treatment. Moreover, offspring exhibited decreased uterine wet weight, uterine organ coefficients, decidual areas, and expression of BMP2 due to maternal exposure to PS-MPs. These results highlighted the detrimental effects of PS-MPs on maternal decidualization and embryo implantation, suggesting a link to oxidative stress and inflammation, and maternal exposure to PS-MPs during pregnancy impaired reproductive function in offspring females.

The receptive endometrium is a prerequisite for successful embryo implantation, and abnormal endometrial receptivity would lead to infertility. Many key proteins involved in endometrial receptivity have been confirmed to undergo post transcriptional modifications. However, there are limited reports on deubiquitination modification during this process. Our previous studies found that Rictor participated in the endometrial receptivity, and maintained at a high level in the endometrium during implantation, but the mechanism for maintaining stability of Rictor protein remains unclear. Here, we showed that USP9X expression in endometrium was dynamic with the establishment of endometrial receptivity, and promoted the protein stability of Rictor through deubiquitination. Inhibition of USP9X could suppress the adhesion action of trophoblast cells to endometrial epithelial cells, reduce the filamentous pseudopodia of epithelial cells, and inhibit the epithelial mesenchymal transformation. Rictor is partially responsible for the derailment of epithelial cell transformation in response to USP9X inhibition. Membrane fluidity mediated by lipid metabolism is involved in regulation of Rictor on endometrial receptivity. This study revealed the role of USP9X in endometrial receptivity for the first time, and confirmed that Rictor was the target protein of USP9X in endometrium. In addition, we described the unique lipidomics characteristics of the endometrial epithelial cells regulated by Rictor. These data would further improve the molecular network of endometrial receptivity, supplement the regulatory factors of lipid metabolism in endometrial cells, and provide insights into the new therapeutics, pre-diagnosis and preventive strategies for the derailment of endometrial receptivity and subsequently adverse "ripple effect" including infertility.

Objective To evaluate the effect of dapagliflozin on myocardial function in early spontaneously hypertensive rats(SHR)with layer-specific global longitudinal strain(GLS).Methods A total of 45 male SHR aged 6 weeks were randomly divided into control group(normal saline),dapagliflozin group[1 mg/(kg·day)],and losartan group[10 mg/(kg·day)].Fifteen male Wistar-Kyoto(WKY)rats at same age with normal blood pressure were subjected and served as blank control group.During 8 weeks of intervention,systolic blood pressure(SBP)was measured,and conventional echocardiography and two-dimensional speckle tracking echocardiography(2DSTE)were performed and the results were collected to acquire the longitudinal strain of each layer of left ventricular(LV)myocardium.The parameters were compared among the groups.The pathological changes of myocardium were observed in each group of rats.Results Compared with the WKY group,LV ejection fraction(LVEF)and LV fraction shortening(LVFS)at week 8 were decreased in the control group(P＜0.05),but no such decreases were observed in the dapagliflozin group and the losartan group.The GLS of endo-myocardium(GLSendo)at the 6th week was decreased,and GLSendo,GLSmid and GLSepi at the 8th week were all decreased in the control group than the WKY group(all P＜0.05).But there were no statistical differences in the above 3 indicators in the dapagliflozin and losartan groups when compared with the WKY group(all P＞0.05).The pathological results showed that myocardial interstitial fibrosis was observed in the control group at the 6th week.Conclusion Dapagliflozin can effectively improve myocardial function in early SHR.

Phthalate-induced female reproductive health issues, particularly those related to di (2-ethylhexyl) phthalate (DEHP), are growing global concerns. Although most studies have focused on single-generation exposure, studies on prolonged DEHP exposure across multiple generations are limited. This study assessed the effects of multigenerational DEHP exposure on endometrial decidualization, which is crucial for embryo implantation. The results showed that sustained DEHP exposure over three generations exacerbated decidualization injury and led to adverse pregnancy outcomes. RNA sequencing revealed upregulation of the imprinted gene Snurf in the decidua, with changes that may not depend on alterations in DNA methylation. Knockdown of Snurf significantly alleviated in vitro decidualization deficiency induced by mono(2-ethylhexyl) phthalate (MEHP), the biologically active metabolite of DEHP. Proteomic analysis and the AlphaFold 3 algorithm indicated that Stn1 is a downstream target of Snurf, with silencing Stn1 resensitizing Snurf-knockdown stromal cells to MEHP. Human decidual stromal cells (hDSCs) from healthy participants showed sensitivity to MEHP, with the inhibition of decidualization. Epidemiological data from the 2017-2018 National Health and Nutrition Examination Survey (NHANES) indicated a positive association between DEHP exposure and female infertility. This study highlighted the cumulative toxic effects of multigenerational DEHP exposure on female reproduction and revealed the contribution of imprinted genes.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine and metabolic disorder affecting women of reproductive age. Oxidative stress (OS) is suggested to play a significant role in the development of PCOS. Using antioxidants to reduce OS and maintain a healthy balance in the body could be a novel treatment approach for PCOS. This study analyzed transcriptome data from the Gene Expression Omnibus database, focusing on genes associated with OS. By implementing two machine learning algorithms, three OS-related biomarkers—HMOX1, MMP9, and KLF2—were successfully identified. To evaluate the diagnostic potential of these biomarkers, a Logistic regression model was employed. Additionally, granulosa cells were collected from healthy individuals and infertile women with PCOS, and the reliability of HMOX1, MMP9, and KLF2 was verified by quantitative real-time PCR experiments. Furthermore, small molecule drugs targeting proteins encoded by genes HMOX1 and MMP9 were predicted through the Drug Signature Database. Molecular docking of drugs to proteins identified two antioxidants, butein and demethoxycurcumin, as potential candidates for PCOS therapy.

Background Breast cancer (BC) is the leading cancer among women globally, which has the highest incidence and mortality rate in over a hundred countries. This study was intended to discover a new prognostic biomarker, facilitating personalized treatment approaches. Methods RNA sequencing data from The Cancer Genome Atlas database and Gene Expression Omnibus database were utilized to download to evaluate expression levels and prognostic significance of Keratin 14 (KRT14). Methylation of KRT14 was also assessed. The CIBERSORT and single-sample gene set enrichment analysis algorithms were applied to explore the connection between KRT14 and the tumor microenvironment. Primary drugs' sensitivity and potential small molecule therapeutic compounds were analyzed through the "pRRophetic" R package and the Connectivity Map. The prognostic value of KRT14 was additionally corroborated through a comparison of protein levels in peritumoral and cancerous tissues via immunohistochemistry. Moreover, an immune-related prognostic model based on KRT14 was designed to enhance the prediction accuracy for the prognosis of BC patients. Results The study found that KRT14 expression was generally downregulated in BC, correlating strongly with poor prognosis. Compared to normal tissues, the methylation level of KRT14 was higher in BC tissues. Lower expression of KRT14 was linked to decreased anti-tumoral immune cells infiltration and increased immunosuppressive cells infiltration. Sensitivity to various key therapeutic drugs was lower in groups with diminished KRT14 expression. In addition, several potential anti-BC small molecule compounds were identified. The model designed in this study significantly enhanced the predictive capability for BC patients compared to predictions based solely on KRT14 expression levels. Conclusion Overall, KRT14 was closely correlated with the prognosis in BC, making it a reliable biomarker.

Nanoplastics have recently emerged as persistent pollutants of global concern that pose substantial risks to human health. However, the long-term adverse effects of nanoplastics on the female reproductive system remain unclear. Polystyrene nanoplastics (PS-NPs; 50 nm diameter) were selected as representative nanosized plastic particles to investigate the potential effects of subchronic prenatal and gestational exposure via drinking water on placental development in ICR (CD-1) mice. Maternal exposure to 10 mg/L PS-NPs induced an increase in fetal resorption rate and significantly increased fetal weight. Further observation of the placental morphology showed that PS-NPs exposure led to an aberrant placental structure and damaged the trophoblast cells. At the cellular level, PS-NPs exposure promoted the proliferation, migration, and invasion of HTR-8/SVneo cells. Mechanistically, transcriptomic and proteomic analyses revealed that PS-NPs triggered placental calcium disturbances and upregulated the Stam2 expression in mice. STAM2 induced by PS-NPs mediates the disruption of trophoblastic calcium homeostasis and regulates cell functions by disturbing the lysosomal degradation of the calcium channel protein IP3R3 and promoting intracellular calcium inflow by increasing the level of TRPV6 in HTR-8/SVneo cells. Therefore, our results indicated that trophoblastic calcium dyshomeostasis is the main mechanism by which subchronic PS-NPs exposure induces abnormal placental development. These findings reveal a link between subchronic PS-NPs exposure and placental damage and elucidate the underlying molecular mechanism, providing evidence for environmental triggers of adverse pregnancy and highlighting the risk of plastic products to pregnant women.

Embryo implantation relies on complex mother-fetus interactions. Abnormal decidualization can cause various pregnancy complications such as placental abnormalities, preeclampsia, and fetal growth restriction. circRNAs play a key role in various cellular processes. This study focuses on the role of circ-Hdac4, a circRNA derived from the Hdac4 gene, in decidualization and placental function. Mouse models revealed a spatiotemporally regulated expression of circ-Hdac4 in the endometrium during early pregnancy, with enhanced expression surrounding implantation sites. In vitro and in vivo assays confirmed that circ-Hdac4 is crucial for stromal cell decidualization, as its knockdown resulted in reduced expression of decidualization markers and disrupted endometrial architecture. Furthermore, we found that circ-Hdac4 functions as a microRNA sponge for miR-30c, which negatively regulates RBPJ, a critical protein for decidual remodeling. Proteomic analysis revealed that RBPJ was downregulated upon circ-Hdac4 silencing, and we validated the direct interaction between miR-30c and RBPJ using luciferase reporter assays. A mouse preeclampsia model showed that downregulation of circ-Hdac4 during decidualization exacerbated preeclampsia-related phenotypes, including reduced fetal counts, weights, and placental weights. In addition, we observed decreased expression of circ-Hdac4 and RBPJ in the decidual surface of placental tissues from preeclampsia patients, further supporting our findings in the mouse model. Collectively, our study provides evidence that circ-Hdac4 regulates decidualization through the miR-30c-RBPJ axis and that its abnormal expression during decidualization contributes to placental dysfunction in preeclampsia. This research offers novel insights into the molecular mechanisms underlying pregnancy complications and potential therapeutic targets for their prevention and treatment. 1. circ-Hdac4 can regulate endometrial decidualization by targeting Mir-30c-RBPJ axis in early pregnancy mice 2. circ-Hdac4/miR-30c/RBPJ axis regulating decidualization through miRNA sponging, 3. Reduced circ-Hdac4 and RBPJ expression in human preeclampsia decidua correlates with placental dysfunction

Cetylpyridinium chloride (CPC), a widely used surfactant, functions as an antimicrobial agent in pharmaceuticals and personal care products (PPCPs). However, its effect on the female reproductive system remains largely unknown. Herein, female mice were gavaged with 0.01, 0.1, or 1 mg CPC/kg body weight (bw)/d during adolescence. Results showed reduced body and ovarian weights, decreased primordial follicle numbers, and increased atretic follicles. Additionally, CPC disrupted serum hormone levels, reduced cell viability and proliferation, and increased apoptosis in granulosa cells. Transcriptomic analysis of primary granulosa cells revealed altered genes in homologous recombination (HR) repair pathway, including the downregulation of FOXM1 and the MRN complex. Further validation demonstrated decreased expression of HR repair components and increased DNA damage in both in vivo and in vitro. Mechanistically, CPC inhibited the FOXM1/CREBBP interaction and inhibited HR repair gene transcription, including MRE11 and NBS1. Finally, FOXM1 overexpression partially reversed the detrimental effects of CPC on HR repair and cell proliferation. These results indicate that CPC-induced ovarian dysfunction during adolescence is mediated through FOXM1/CREBBP complex inhibition and homologous recombination repair impairment, potentially increasing the risk for the development of diminished ovarian reserve (DOR) and providing new experimental evidence to assess the reproductive toxicity effects of CPC.

Aristolochic acid I (AAI), the predominant compound in Aristolochiaceae plants and Asarum species, is a widespread environmental contaminant capable of accumulating in soil, contaminating water and crops, ultimately entering the human body. Its nephrotoxic, carcinogenic, and reproductive toxic effects pose significant health concerns. This study investigates the impact of maternal AAI exposure on meiotic prophase I (MPI) during early fetal oogenesis. Pregnant mice were orally administered AAI at doses of 0.03125, 0.125, and 1 mg/kg from 14.5 to 16.5 dpc, with fetal ovaries collected at 17.5 dpc. AAI exposure induced meiotic defects in fetal oocytes, including delayed progression of MPI, increased DNA damage, and impaired homologous recombination. Furthermore, AAI induced oxidative stress, reduced mitochondrial membrane potential and triggered apoptosis, leading to a diminished ovarian reserve in neonatal ovaries. Mechanistically, these defects were mediated by heat shock proteins which altered protein-protein interactions crucial for DNA repair. Given the pivotal role of early oogenesis in determining female fertility and ensuring the health of offspring, these findings underscore the potential reproductive risks of AAI exposure during pregnancy. This study highlights the urgent need for greater awareness of foodborne contaminants and the implementation of preventative measures to mitigate maternal AAI exposure, thereby safeguarding offspring fertility and health.

Phthalates (PAEs) can impair trophoblast cell and subsequent placental development, adversely affecting pregnancy. The effects of dicyclohexyl phthalate (DCHP), the main PAE homologue in urban household dust, on trophoblast function and placental development are unknown. In this study, we investigated the effects and potential mechanisms of DCHP on trophoblast function and placental development by constructing in vitro trophoblast (10, 20, 30 μM) and in vivo mouse pregnancy (25, 50, 100 mg/kg bw) exposure models. We found that exposure to DCHP during pregnancy led to the accumulation of placental lipid droplets and foetal weight gain. Consistently, DCHP induced the uptake of fatty acids by HTR-8/SVneo cells, leading to intracellular lipid droplet accumulation and mitochondrial dysfunction while inhibiting cell migration and invasion. This suggests that metabolic processes can serve as important links for environmental pollutants to interfere with bodily functions. Knocking down N-myc Downstream-Regulated Gene 1 (NDRG1) can alleviate lipid metabolism abnormalities caused by DCHP exposure while restoring cell migration and invasion abilities. Further research has found that the enhanced transcriptional activity of PPARα:RXRα is an important molecular initiating event for the role of DCHP, which promotes the transcription of downstream target gene NDRG1 by binding to PPARα:RXRα. These findings fill the research gap regarding the effects and related mechanisms of DCHP exposure on the placenta, help explore prevention and treatment strategies for DCHP reproductive toxicity, and provide new insights into toxicological research on environmental pollutants.