Next Generation Sequencing to assess pesticides capacity in vitro to act as agonists/antagonists of the thyroid hormone nuclear receptors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA718198 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14092411.fastq.gz | Fastqsanger.gz | |||
| SRR14092412.fastq.gz | Fastqsanger.gz | |||
| SRR14092413.fastq.gz | Fastqsanger.gz | |||
| SRR14092414.fastq.gz | Fastqsanger.gz | |||
| SRR14092415.fastq.gz | Fastqsanger.gz |
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Project description:We combined in vitro tests to fully assess the capacity of pesticides to act as thyroid hormone disruptors (THD). Pesticides which were active in these tests were selected for a transcriptome analysis of neural cells. We took advantage of this technique to decipher what were the transcriptomic effects of these chemical in vitro. We also compared the expression of thyroid hormone responsive genes in presence or absence of the pesticides to determine if the transcriptomic changes could impact thyroid hormone receptor signaling. Although some pesticides elicit a cellular response, which sometimes interferes with thyroid hormone signaling, we found no evidence that they can act as TRα1 agonists or antagonists. We conclude that their neurodevelopmental toxicity in mammals is not explained by an alteration of the neural cell response to thyroid hormone.
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Project description:Chemicals acting as thyroid hormone disruptors (THDs) are of a particular concern for public health, considering the importance of this hormone in neurodevelopment and metabolic processes. They might either alter the circulating level of thyroid hormone (TH) or interfere with the cellular response to the hormonal stimulation. In order to assess this later possibility we selected 39 pesticides and combined several in vitro tests. Reporter assays respectively addressed the transactivation capacity of the full-length TH nuclear receptor TRα1, the transactivation capacity of its C-terminal ligand binding domain, or the ability of the hormone to destabilize the interaction between TRα1 and the transcriptional corepressor NcoR. Although some pesticides elicit a cellular response, which sometimes interferes with TH signaling, RNA-seq analysis provided no evidence that they can act as TRα1 agonists or antagonists. Their neurodevelopmental toxicity in mammals cannot be explained by an alteration of the response to TH.
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Project description:Affymetrix gene expression profiling in cumulus cells (CC) retrieved from patients undergoing GnRH agonists and GnRH antagonists IVF treatment. Oocytes from three different maturity stages were considered: metaphase I oocytes (MI), nonfertilized metaphase II (MII) oocytes (MII-NF) and MII oocytes developed to blactocyst stage embryo (MII-BL).
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Project description:Affymetrix gene expression profiling in cumulus cells (CC) retrieved from patients undergoing GnRH agonists and GnRH antagonists IVF treatment. Oocytes from three different maturity stages were considered: metaphase I oocytes (MI), nonfertilized metaphase II (MII) oocytes (MII-NF) and MII oocytes developed to blactocyst stage embryo (MII-BL). From 4 GnRH agonist treated patients, CC MI, CC MII-NF and CC MII-BL samples were collected; from 5 GnRH agonist and 6 GnRH antagonist treated patients, CC MII-NF and CC MII-BL samples were collected; and from 2 GnRH agonist and 4 GnRH antagonist treated patients, CC MI and CC MII-BL were collected. Altogether, 10 CC MI, 15 CC MII-NF and 21 CC MII-BL were collected and considered for transcriptome analysis.
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Project description:Melatonin is a known modulator of follicle development, it acts through several molecular cascades via binding to its two high-affinity, G-protein coupled receptors MT1 and MT2. Even though it is believed that melatonin can modulate granulosa cell (GC) functions, there is still limited knowledge of how it can act in human GC through MT1 and MT2 and which one is the major receptor implicated in the effects of melatonin on the metabolic processes in the dominant follicle. To better characterize the roles of the MT1 and MT2 receptors on the effects of melatonin on follicular atresia and the regulation of proliferation and differentiation of granulosa cells during the antral stage, human granulosa-like tumor cells (KGN) were treated with specific melatonin receptor agonists and antagonists, 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) for each treatment, lists of the principal differentially expressed genes (DEGs) are generated. Analysis of major upstream regulators suggested that the MT1 receptor may be involved in the melatonin antiproliferative effect by reprogramming the metabolism of human GC by activating the PKB signaling pathway. Our data suggest that melatonin may act complementary through both MT1 and MT2 receptors to modulate human GC steroidogenesis, proliferation, and differentiation. However, MT2 receptors may be the ones implicated in transducing the effects of melatonin on the prevention of GC luteinization and follicle atresia at the antral follicular stage through stimulating the PKA pathway.
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Project description:Hormone replacement therapy associated risks, and the concomitant reluctance of usage, has instigated the search for new generations of estrogen analogues that would maintain estrogen benefits without associated risks. Furthermore, if these analogues display chemo-preventative properties in breast and endometrial tissues it would be of great value. Both the selective estrogen receptor modulators as well as the selective estrogen receptor subtype modulators have been proposed as estrogen analogues with improved risk profiles. Phytoestrogen containing extracts of Cyclopia, an indigenous South African fynbos plant used to prepare Honeybush tea may serve as a source of new estrogen analogues. In this study three extracts, P104, SM6Met, and cup-of-tea, from two species of Cyclopia, C. genistoides and C. subternata, were evaluated for ER subtype specific agonism and antagonism both in transactivation and transrepression. For transactivation, the Cyclopia extracts displayed ER? antagonism and ER? agonism when ER subtypes were expressed separately, however, when co-expressed only agonism was uniformly observed. In contrast, for transrepression, this uniform behavior was lost, with some extracts (P104) displaying uniform agonism, while others (SM6Met) displayed antagonism when subtypes were expressed separately and agonism when co-expressed. In addition, breast cancer cell proliferation assays indicate that extracts antagonize cell proliferation in the presence of estrogen at lower concentrations than that required for proliferation. Furthermore, lack of uterine growth and delayed vaginal opening in an immature rat uterotrophic model validates the ER? antagonism of extracts observed in vitro and supports the potential of the Cyclopia extracts as a source of estrogen analogues with a reduced risk profile.
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Project description:Exposure to organophosphorus pesticides (OP) can have chronic adverse effects that are independent of inhibition of acetylcholinesterase, the classic target for acute OP toxicity. In pure proteins, the organophosphorus pesticide chlorpyrifos oxon induces a crosslink between lysine and glutamate (or aspartate) with loss of water. Tubulin is particularly sensitive to OP-induced crosslinking. Our goal was to explore OP-induced crosslinking in a complex protein sample, MAP-rich tubulin from Sus scrofa, and to test 8 OP for their capacity to catalyze isopeptide crosslinking. We treated 100 µg of MAP-rich tubulin with 100 µM chlorpyrifos, chlorpyrifos oxon, methamidophos, paraoxon, diazinon, diazoxon, monocrotophos, or dichlorvos. Each sample was separated on SDS PAGE and stained with Coomassie blue. Five gel slices (at about 30, 50, 150, and 300 kDa, and the top of the separating gel) were removed from the lanes for each of the eight OP samples and from untreated control lanes. These gel slices were subjected to in-gel trypsin digestion. MSMS fragmentation spectra of the tryptic peptides were examined for isopeptide crosslinks. Sixteen spectra yielded convincing evidence for isopeptide crosslinked peptides. Ten were from the chlorpyrifos oxon reaction, 1 from dichlorvos, 1 from paraoxon, 1 from diazinon, and 3 from diazoxon. It was concluded that catalysis of protein crosslinking is a general property of organophosphorus pesticides and pesticide metabolites.
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