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Toxicological Mechanisms and Potencies of Organophosphate Esters in KGN Human Ovarian Granulosa Cells as Revealed by High-throughput Transcriptomics

ABSTRACT: Toxicological Mechanisms and Potencies of Organophosphate Esters in KGN Human Ovarian Granulosa Cells as Revealed by High-throughput Transcriptomics

PROVIDER: PRJNA1010940 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25819200.fastq.gz	Fastqsanger.gz
	SRR25819300.fastq.gz	Fastqsanger.gz
	SRR25819400.fastq.gz	Fastqsanger.gz
	SRR25819500.fastq.gz	Fastqsanger.gz
	SRR25819201.fastq.gz	Fastqsanger.gz

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Toxicological Mechanisms and Potencies of Organophosphate Esters in KGN Human Ovarian Granulosa Cells as Revealed by High-throughput Transcriptomics

Project description:Despite the growing number of studies reporting potential risks associated with exposure to organophosphate esters (OPEs), their molecular mechanisms of action remain poorly defined. We used the high-throughput TempO-Seq platform to investigate the effects of frequently detected OPEs on the expression of ~3000 environmentally responsive genes in KGN human ovarian granulosa cells. Cells were exposed for 48 h to one of five OPEs (0.1 to 50 μM): tris(methylphenyl) phosphate (TMPP), isopropylated triphenyl phosphate (IPPP), tert-butylphenyl diphenyl phosphate (BPDP), triphenyl phosphate (TPHP), or tris(2-butoxyethyl) phosphate (TBOEP). The sequencing data indicate that four OPEs induced transcriptional changes, whereas TBOEP had no effect within the concentration range tested. Multiple pathway databases were used to predict alterations in biological processes based on differentially expressed genes. At lower concentrations, inhibition of the cholesterol biosynthetic pathway was the predominant effect of OPEs; this was likely a consequence of intracellular cholesterol accumulation. At higher concentrations, BPDP and TPHP had distinct effects, primarily affecting pathways involved in cell cycle progression and other stress responses. Benchmark concentration (BMC) modelling revealed that BPDP had the lowest transcriptomic point of departure. However, in vitro to in vivo extrapolation modeling indicated that TMPP was bioactive at lower concentrations than the other OPEs. We conclude that these new approach methodologies provide information on the mechanism(s) underlying the effects of data-poor compounds and assist in the derivation of protective points of departure for use in chemical read-across and decision-making.

2023-11-07 | GSE241995 | GEO

House Dust-Derived Mixtures of Organophosphate Esters Alter the Phenotype, Function, Transcriptome, and Lipidome of KGN Human Ovarian Granulosa Cells

Project description:Background: Organophosphate esters (OPEs), used as flame retardants and plasticizers, are present ubiquitously in the environment. Previous studies suggested that exposure to OPEs may be detrimental to female fertility in humans. However, no experimental information is available on the effects of OPE mixtures on ovarian granulosa cells, which play essential roles in female reproduction. Objectives: The goal of this study was to elucidate the effects of OPE mixtures representative of those found in Canadian house dust on ovarian granulosa cells. Methods: We used high-content imaging to investigate the effects an environmentally relevant OPE mixtures on KGN human granulosa cell phenotypes. Perturbation to steroidogenesis was assessed using ELISA and qRT-PCR. A high-throughput transcriptomic approach, TempO-Seq, was used to identify transcriptional changes in a targeted panel of genes. Effects on lipid homeostasis were explored using cholesterol assay and global lipidomic profiling. Results: OPE mixtures with distinct structural characteristics altered multiple phenotypic features of KGN cells with different potencies. The mixtures increased basal production of steroid hormones; this was mediated by significant changes in the expression of critical transcripts involved in steroidogenesis. Further, the total-OPE mixture disrupted cholesterol homeostasis and the composition of intracellular lipid droplets. Discussion: Exposure to house dust-derived mixtures of OPEs may adversely affect female reproductive health by altering a multitude of phenotypic and functional endpoints in granulosa cells. This study provides novel insights into the mechanisms of actions underlying the toxicity induced by OPE mixtures and highlights the need to examine the effects of human relevant chemical mixtures.

2024-07-03 | GSE247310 | GEO

House Dust-Derived Mixtures of Organophosphate Esters Alter the Phenotype, Function, Transcriptome, and Lipidome of KGN Human Ovarian Granulosa Cells

Project description:House Dust-Derived Mixtures of Organophosphate Esters Alter the Phenotype, Function, Transcriptome, and Lipidome of KGN Human Ovarian Granulosa Cells

| PRJNA1037087 | ENA

Role of YAP/TAZ in KGN human granulosa cell line

Project description:To identify the YAP/TAZ target genes in granulosa cells, DNA microarray experiments were performed in KGN cells where YAP/TAZ were knocked down. The effect of the presence or absence of 8Br-cAMP, an intracellular second messenger of FSH, was also investigated in KGN cells.

2022-11-04 | GSE203080 | GEO

Role of YAP/TAZ in KGN human granulosa cell line [Clariom_S_Human]

2022-11-04 | GSE213916 | GEO

Mitochondrial dynamics in ovarian granulosa cells during follicular growth and in human KGN cells

Project description:In the ovary, proliferation and differentiation of granulosa cells (GCs) drive the growth of follicles. This is, in part, dependent on gonadotropins. Our immunohistochemical studies provided hints of mitochondrial biogenesis and intracellular redistribution in GCs of growing follicles. A cellular model, human KGN cells (granulosa cell tumor cells, derived from growing follicles) was used to study aspects of mitochondrial dynamics. To elevate cAMP and thereby mimic gonadotropin actions, forskolin (FSK) was used, which increased KGN cell size and mitochondrial DNA within 24 h. MitoTracker experiments and ultrastructural 3D reconstruction revealed that FSK treatment induced the formation of elaborate mitochondrial networks. H89, a protein kinase A (PKA) inhibitor, reduced network formation. A proteomic analysis indicated that FSK among others elevated levels of regulators of the cytoskeleton and the steroidogenic enzyme CYP11A1, located in mitochondria, was more than 3-fold increased, implying that cAMP/PKA-associated structural changes go in parallel with the acquisition of steroidogenic competence of mitochondria in KGN cells. In summary, in situ observations showed increases in mitochondria and suggested intracellular trafficking in GCs during follicular growth and indicated that they may partially be under the control of gonadotropins/cAMP. In line with this, elevation of cAMP in KGN profoundly affected mitochondria dynamics in a PKA-dependent manner and implicated cytoskeletal changes.

2022-10-14 | PXD032160 | Pride

Impacts of Gestational FireMaster 550 (FM 550) Exposure on the Neonatal Cortex are Sex Specific and Largely Attributable to the Organophosphate Esters

Project description:To investigate the potential underlying neurotoxic effect of developmental exposure to flame retardant mixture, Fire Master 550, or it brominated and organophosphate we performed gene expression profiling in PND1 rat prefrontal cortex.

2022-08-20 | GSE211430 | GEO

ChIP-chip by array of human adult ovarian granulosa cell tumor derived cell line KGN using anti-FOXL2 antibodies

Project description:ChIP-on-Chip experiment using chromatin from the human adult ovarian granulosa cell tumor derived cell line KGN (Nishi et al, 2001), or from a KGN subclone overexpressing WT FOXL2 (KF3 subclone), and an isovolumic blend of our custom anti-FOXL2 polyclonal antibodies (Cocquet J et al, 2002). Non precipitated sheared matched deproteinized chromatin (Input) was used a control to estimate enrichment peaks (and thus FOXL2 binding sites) from IPed DNA. DNA from three independent ChIP assays (Input extractions) was pooled, and 100ng of DNA was linearly amplified using the Whole Genome Amplification kit (Sigma). The two ChIP-chip experiments serve as biological replicates. Moreover, 42 out of 48 targets promoters chosen from the âenrichment peakâ list were subsequently confirmed as enrichment sites in anti-FOXL2 ChIPed DNA for subsequent experiments.

2011-02-22 | E-MTAB-399 | biostudies-arrayexpress

Effects of an environmentally relevant mixture of organophosphate esters derived from house dust on endochondral ossification in murine limb bud cultures

Project description:Organophosphate esters (OPEs) are used widely as flame retardants and plasticizers but much remains unknown about their potential toxicity. Previously, we reported that four individual OPEs suppress endochondral ossification in murine limb bud cultures. However, real-life exposure is to complex OPE mixtures. In the present study, we tested the hypothesis that a Canadian household dust-based OPE mixture will affect endochondral ossification in gestation day 13 CD1 mouse embryo limb buds expressing fluorescent markers for the major cell populations involved in the process: COL2A1-ECFP (proliferative chondrocytes), COL10A1-mCherry (hypertrophic chondrocytes), and COL1A1-YFP (osteoblasts). Limbs were cultured for six days in the presence of vehicle or dilutions of the OPE mixture (1/1,000,000, 1/600,000, and 1/300,000). All three OPE mixture dilutions affected cartilage template development and the progression of endochondral ossification, as indicated by the fluorescent markers. The expression of Sox9, the master regulator of chondrogenesis, was unchanged, but the expression of Runx2 and Sp7, which drive chondrocyte hypertrophy and osteoblastogenesis, was dilution-dependently suppressed. RNA sequencing revealed that exposure to the 1/300,000 dilution of the OPE mixture for 24 h downregulated 153 transcripts and upregulated 48 others by at least 1.5-fold. Downregulated transcripts were enriched for those related to the immune system and bone formation. In contrast, upregulated transcripts were enriched for those with stress response functions known to be regulated by ATF4 activation. Thus, exposure to the mixture of OPEs commonly found in house dust may have adverse effects on bone formation.

2020-12-28 | GSE157940 | GEO

Melatonin signaling pathways implicated in metabolic processes in human granulosa cells (KGN)

Project description:Female reproduction depends on the metabolic status especially during the period of folliculogenesis. Even though it is believed that melatonin can improve oocyte competence, there is still limited knowledge of how it can modulate metabolic processes during folliculogenesis, and of which signaling pathways are involved in regulating gene expression. To investigate the effects of melatonin on metabolic signals during the antral stage of follicular development, human granulosa-like tumour cells (KGN) were treated with melatonin or forskolin and gene expression was analyzed with RNA seq technology. Following appropriate normalization and the application of a fold change cut-off of 1.5 (FC 1.5, P ≤ 0.05), 1,009 and 922 genes were identified as differentially expressed in response to melatonin and forskolin, respectively. Analysis of major upstream regulators suggested that melatonin may activate PKB/mTOR signaling pathways to program the metabolism of KGN cells to support slower growth and differentiation and to prevent follicular atresia. Similarly, PKA activation through stimulation of cAMP synthesis with FSK seemed to exert the same effects as melatonin in reducing follicular growth and regulating differentiation. This study suggests that it is possible that melatonin acts through PKA and PKB simultaneously in human granulosa cells to prevent follicular atresia and early luteinisation at the antral stage.

2022-03-09 | GSE189124 | GEO

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