TGF-β signaling links early-life endocrine-disrupting chemicals exposure to suppression of nucleotide excision repair in rat myometrial stem cells
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PROVIDER: PRJNA936864 | ENA |
REPOSITORIES: ENA
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Project description:Environmental exposure to endocrine-disrupting chemicals (EDCs) is associated with uterine fibroids (UFs) development, the most common benign tumors in women of reproductive age. It has been shown that UFs originate from abnormal myometrial stem cells (MMSCs) and there is evidence that defective DNA repair capacity could be involved in the emergence of mutations with implications for tumorigenesis. Moreover, the multifunctional cytokine TGF-β1 has been related to UF progress and some works revealed its connection with certain DNA damage repair pathways. Eker rats develop spontaneous uterine tumors in adulthood, which makes it a useful model for the study of UFs emergence The purpose of this study was to evaluate the impact of endocrine-disrupting chemicals (EDCs exposure on TGF-β1 pathway and nucleotide excision repair (NER) capacity, on Eker rat myometrial stem cells (MMSCs).
2023-08-07 | GSE225636 | GEO
Project description:Environmental exposure to endocrine-disrupting chemicals (EDCs) is linked to the development of uterine fibroids (UFs) in women. UFs, non-cancerous tumors, are thought to originate from abnormal myometrial stem cells (MMSCs). Defective DNA repair capacity may contribute to the emergence of mutations that promote tumor growth. The multifunctional cytokine TGFβ1 is associated with UF progression and DNA damage repair pathways. To investigate the impact of EDC exposure on TGFβ1 and nucleotide excision repair (NER) pathways, we isolated MMSCs from 5-months old Eker rats exposed neonatally to Diethylstilbestrol (DES), an EDC, or to vehicle (VEH). EDC-MMSCs exhibited overactivated TGFβ1 signaling and reduced mRNA and protein levels of NER pathway components compared to VEH-MMSCs. EDC-MMSCs also demonstrated impaired NER capacity. Exposing VEH-MMSCs to TGFβ1 decreased NER capacity while inhibiting TGFβ signaling in EDC-MMSCs restored it. RNA-seq analysis and further validation revealed decreased expression of Uvrag, a tumor suppressor gene involved in DNA damage recognition, in VEH-MMSCs treated with TGFβ1, but increased expression in EDC-MMSCs after TGFβ signaling inhibition. Overall, we demonstrated that the overactivation of the TGFβ pathway links early-life exposure to EDCs with impaired NER capacity, which would lead to increased genetic instability, arise of mutations, and fibroid tumorigenesis. We demonstrated that the overactivation of the TGFβ pathway links early-life exposure to EDCs with impaired NER capacity, which would lead to increased fibroid incidence.
| S-EPMC10274956 | biostudies-literature
Project description:The goal of this study was to compare NGS-derived murine myometrial progenitor cell transcriptome profiling (RNA-seq) of an animal model of uterine fibroid tumorigenesis in rats exposed during uterine development to an endocrine-disrupting chemical, diethylstilbestrol (DES) versus vehicle (VEH) control, unexposed animals, to determine the pathways and biological processes, whose gene expression may be altered as a result of the exposure.
2020-11-05 | GSE106655 | GEO
Project description:Developmental Exposure to Endocrine-Disrupting Chemicals Alters Gene Expression in Myometrium of Exposed Animals
| PRJNA417556 | ENA
Project description:Background: Development and application of transcriptomics-based gene classifiers for ecotoxicological applications lag far behind those of human biomedical science. Many such classifiers discovered thus far lack vigorous statistical and experimental validations, with their stability and reliability unknown. A combination of genetic algorithm/support vector machines and genetic algorithm/K nearest neighbors were used in this study to search for classifiers of endocrine disrupting chemicals (EDCs) in zebrafish. Searches were conducted on both tissue-specific and all tissue combined datasets, either across the entire transcriptome or within individual transcription factor (TF) networks previously linked to EDC effects. Candidate classifiers were evaluated by gene set enrichment analysis (GSEA) on both the original training data and a dedicated validation dataset. Results: Multi-tissue dataset yielded no classifiers. Among the 19 chemical-tissue conditions evaluated, the transcriptome-wide searches yielded classifiers for six of them, each having approximately 20 to 30 gene features unique to a condition. Searches within individual TF networks produced classifiers for 15 chemical-tissue conditions, each containing 100 or fewer top-ranked gene features pooled from those of multiple TF networks and also unique to each condition. For the training dataset, 10 out of 11 classifiers successfully identified the gene expression profiles (GEPs) of their intended chemical-tissue conditions by GSEA. For the validation dataset, classifiers for prochloraz-ovary and flutamide-ovary also correctly identified the GEPs of corresponding conditions while no classifier could predict the GEP from prochloraz-brain. Conclusions: The discrepancies in the performance of these classifiers were attributed in part to varying data complexity among the conditions, as measured to some degree by Fisher’s discriminant ratio statistic. This variation in data complexity could likely be compensated by adjusting sample size for individual chemical-tissue conditions, thus suggesting a need for a preliminary survey of transcriptomic responses before launching a full scale classifier discovery effort. While GSEA appeared to provide a flexible and effective tool for application of gene classifiers, a similar but more refined algorithm, connectivity mapping, should also be explored for ecotoxicological applications. The distribution characteristics of classifiers across tissues, chemicals, and TF networks suggested a differential biological impact among the EDCs on zebrafish transcriptome involving some basic cellular functions. chemical abbreviations: EE2, 17α-ethynyl estradiol; FAD, fadrozole; TRB, 17 -trenbolone; FIP, fipronil; PRO, prochloraz; FLU, flutamide; MUS, muscimol; KET, ketoconazole; TRI, trilostane; VIN, vinclozolin Since this study was conducted in several phases, three different version of Agilent zebrafish two color microarrays were used based on their availability at the time. These include G2518A (designID 013223) and G2519F (designID 015064, 019161). There were a total of 58 treatment conditions with various combinations of chemical, tissue type, exposure time, and gender. Each condition contained eight to 12 independent samples, half from chemical-treated fish and half from water- control fish.
2012-08-22 | E-GEOD-38070 | biostudies-arrayexpress
Project description:The transcriptomic dose-dependent response of rat immortalized thyrocytes to two thyroid disrupting chemicals was investigated by RNA-seq experiment. PCCl3 cells were exposed for one week to different doses of ethylenethiourea (ETU) and chlorpyrifos (CPF) and to their combinations.
2016-12-06 | E-MTAB-5269 | biostudies-arrayexpress
Project description:A growing epidemic of nonalcoholic fatty liver disease (NAFLD) is paralleling the increase in the incidence of obesity and diabetes mellitus in countries that consume a Western diet. As NAFLD can lead to life-threatening conditions such as cirrhosis and hepatocellular carcinoma, an understanding of the factors that trigger its development and pathological progression is needed. Although by definition this disease is not associated with alcohol consumption, exposure to environmental agents that have been linked to other diseases might have a role in the development of NAFLD. Here, we focus on one class of these agents, endocrine-disrupting chemicals (EDCs), and their potential to influence the initiation and progression of a cascade of pathological conditions associated with hepatic steatosis (fatty liver). Experimental studies have revealed several potential mechanisms by which EDC exposure might contribute to disease pathogenesis, including the modulation of nuclear hormone receptor function and the alteration of the epigenome. However, many questions remain to be addressed about the causal link between acute and chronic EDC exposure and the development of NAFLD in humans. Future studies that address these questions hold promise not only for understanding the linkage between EDC exposure and liver disease but also for elucidating the molecular mechanisms that underpin NAFLD, which in turn could facilitate the development of new prevention and treatment opportunities.
| S-EPMC5657429 | biostudies-other
Project description:We report that developmental exposure to the endocrine disrupting chemical (EDC) diethylstilbestrol increases the estrogen action in myometrial stem cells (MMSCs), the origin from which UFs originate. The expression of reprogrammed estrogen responsive genes (ERGs) is driven by activated mixed lineage leukemia protein-1 (MLL1) in MMSCs. Deactivation of MLL1 reverses reprogramming of ERG expression. In addition, upregulation of ERGs occurs via DNA hypomethylation mechanism. Furthermore, the secretome of reprogrammed MMSCs enhances the proliferation of differentiated myometrial cells through activation of β-catenin signaling. This work identifies epigenetic mechanisms of MLL1/DNA methyltransferase- mediated MMSC reprogramming, and EDC exposure epigenetically targets MMSCs and imparts a hormonal imprint on the ERGs resulting in a “hyper-estrogenized” phenotype and increased hormone-dependent risk of UFs.
2023-08-07 | GSE157502 | GEO
Project description:Since reports published in 2015 and 2016 identified 15 probable exposure-outcome associations, there has been an increase in studies in humans of exposure to endocrine-disrupting chemicals (EDCs) and a deepened understanding of their effects on human health. In this Series paper, we have reviewed subsequent additions to the literature and identified new exposure-outcome associations with substantial human evidence. Evidence is particularly strong for relations between perfluoroalkyl substances and child and adult obesity, impaired glucose tolerance, gestational diabetes, reduced birthweight, reduced semen quality, polycystic ovarian syndrome, endometriosis, and breast cancer. Evidence also exists for relations between bisphenols and adult diabetes, reduced semen quality, and polycystic ovarian syndrome; phthalates and prematurity, reduced anogenital distance in boys, childhood obesity, and impaired glucose tolerance; organophosphate pesticides and reduced semen quality; and occupational exposure to pesticides and prostate cancer. Greater evidence has accumulated than was previously identified for cognitive deficits and attention-deficit disorder in children following prenatal exposure to bisphenol A, organophosphate pesticides, and polybrominated flame retardants. Although systematic evaluation is needed of the probability and strength of these exposure-outcome relations, the growing evidence supports urgent action to reduce exposure to EDCs.
| S-EPMC7437820 | biostudies-literature
Project description:We report that developmental exposure to the endocrine disrupting chemical (EDC) diethylstilbestrol increases the estrogen action in myometrial stem cells (MMSCs), the origin from which UFs originate. The expression of reprogrammed estrogen responsive genes (ERGs) is driven by activated mixed lineage leukemia protein-1 (MLL1) in MMSCs. Deactivation of MLL1 reverses reprogramming of ERG expression. In addition, upregulation of ERGs occurs via DNA hypomethylation mechanism. Furthermore, the secretome of reprogrammed MMSCs enhances the proliferation of differentiated myometrial cells through activation of β-catenin signaling. This work identifies epigenetic mechanisms of MLL1/DNA methyltransferase- mediated MMSC reprogramming, and EDC exposure epigenetically targets MMSCs and imparts a hormonal imprint on the ERGs resulting in a “hyper-estrogenized” phenotype and increased hormone-dependent risk of UFs.
2023-08-07 | GSE157500 | GEO