Decidual Disrupting Effects of Low-Dose Benzophenone-Type UV Filters in Human Endometrial Stromal Cells via ER/PR/FOXO1 SignalingZhan, Shen, Zhang
et alEnviron Sci Technol (2025)
Abstract: Exposure to endocrine disrupting chemicals (EDCs), particularly benzophenone (BP)-type UV filters, has been epidemiologically linked to endometrium-related reproductive risks in women. However, their effects on hormone-driven endometrial events and key receptor signaling at the human cellular level remain unexplored. Herein, using human primary endometrial stromal cells (HESCs), we investigated the disrupting effects of five BP congeners and deciphered the underlying mechanism on decidualization, a functional change of the endometrium preparing for pregnancy. BP-8, its two metabolites, BP-3, and BP-1 at 10 nM significantly disrupted progesterone-dependent decidualization in HESCs, marked by 1.5-1.8-fold and 2.2-2.6-fold upregulation of IGFBP-1 and LEFTY, respectively. Decidual transcriptional activators, WNT-FOXO1, were significantly induced by BPs, which are implicated in G2 phase cell arrest (from 3.26% to 8.93%) and apoptosis (from 12.29% to 25.61%). Mechanistically, the inhibition of estrogen receptor α (ERα) effectively alleviated these decidual disrupting effects. BPs increased the transcription of ERα and progesterone receptor (PR) signaling and enhanced nuclear translocation and interaction between ERα and PR during decidualization. The ERα-mediated enhancement of PR signaling activity by BPs was further validated in progesterone response element-luciferase transfected cells. Collectively, our findings elucidate the molecular pathway through which BPs disrupt endometrial decidualization via ERα/PR/FOXO1, providing critical mechanistic insights for the reproductive risk assessment of BPs and structurally related EDCs.
Expression and Methylation of Insulin-Like Growth Factor Binding Protein-1 Gene in Cord Blood of Intrauterine Growth Restricted NeonatesGurugubelli, Ballambattu
Indian J Pediatr (2025)
Abstract: To compare the insulin-like growth factor binding protein-1 (IGFBP-1) gene methylation and expression in the cord blood among intrauterine growth restricted (IUGR) and appropriate for gestational age (AGA) neonates and find their association with anthropometry at birth.Cord blood samples from IUGR and AGA neonates were collected. Anthropometric measurements i.e., Weight, length and head circumference of the infants were measured. RT-PCR was performed to examine IGFBP-1 gene expression and DNA methylation analysis by bisulfite sequencing PCR. The results were analyzed by using Mann-Whitney U test and Pearson correlation.IUGR neonates had significantly lower anthropometry (weight, length and head circumference) measurements at birth compared to AGA neonates. Gene expression analysis showed significantly higher IGFBP-1 gene expressions among IUGR compared to AGA neonates and gene expression level correlated with anthropometric measurements. There was no difference in IGFBP-1 gene methylation rate between the two groups of neonates and no correlation was observed with anthropometry.IGFBP-1 gene expression in cord blood was significantly higher among IUGR neonates and was associated with reduced birth weight, birth length and head circumference while the gene methylation was similar. This suggests involvement of multiple factors in occurrence of fetal growth restriction.© 2025. The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation.
Role of syndecan-4 in angiogenesis and vasculogenic mimicry in triple negative breast cancer cellsOnyeisi, El-Shorafa, Greve
et alMatrix Biol (2025) 136, 127-133
Abstract: Syndecan-4 (SDC4), a heparan sulfate proteoglycan, is aberrantly expressed in breast cancer and plays a significant role in tumor progression by influencing cell proliferation and promoting invasive growth. This study aimed to characterize its role in the tumor microenvironment by analyzing the contribution of SDC4 to vasculogenic mimicry (VM) and angiogenesis in human breast cancer cells. We silenced SDC4 in the triple-negative breast cancer (TNBC) cell lines MDA-MB-231, MDA-MB-468, and SUM-149 and analyzed its functions in vitro. SDC4 knockdown inhibited the VM of MDA-MB-231 cells as analyzed by fluorescence microscopy. Moreover, RT-qPCR revealed decreased expression of KLF4, EGR1, and HPSE, factors involved in VM, proangiogenic and pro-invasive processes in all TNBC cell lines. Western blotting revealed a partially cell-line-dependent regulation of these proteins by SDC4. At the functional level, SDC4 knockdown also impaired angiogenesis, decreasing the number of nodes and meshes in a 3D co-culture model comprising endothelial cells and TNBC cells. Using a Proteome Profile Human Angiogenesis Array, we observed that SDC4 knockdown decreased the secretion of VEGF and IGFBP-1, while it increased the secretion of IL-8, uPA, and amphiregulin in the conditioned media of the MDA-MB-231 and MDA-MB-468 co-cultures. Independent RT-qPCR analyses of gene expression were consistent with those of the angiogenesis array. Overall, these findings highlighted the crucial role of SDC4 in regulating both vasculogenic mimicry and angiogenesis in TNBC cells. The data indicate that SDC4 acts as a crucial regulatory molecule and represents a promising target for therapeutic strategies in breast cancer.Copyright © 2025. Published by Elsevier B.V.
Phosphatidic acid induces cytoskeletal rearrangements through the Src-FAK-RhoA/ROCK signaling pathway during decidualizationJun, Lee, Park
et alFEBS J (2025)
Abstract: Decidualization, the transformation of human endometrial stromal cells from a fibroblast-like to a rounded morphology, is crucial for creating a receptive intrauterine environment that supports successful embryo implantation. While decidual markers such as insulin-like growth factor-binding protein 1 and prolactin are well studied, the specific signaling mechanisms underlying morphological changes during decidualization remain unclear. In this study, we identified the phosphatidic acid (PA)-Src-focal adhesion kinase (FAK)-RhoA/Rho-associated protein kinase (ROCK) signaling pathway as a critical regulator of cytoskeletal rearrangement during PA-induced decidualization in human endometrial stromal cells. PA, a product of phospholipase D1, activates FAK, initiating a cascade of events involving Src-family kinases and RhoA signaling, ultimately leading to the cytoskeletal changes necessary for decidualization. Our in vitro experiments showed that PA-induced decidualization involved the formation of stress fibers mediated by ROCK activation. The traditional decidual markers, insulin-like growth factor-binding protein 1 and prolactin, did not significantly influence these morphological changes, suggesting that the PA-induced pathway operates independently of these markers. In vivo studies in ovariectomized mice demonstrated that PA injection into the uterine horn increased the uterine cavity weight and wall thickness, reinforcing the role of PA in promoting decidualization. These findings highlight the importance of the PA-Src-FAK-RhoA-ROCK pathway in regulating cytoskeletal dynamics during decidualization and suggest potential therapeutic targets for addressing implantation-associated infertility.© 2025 The Author(s). The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
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