Biology subjects

Bhurke, A.

Publications and source records attributed to Bhurke, A..

3 recordsLinked to original sources

bioRxiv2026

Loss of Glucose Transporter 1 in Mouse Uterine Cells Disrupts Trophoblast Differentiation and Promotes Gestational Diabetes

A successful pregnancy hinges on a finely coordinated dialogue between the maternal endometrium and the implanting embryo. Following embryo attachment to the uterine epithelium, underlying stromal cells undergo a transformation into decidual cells that promote a vascularized maternal-fetal interface and direct trophoblast lineage decisions through paracrine cues. However, the metabolic adaptations that enable decidual cells to support these energetically demanding processes remain poorly understood. Here, using a uterine-specific knockout mouse model, we identify Glucose Transporter 1 (Glut1) as a critical metabolic regulator linking endometrial glucose uptake to reproductive success. We demonstrate that stromal Glut1, induced by hypoxia-inducible factor 2 (Hif2), sustains a Hif2-Rab27b feed-forward circuit that drives vesicular trafficking during pregnancy through the glucose-sensing transcription factor MAX-like protein X (Mlx). Mice lacking endometrial Glut1 are severely subfertile despite normal embryo attachment. Glut1-deficient uteri exhibit impaired stromal extracellular vesicle secretion, defective decidual angiogenesis, and marked dysregulation of trophoblast differentiation, including expansion of trophoblast progenitors, accumulation of glycogen trophoblast cells, and altered placental lactogen production. These placental defects culminate in mid-gestation fetal loss and maternal gestational diabetes mellitus (GDM). Collectively, our findings establish endometrial Glut1 as a metabolic gatekeeper of maternal glucose homeostasis and placentation and introduce a genetically tractable mouse model of spontaneously developing GDM, a disorder affecting nearly one in seven pregnancies worldwide. SIGNIFICANCEThis study uncovers endometrial Glut1 as a previously unrecognized metabolic regulator of placentation, demonstrating that maternal stromal glucose uptake dictates trophoblast fate and maternal glycemic control, and providing the field with its first genetically defined mouse model of spontaneously arising gestational diabetes.

physiology↗

bioRxiv2024

Phthalates Impair Estrogenic Regulation of HIF2α and Extracellular Vesicle Secretion by Human Endometrial Stromal Cells

Di(2-ethylhexyl) phthalate (DEHP), a known endocrine-disrupting chemical, is a plasticizer found in many common consumer products. High levels of DEHP exposure have been linked to adverse pregnancy outcomes, yet little is known about how it affects human uterine functions. We previously reported that the estrogen-regulated transcription factor hypoxia-inducible factor 2 alpha (HIF2) promotes the expression of Rab27b, which controls the trafficking and secretion of extracellular vesicles (EVs). EVs facilitate communication between multiple cell types within the pregnant uterus, ensuring reproductive success. In this study, we report that exposure of differentiating primary human endometrial stromal cells (HESC) to an environmentally relevant concentration (1 g/mL) of DEHP or its primary metabolite mono(2-ethylhexyl) phthalate (MEHP) markedly reduces the expression of HIF2. We also observed a concomitant decrease in RAB27B expression, reducing EV secretion from HESC. Interestingly, we found that DEHP or MEHP exposure disrupts estrogenic regulation of the HIF2/Rab27b signaling pathway. Estrogen receptor alpha (ER) could no longer bind to the HIF2 regulatory region following phthalate treatment, and epigenetic analysis suggested that this may be due to hypermethylation of nearby CpG islands. Further investigation revealed a potential interaction between ER and the transcription factor Sp1 within the HIF2 regulatory region, which is affected by the inhibition of Sp1 binding to the phthalate-induced hypermethylated DNA. Additionally, our results suggest that the abnormal DNA methylation is likely due to increased expression of the DNA methyltransferase 1 (DNMT1) gene in response to phthalate exposure. Overall, this study provides valuable mechanistic insights into how phthalate-induced differential DNA methylation disrupts estrogenic regulation of the HIF2 gene and, consequently, EV secretion during HESC differentiation. This knowledge is crucial for our understanding of how phthalates may cause adverse reproductive outcomes by disrupting the hormonal regulation of cell-to-cell communication within the pregnant uterus.

pharmacology and toxicology↗

bioRxiv2023

Murine uterine gland branching is necessary for gland function in implantation

Uterine glands are branched, tubular structures whose secretions are essential for pregnancy success. It is known that pre-implantation glandular expression of leukemia inhibitory factor (LIF) is crucial for embryo implantation, however contribution of uterine gland structure to gland secretions such as LIF is not known. Here we use mice deficient in estrogen receptor 1 (ESR1) signaling to uncover the role of ESR1 signaling in gland branching and the role of a branched structure in LIF secretion and embryo implantation. We observed that deletion of ESR1 in neonatal uterine epithelium, stroma and muscle using the progesterone receptor PgrCre causes a block in uterine gland development at the gland bud stage. Embryonic epithelial deletion of ESR1 using a mullerian duct Cre line - Pax2Cre, displays gland bud elongation but a failure in gland branching. Surprisingly, adult uterine epithelial deletion of ESR1 using the lactoferrin-Cre (LtfCre) displays normally branched uterine glands. Intriguingly, unbranched glands from Pax2Cre Esr1flox/flox uteri fail to express glandular pre-implantation Lif, preventing implantation chamber formation and embryo alignment along the uterine mesometrial-antimesometrial axis. In contrast, branched glands from LtfCre Esr1flox/flox uteri display reduced expression of glandular Lif resulting in delayed implantation chamber formation and embryo-uterine axes alignment but deliver a normal number of pups. Finally, pre-pubertal unbranched glands in control mice express Lif in the luminal epithelium but fail to express Lif in the glandular epithelium even in the presence of estrogen. These data strongly suggest that branched glands are necessary for pre-implantation glandular Lif expression for implantation success. Our study is the first to identify a relationship between the branched structure and secretory function of uterine glands and provides a framework for understanding how uterine gland structure-function contributes to pregnancy success.

developmental biology↗