Low-dose exposure to PBDE disrupts genomic integrity and innate immunity in mammary tissue
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA818201 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18396400.fastq.gz | Fastqsanger.gz | |||
| SRR18396401.fastq.gz | Fastqsanger.gz | |||
| SRR18396402.fastq.gz | Fastqsanger.gz | |||
| SRR18396403.fastq.gz | Fastqsanger.gz | |||
| SRR18396404.fastq.gz | Fastqsanger.gz |
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Project description:The low-dose mixture hypothesis of carcinogenesis proposes that exposure to an environmental chemical that is not individually oncogenic may nonetheless be capable of enabling carcinogenesis when it acts in concert with other factors. A class of ubiquitous environmental chemicals that are hypothesized to potentially function in this low-dose capacity are synthesized polybrominated diphenyl ethers (PBDEs). PBDEs can affect correlates of carcinogenesis that include genomic instability and inflammation. However, the effect of low-dose PBDE exposure on such correlates in mammary tissue has not been examined. In the present study, low-dose long-term (16 weeks) administration of PBDE to mice modulated transcriptomic indicators of genomic integrity and innate immunity in normal mammary tissue. PBDE increased transcriptome signatures for the Nuclear Factor Erythroid 2 Like 2 (NFE2L2) response to oxidative stress and decreased signatures for non-homologous end joining DNA repair (NHEJ). PBDE also decreased transcriptome signatures for the cyclic GMP-AMP Synthase - Stimulator of Interferon Genes (cGAS-STING) response, decreased indication of Interferon Stimulated Gene Factor 3 (ISGF3) and Nuclear Factor Kappa B (NF-κB) transcription factor activity, and increased digital cytometry estimates of immature dendritic cells (DCs) in mammary tissue. Replication of the PBDE exposure protocol in mice susceptible to mammary carcinogenesis resulted in greater tumor development. The results support the notion that ongoing exposure to low levels of PBDE can disrupt facets of genomic integrity and innate immunity in mammary tissue. Such effects affirm that synthesized PBDEs are a class of environmental chemicals that reasonably fit the low-dose mixture hypothesis.
| S-EPMC9413140 | biostudies-literature
Project description:RNAseq results were generated from the normal mammary tissues of nude mice in a simple 2-group experiment (BDE-47 exposure vs. Vehicle-only exposure) after 16 weeks of exposure from subcutaneous osmotic minipumps
2022-10-01 | GSE199054 | GEO
Project description:Liver gene transcripts patterns were used to characterize toxicity from exposure to polybrominated diphenyl ethers (PBDEs), flame retardant components. In this study, Wistar Han dams were exposed by gavage to the PBDE mixture (DE71) starting at gestation day 6 (GD 6) and continuing to weaning on postnatal day 21 (PND 21). Offspring from the dams began PBDE direct dosing on PND 12 and were dosed daily through PND 21. After weaning, they were dosed 5 days per week for another 13 weeks. Liver samples were collected at PND 22 and week 13 for liver gene expression analysis and interrogated with the Affymetrix Rat Genome 230 2.0 Array. PBDE treatment induced 1,066 liver gene transcript changes in females and 1,200 transcriptional changes in males at PND 22 (false discovery rate (FDR) < 0.01), but only 263 liver transcriptional changes at 13 weeks in male rats (FDR <0.05). No significant differences in dose response were found between male and female pups. There were a total of 6 groups and 5x replication for each group, for 30 total samples that were analyzed. The groups were (1) pup-male-CTL, (2) pup-female-CTL, (3) pup-male-PBDE, (4) pup-female-PBDE, (5) rat-male-CTL, (6) rat-male-PBDE. We generated the following pairwise comparisons using R/maanova: malePups(PBDE vs CTL), femalePups(PBDE vs CTL), maleRats(PBDE vs CTL), CTLpups(male vs female), PBDEpups(male vs female). We also performed ANOVA test for SEX-by-DOSE (pups) and AGE-by-DOSE (males). For pups, genes with an FDR≤1% were selected; for rats, genes with FDR < 5% were selected.
2011-10-04 | E-GEOD-32156 | biostudies-arrayexpress
Project description:Liver gene transcripts patterns were used to characterize toxicity from exposure to polybrominated diphenyl ethers (PBDEs), flame retardant components. In this study, Wistar Han dams were exposed by gavage to the PBDE mixture (DE71) starting at gestation day 6 (GD 6) and continuing to weaning on postnatal day 21 (PND 21). Offspring from the dams began PBDE direct dosing on PND 12 and were dosed daily through PND 21. After weaning, they were dosed 5 days per week for another 13 weeks. Liver samples were collected at PND 22 and week 13 for liver gene expression analysis and interrogated with the Affymetrix Rat Genome 230 2.0 Array. PBDE treatment induced 1,066 liver gene transcript changes in females and 1,200 transcriptional changes in males at PND 22 (false discovery rate (FDR) < 0.01), but only 263 liver transcriptional changes at 13 weeks in male rats (FDR <0.05). No significant differences in dose response were found between male and female pups.
2011-10-05 | GSE32156 | GEO
Project description:To identify liver transcripts differentially expressed between control samples and animals exposed to PBDE-47, we collected RNA from male pups at postnatal day 4 (PND4) after the Wistar Han dams were exposed to 0, 0.1, 15, or 50 mg/kg PBDE-47. These samples were interrogated with the Affymetrix Rat Genome 230 2.0 GeneChip array. A total of 7, 50, and 149 gene transcripts were differentially expressed between control samples and 0.1, 15, and 50 mg/kg PBDE-47 (using a false discovery rate (FDR) threshold of 0.05). These transcripts were mapped to 2, 40, and 139 genes using Ingenuity Pathway Analysis.
2020-07-22 | GSE154912 | GEO
Project description:Polybrominated diphenyl ethers (PBDEs) are commonly used as flame retardants in a variety of commercial and household products. They have been detected in the environment and accumulate in mammalian tissues and fluids. PBDE toxicity is thought to be associated with endocrine disruption, developmental neurotoxicity and changes in fetal development. Although humans are exposed to PBDEs, our knowledge of the effects of PBDE metabolites on human cells with respect to health risk is insufficient. Two hydroxylated PBDEs (OH-PBDEs), 2-OH-BDE47 and 2-OH-BDE85, were investigated for their effects on cell viability/proliferation, DNA damage, cell cycle distribution and gene expression profiling in H295R adrenocortical carcinoma cells. We show that the two agents are cytotoxic in a dose-dependent manner only at micromolar concentrations, with 2-OH-BDE85 being more toxic than 2-OH-BDE47. However, no DNA damage was observed for either chemical, suggesting that the biological effects of OH-PBDEs occur primarily via non-genotoxic routes. Furthermore, no evidence of aryl hydrocarbon receptor (AHR)-mediated, dioxin-like toxicity was observed. Instead, we report that a micromolar concentration of OH-PBDEs induces transcriptional changes associated with endoplasmic reticulum stress and the unfolded protein response. We discuss whether OH-PBDE bioaccumulation could result in impairment of the adrenocortical secretory function.
2008-12-25 | GSE8588 | GEO
Project description:Test articles used: DE-71 (Pentabromodiphenyl Ether Mixture [Technical Grade), CAS Number 32534-81-9, DTXSID2024246); PBDE-47 (CAS Number 5436-43-1); PB (Phenobarbital, CAS Number 50-06-6 ); PCB (PCB126, CAS Number 57465-28-8)
2019-01-05 | GSE124431 | GEO
Project description:Brominated flame retardants (BFRs) are incorporated into consumer products to prevent flame propagation. These compounds leach into the domestic environment, resulting in chronic exposure and contamination. Pregnancy failure is associated with high levels of BFRs in human follicular fluid, raising serious questions regarding their impact on female fertility. Our goal was to elucidate effects of a mixture reflecting human follicular fluid levels of polybrominated flame retardants (PBDEs), the major class of BFRs, on an immortalized human granulosa cell line, the KGN cell line. We showed that cell viability was altered and oxidative stress was induced, as reflected by increased reactive oxygen species formation, at 20 µM of the PBDE mixture. Transcriptomic analysis revealed that several genes showing an altered expression after the PBDE treatment were involved in oxidative stress signaling pathways. Significant dose-dependent reduction of progesterone and estradiol levels was measured after PBDE treatment; expression of genes involved in steroid hormone metabolism, namely CYP1A1, was significantly affected by PBDEs. Treatment with the PBDE mixture also modified genes encoding for members of the transforming growth factor β superfamily like inhibins and cytokines, including the pro-inflammatory factor, interleukin-6 (IL6). Concentration of IL-6 in KGN cell culture media was consistently increased after treatment with the PBDE mixture. Our results clearly demonstrate that the PBDEs detected in human follicular fluid alter human granulosa cell functions by inducing oxidative stress, disrupting steroidogenesis and triggering an inflammatory response. This strengthens the fact that PBDEs are detrimental to ovarian functions and thus, to women’s reproductive health.
2016-05-25 | GSE77963 | GEO
Project description:Affymetrix high-density oligonucleotide microarray analysis was performed to analyse hydroxylated polybrominated diphenyl ethers (OH-PBDE)-induced gene expression changes in H295R adrenocortical carcinoma cells. Cells were treated with growth medium in the presence or absence of 10 µM 2-OH-BDE47 or 2-OH-BDE85 for 24 hours before the gene expression changes were investigated. Experiment Overall Design: Gene expression changes in response to hydroxylated polybrominated diphenyl ethers (OH-PBDEs) were analysed by Microarray technology in H295R adrenocortical carcinoma cells. Cells were treated with 10 µM of 2-OH-BDE47 or 2-OH-BDE85 (or growth medium alone) for 24 hours before the OH-PBDE-induced gene expression changes were investigated. Control, 2-OH-BDE47- and 2-OH-BDE85-treated samples were collected from three independent experiments each.
2009-01-02 | E-GEOD-8588 | biostudies-arrayexpress
Project description:Fusion of the EWS gene to FLI1 produces a fusion oncoprotein that drives an aberrant gene expression program responsible for the development of Ewing sarcoma. We used a homogenous proximity assay to screen for compounds that disrupt the binding of EWS-FLI1 to its cognate DNA targets. A number of DNA-binding chemotherapeutic agents were found to non-specifically disrupt protein binding to DNA. In contrast, actinomycin D was found to preferentially disrupt EWS-FLI1 binding by comparison to p53 binding to their respective cognate DNA targets in vitro. In cell-based assays, low concentrations of actinomycin preferentially blocked EWS-FLI1 binding to chromatin, and disrupted EWS-FLI1-mediated gene expression. Higher concentrations of actinomycin globally repressed transcription. These results demonstrate that actinomycin preferentially disrupts EWS-FLI1 binding to DNA at selected concentrations. Although the window between this preferential effect and global suppression is too narrow to exploit in a therapeutic manner, these results suggest that base-preferences may be exploited to find DNA-binding compounds that preferentially disrupt subclasses of transcription factors. Using proximity assays in A673 Ewing Sarcoma cells, we screened 7 bioactive-enriched small molecule libraries, totaling 5,200 compounds to identify compounds that could disrupt the binding of EWS-FLI1 to its cognate DNA binding sequence. We defined a set of EWS-FLI1-regulated genes by shRNA depletion of EWS-FLI1in the same cell line. Duplicate knock down experiments were carried out and compared to duplicate scrambled shRNA controls. This signature was used to interrogate the effects in duplicate experiments of low- and high-dose actinomycin D treatment in A673 cells as compared to DMSO and untreated controls (2 each).
2013-08-26 | E-GEOD-45414 | biostudies-arrayexpress