Physiologically-relevant Bisphenol A levels alter the developmental trajectory of an in vitro model of mouse Primordial Germ Cells
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PROVIDER: PRJNA661766 | ENA |
REPOSITORIES: ENA
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Project description:Background: Animal-based studies indicate that Bisphenol A (BPA) exposure is detrimental to reproductive health, but its impact on the earliest stages of germ cell development remain poorly defined. Objective: Using a murine in vitro model of early germ cell specification and differentiation, we sought to assess whether exposure to low levels of BPA prior to Primordial Germ Cell (PGC) formation alters their differentiation trajectory and unique molecular program. Methods: We used an established method of in vitro differentiation of mouse Embryonic Stem Cells (ESCs) into Epiblast-like Cells (EpiLCs) followed by PGC-Like Cells (PGCLCs) which together recapitulates defined stages of early germ cell development. Cellular consequences were determined using hemocytometer-based cell counting, fixation and intracellular staining followed by flow cytometry/FACS on cells exposed to increasing doses of BPA. We also generated RNA-seq libraries from RNA extracted from FACS-purified PGCLCs and performed transcriptome analysis using bioinformatics-based approaches, to interrogate and characterise gene expression changes resulting from BPA exposure. Results: Exposure of EpiLCs to BPA resulted in a dose-dependent increase in cell number, associated with an increase proportion of cells in S-phase as well as a reduced proportion undergoing apoptosis. Exposure also resulted in a greater proportion of EpiLCs showing signs of DNA damage. Remarkably, EpiLC exposure did not negatively impact PGC specification and resulted in dose-dependent increase in PGCLC proliferation. However, PGCLC transcriptome analysis revealed an aberrant program with significant deregulation of X-linked genes and retrotransposon expression. Differential gene expression analysis also revealed the deregulation of genes associated with lipid metabolism as well as deregulated expression of genes associated with later stages of gametogenesis. Conclusions: Our findings represent the first characterisation of the consequences of early BPA exposure on a model of PGC development, highlighting altered cell behaviour and underlying pathways and molecular processes.
2021-09-01 | GSE157570 | GEO
Project description:BackgroundAnimal-based studies indicate that bisphenol A (BPA) exposure is detrimental to reproductive health, but its impact on the earliest stages of germ cell development remains poorly defined.ObjectivesUsing a murine in vitro model of early germ cell specification and differentiation, we sought to assess whether exposure to low levels of BPA prior to formation of primordial germ cells (PGCs) alters their differentiation trajectory and unique molecular program.MethodsWe used an established method of in vitro differentiation of mouse embryonic stem cells (ESCs) into epiblast-like cells (EpiLCs) followed by PGC-like cells (PGCLCs), which together recapitulate defined stages of early germ cell development. Cellular consequences were determined using hemocytometer-based cell counting, fixation, and intracellular staining, followed by flow cytometry/fluorescence-activated cell sorting (FACS) of cells exposed to increasing concentrations (range: 1 nM-10 μM) of BPA. To interrogate and characterize gene expression differences resulting from BPA exposure, we also generated RNA-seq libraries from RNA extracted from FACS-purified PGCLCs and performed transcriptome analysis using bioinformatics-based approaches.ResultsExposure of EpiLCs to BPA resulted in higher numbers of cells that were associated with a higher proportion of cells in S-phase as well as a lower proportion undergoing apoptosis; this difference occurred in a concentration-dependent manner. Exposure also resulted in a greater fraction of EpiLCs showing signs of DNA damage. Remarkably, EpiLC exposure did not negatively affect PGC specification and resulted in a concentration-dependent effect on PGCLC proliferation in XX but not XY cells. PGCLC transcriptome analysis revealed an aberrant program with significant deregulation of X-linked genes and retrotransposon expression. Differential gene expression analysis also revealed the deregulation of genes associated with lipid metabolism as well as deregulated expression of genes associated with later stages of gametogenesis.ConclusionsTo the best of our knowledge our findings represent the first characterization of the consequences of early BPA exposure on a model of mammalian PGC development, highlighting altered cell behavior, altered underlying pathways, and altered molecular processes. https://doi.org/10.1289/EHP8196.
| S-EPMC8480152 | biostudies-literature
Project description:Bisphenol A (BPA) analogs, bisphenol B (BPB) and bisphenol AF (BPAF) have been widely detected in the environment and human products with increasing frequency. However, uterine health risks caused by BPBBisphenol A (BPA) analogs, bisphenol B (BPB) and bisphenol AF (BPAF) have been widely detected in the environment and human products with increasing frequency. However, uterine health risks caused by BPB and BPAF exposure need to be further elucidated. The study aimed to explore whether BPB or BPAF exposure will induce adverse outcomes in uterus. We then performed gene expression profiling using data obtained from mouse uterus exposed to BPB and BPAF at 28 days.
2023-05-12 | GSE223464 | GEO
Project description:Animal studies have linked perinatal bisphenol A (BPA) exposure to altered DNA methylation, but little attention is given to analyzing multiple physiologically relevant doses. Utilizing the viable yellow agouti (A(vy)) mouse, we examine the effects of developmental exposure through maternal diet to 50 ng BPA/kg (n = 14 litters), 50 ?g BPA/kg (n = 9 litters), or 50 mg BPA/kg (n = 13 litters) on global and candidate gene methylation at postnatal day 22. Global methylation analysis reveals hypermethylation in tail tissue of a/a and A(vy)/a offspring across all dose groups compared with controls (n = 11 litters; P < 0.02). Analysis of coat color phenotype replicates previous work showing that the distribution of 50 mg BPA/kg A(vy)/a offspring shifts toward yellow (P = 0.006) by decreasing DNA methylation in the retrotransposon upstream of the Agouti gene (P = 0.03). Maternal exposure to 50 ?g or 50 ng BPA/kg, however, results in altered coat color distributions in comparison with control (P = 0.04 and 0.02), but no DNA methylation effects at the Agouti gene are noted. DNA methylation at the CDK5 activator-binding protein (Cabp(IAP)) metastable epiallele shows hypermethylation in the 50 ?g BPA/kg offspring, compared with controls (P = 0.02). Comparison of exposed mouse liver BPA levels to human fetal liver BPA levels indicates that the three experimental exposures are physiologically relevant. Thus, perinatal BPA exposure affects offspring phenotype and epigenetic regulation across multiple doses, indicating the need to evaluate dose effects in human clinical and population studies.
| S-EPMC3570056 | biostudies-literature
Project description:Multiple sclerosis (MS) is a complex disease influenced by genetic and environmental contributing factors. Endocrine disrupting compounds (EDCs) such as bisphenol A (BPA) affect gene expression and hormone-regulated systems throughout the body. We investigated the effects of BPA on Theiler’s-virus induced demyelination (TVID), a mouse model of MS. Perinatal BPA exposure, combined with viral infection, resulted in a decreased level of viral antibodies, accelerated the onset of TVID symptoms, increased inflammation in both the spinal cord and digestive tract, and amplified immune-related gene expression changes induced by viral infection. These results demonstrate the effect of BPA on the trajectory of TVID, and illustrate how multiple factors collectively influence autoimmune disease. For microarray: 7 samples
2013-08-01 | E-GEOD-46551 | biostudies-arrayexpress
Project description:Pseudomonas aeruginosa causes severe multi-drug resistant infections that often lead to bacteremia and sepsis. Physiologically relevant conditions can increase the susceptibility of pathogens to antibiotics, such as azithromycin (AZM). When compared to minimal inhibitory concentrations (MIC) in lab media, AZM had a 16-fold lower MIC in tissue culture medium with 5% MHB, and a 64-fold lower MIC in this tissue culture medium with 20% human serum. AZM also demonstrated increased synergy in combination with synthetic host defence peptides DJK-5 and IDR-1018 under host-like conditions and in a murine abscess model. To mechanistically study the altered effects of AZM under physiologically relevant conditions, global transcriptional analysis was performed on P. aeruginosa with and without effective concentrations of AZM. This revealed that the arn operon, mediating arabinosaminylation of lipopolysaccharides, and related regulatory systems, were downregulated in host-like media when compared to MHB. Inactivation of genes within the arn operon led to increased susceptibility of P. aeruginosa to AZM and great increases in synergy between AZM and other antimicrobial agents, indicating that dysregulation of the arn operon might explain increased AZM uptake and synergy in host-like media. Furthermore, genes involved in central and energy metabolism, and ribosome biogenesis were dysregulated more in physiologically relevant conditions treated with AZM, likely due to general changes in cell physiology as a result of the increased effectiveness of AZM in these conditions. These data suggest that, in addition to the arn operon, there are multiple factors in host-like environments that are responsible for observed changes in susceptibility.
2020-12-21 | GSE151259 | GEO
Project description:We studied alterations in gene expression profiles of the MCF7 human breast cancer cells caused by bisphenol A, bisphenol AF and glyphosate using Illumina RNA sequencing platform.
2017-07-14 | GSE87701 | GEO
Project description:Female primordial germ cell differentiation undergoes sex determination and meiosis initiation asynchronously. Here we investigate the transcriptional profiles of 20519 single cells collected from E12.5, E14.5 and E16.5 mouse fetal ovaries. Clustering analysis identifies ten clusters and defines dozens of corresponding marker genes and provides a global view of cellular differentiation from undifferentiated primordial germ cells towards meiotic oocytes. We explore the dynamics of gene expression within the differentiation trajectory with special focus on the mechanisms for meiotic initiation.
2020-04-01 | GSE130212 | GEO
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Project description:Analysis primordial follicle compared to ovarian somatic cells proteome in humans.
2022-05-09 | PXD025369 | Pride