Development of a comprehensive toxicity pathway model for 17α-ethinylestradiol (EE2) in early life stage fathead minnows (Pimephales promelas)
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ABSTRACT:
PROVIDER: PRJNA659507 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12521607_1.fastq.gz | Fastqsanger.gz | |||
| SRR12521607_2.fastq.gz | Fastqsanger.gz | |||
| SRR12521608_1.fastq.gz | Fastqsanger.gz | |||
| SRR12521608_2.fastq.gz | Fastqsanger.gz | |||
| SRR12521609_1.fastq.gz | Fastqsanger.gz |
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Project description:Aquatic organisms are continuously exposed to complex mixtures of chemicals, many of which can interfere with their endocrine system, resulting in impaired reproduction, development or survival, among others. In order to analyze the effects and mechanisms of action of estrogen/anti-estrogen mixtures, we exposed male fathead minnows (Pimephales promelas) for 48 hours via the water to 2, 5, 10, and 50 ng 17α- ethinylestradiol (EE2)/L, 100 ng ZM 189,154/L (a potent antiestrogen known to block activity of all estrogen receptors) or mixtures of 5 or 50 ng EE2/L with 100 ng ZM 189,154/L. We analyzed gene expression changes in the gonad, as well as hormone and vitellogenin plasma levels. Steroidogenesis was down-regulated by EE2 as reflected by the reduced plasma levels of testosterone in the exposed fish and down-regulation of genes in the steroidogenic pathway. Microarray analysis of testis of fathead minnows treated with 5 ng EE2/L or with the mixture of 5 ng EE2/L and 100 ng ZM 189,154/L indicated that some of the genes whose expression was changed by EE2 were blocked by ZM 189,154, while others were either not blocked or enhanced by the mixture, generating two distinct expression patterns. Gene ontology and pathway analysis programs were used to determine categories of genes for each expression pattern. Our results suggest that response to estrogens occurs via multiple mechanisms, including canonical binding to soluble estrogen receptors, membrane estrogen receptors, and other mechanisms that are not blocked by pure antiestrogens.
2009-01-03 | GSE14235 | GEO
Project description:Adverse outcome pathways (AOPs) are conceptual frameworks that organize and link contaminant-induced molecular changes to adverse biological responses at the individual and population level. The development of AOPs is a priority area of research in ecotoxicology as a means to leverage molecular and high content mechanistic information obtained through top-down ‘omic approaches in regulatory decision-making. Current AOPs for hormonally active agents (HAAs) focus on nuclear receptor-mediated effects despite the overwhelming evidence that HAAs also activate membrane receptors. Activation of membrane receptors triggers propagation of non-genomic signaling cascades often transduced by protein phosphorylation leading to phenotypic changes. To promote investigations of rapid non-genomic signaling mechanisms of environmental contaminants in aquatic species for top-down AOP development, we developed a phosphoproteomic pipeline using label-free LC-MS/MS. We used our optimized pipeline to identify proteins differentially phosphorylated in the brain of fathead minnows (Pimephales promelas) aqueously exposed for 30 minutes to two HAAs, 17α-ethinylestradiol (EE2), a strong estrogenic substance, and levonorgestrel (LNG), a progestin, both components of the birth control pill. Results revealed differential phosphorylation of proteins involved in neuronal processes such as nervous system development, synaptic transmission, and neuroprotection by EE2 while LNG induced differential phosphorylation of proteins involved in axon cargo transport and calcium ion homeostasis. EE2 and LNG caused similar enrichment of cell processes including synaptic plasticity and neurogenesis. This study is the first to identify molecular changes in vivo in fish after short-term exposure and highlights membrane receptors and transduction of rapid, non-genomic signaling mechanisms as targets of HAAs in addition to the well-established nuclear receptor-mediated pathways.
2018-07-11 | PXD007714 | Pride
Project description:The goal of this study is to characterize molecular toxicity pathways associated with ethinylestradiol-induced toxicity and link these molecular perturbations to apical outcomes of regulatory relevance.
2020-10-31 | GSE156916 | GEO
Project description:There is an urgent demand for more efficient and ethical approaches in chemical risk assessment. Using 17α-ethinylestradiol (EE2) as a model compound, this study established a live-animal alternative embryo benchmark-dose (BMD) assay for rainbow trout (RBT; Oncorhynchus mykiss) to derive transcriptomic points-of-departure (tPODs). Embryos were exposed to graded concentrations of EE2 (0, 1.13, 1.57, 6.22, 16.3, 55.1, and 169 ng/L) from hatch to 4 and up to 60 days post-hatch (dph) to assess molecular and apical responses, respectively. Whole proteome analyses of alevins did not show clear estrogenic effects, while transcriptomics revealed responses that were in agreement with apical effects including excessive accumulation of intravascular and hepatic proteinaceous fluid and significant increases in mortality at 55.1 and 169 ng/L EE2 at later time points. Transcriptomic BMD analysis estimated the median of the 20th lowest geneBMD to be 0.18 ng/L; the most sensitive tPOD. Other estimates (0.78, 3.64, and 1.63 ng/L for the tenth percentile geneBMD, first peak geneBMD distribution, and median geneBMD of the most sensitive overrepresented pathway, respectively) were within the same order of magnitude as empirically derived apical P ODs for EE2 in the literature. This 4-day alternative RBT embryonic assay was effective in deriving protective tPODs for EE2.
2021-08-17 | GSE171788 | GEO
Project description:The objective of this study was to gain mechanistic insight into how mummichog are able to produce eggs during exposures to high levels of EE2. Mummichog were exposed to 0, 50 or 250 ng/L of EE2 for 14 d. A mummichog microarray was used to identify genomic responses associated with high EE2 exposure, and effects of EE2 on target genes involved in lipid mobilization and transport and steroidogenesis, two important (EE2 regulated) pathways involved in egg production, were measured using real-time PCR. In addition, changes at higher level biological endpoints such as plasma steroid production and gonad morphology were measured to examine downstream responses to EE2. There were no differences in gonadosomatic index, liversomatic index, gonad development, or plasma estradiol levels after exposure to EE2, although testosterone decreased with EE2 exposures. Similar to other species, mummichog showed alterations to plasma steroid levels, and similar processes at the molecular level were identified as being altered by EE2, including cell processes associated with lipids. However, unlike other species, mummichog showed no differences in GSI or ovarian development. Fatty acids were affected at both the transcript and translation level, which suggests they are a major target of estrogens. Lipids are important for both growth and reproduction, and provide oocytes with nutrients. Interestingly, mummichog showed no effect on apolipoprotein expression, which is important in lipid transport. Therefore, it is hypothesized that mummichog are normally able to transport lipids for energy and nutrients to the ovary, while this is affected in other species. Novel gene regulatory networks for protein modification targets were also constructed to learn more about the potential roles of estrogens in the teleost liver. Although post-translational modifications (PTMs) are important regulatory mechanisms, the roles of PTMs in protein regulation in fish and the susceptibility of PTMs to aquatic pollutants are largely unexplored and may offer novel insight into mechanisms of endocrine disruption.
2013-07-18 | GSE48945 | GEO
Project description:There is an urgent demand for more efficient and ethical approaches in chemical risk assessment. Using 17α-ethinylestradiol (EE2) as a model compound, this study established a live-animal alternative embryo benchmark-dose (BMD) assay for rainbow trout (RBT; Oncorhynchus mykiss) to derive transcriptomic points-of-departure (tPODs). Embryos were exposed to graded concentrations of EE2 (0, 1.13, 1.57, 6.22, 16.3, 55.1, and 169 ng/L) from hatch to 4 and up to 60 days post-hatch (dph) to assess molecular and apical responses, respectively. Whole proteome analyses of alevins did not show clear estrogenic effects, while transcriptomics revealed responses that were in agreement with apical effects including excessive accumulation of intravascular and hepatic proteinaceous fluid and significant increases in mortality at 55.1 and 169 ng/L EE2 at later time points. Transcriptomic BMD analysis estimated the median of the 20th lowest geneBMD to be 0.18 ng/L; the most sensitive tPOD. Other estimates (0.78, 3.64, and 1.63 ng/L for the tenth percentile geneBMD, first peak geneBMD distribution, and median geneBMD of the most sensitive overrepresented pathway, respectively) were within the same order of magnitude as empirically derived apical PODs for EE2 in the literature. This 4-day alternative RBT embryonic assay was effective in deriving protective tPODs for EE2.
2021-08-17 | PXD025251 | Pride
Project description:Transcriptional profiling of fathead minnow liver exposed either to the estrogen EE2 or a mixture of EE2 and the anti-estrogen ZM.
2017-01-17 | GSE93663 | GEO
Project description:This study assessed the impact of 17α-ethynylestradiol (EE2) on activated sludge microbiome
| PRJEB38611 | ENA
Project description:This study aimed to evaluate the utility of microarrays as a biomonitoring tool in field studies. A 15,000-oligonucleotide microarray was used to measure the hepatic gene expression of fathead minnows (Pimephales promelas) caged in four Nebraska, USA watersheds - the Niobrara and Dismal Rivers (low-impact agricultural sites) and the Platte and Elkhorn Rivers (high-impact agricultural sites). Gene expression profiles were site specific and fish from the low- and high-impact sites aggregated into distinct groups. Over 1500 genes were differentially regulated between fish from the low- and high-impact sites. Many gene expression differences (1218) were also noted when the Platte and Elkhorn minnows were compared to one another and Platte fish experienced a higher degree of transcript alterations than Elkhorn fish. These findings indicate that there are differences between the low-impact and high-impact sites, as well as between the high-impact sites. Historical water quality data supports these results as only trace levels of agrichemicals have been detected at the low-impact sites, while substantial levels of agrichemicals have been reported at the high-impact sites with agrichemical loads at the Platte generally exceeding those at the Elkhorn. Overall, this study demonstrates that microarrays can be utilized to discriminate sites with different contaminant loads from one another. A 15,000-oligonucleotide microarray was used to measure the hepatic gene expression of fathead minnows (Pimephales promelas) caged in four Nebraska, USA watersheds - the Niobrara and Dismal Rivers (low-impact agricultural sites) and the Platte and Elkhorn Rivers (high-impact agricultural sites).
2012-03-01 | E-GEOD-33436 | biostudies-arrayexpress
Project description:The goal of this study is to characterize molecular toxicity pathways associated with ethinylestradiol-induced toxicity and link these molecular perturbations to apical outcomes of regulatory relevance.
2021-04-09 | PXD021155 | Pride