Comparative analysis of transcriptomic points-of-departure (tPODs) and adverse apical responses in embryo-larval fathead minnows exposed to fluoxetine
Ontology highlight
ABSTRACT:
ORGANISM(S): Pimephales promelas
PROVIDER: GSE179232 | GEO | 2021/12/12
REPOSITORIES: GEO
Similar Datasets
Project description:RNA-seq expression assays were done in larval Pimephales promelas (Fathead minnow, FHM) exposed to 10 chemicals (3 metals, 4 Neonicotinoids, and 3 pharmaceuticals) over a range of concentrations to derive relatively short term transcriptomics based points of departure (tPODs). tPODs were compared to apical points of departures (aPODs) to investigate the potential use of the FHM tPODS as part of a high throughput approach that might be used in a regulatory context.
2023-01-01 | GSE207231 | 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: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 Division of the National Toxicology Program (DNTP) is currently evaluating high-throughput transcriptomics (HTT) as an approach to provide estimates of chemical exposure that may pose minimal risk. HTT was evaluated in a 5-day in vivo rat model (with repeated dosing) with the objective to determine if benchmark doses (BMD) values for transcriptional pathway changes in the liver and kidney could estimate BMD values for traditional toxicological (apical) endpoints. Eighteen chemicals, most having been tested by the NTP in 2-year bioassays, were chosen for this study. Some of these chemicals are known to be potent hepatotoxicants (e.g. DE71, PFOA, furan, and methyl eugenol) in rodents, some exhibit toxicity but have minimal effects on the liver (e.g. acrylamide and α,β-thujone), and some exhibit little overt toxicity (e.g. ginseng and milk thistle extract) based on traditional toxicological evaluations. Male Sprague Dawley rats were exposed daily for 5 consecutive days by oral gavage to 8 to 10 dose levels of each chemical. Liver and kidney were collected 24 hours after the final exposure and assayed using HTT with the rat S1500+ platform. HTT dose-response data were analyzed using BMD Express 2.2 to determine transcriptional BMD values for liver and kidney. BMDS Wizard was used to determine apical BMD values for histopathological effects from historical chronic or sub-chronic toxicity studies. For many of the chemicals, the lowest transcriptional BMDs from the 5-day assays were within a factor of 5 of the lowest histopathological BMDs estimated from the traditional toxicity studies. These data suggest that using HTT in a 5-day in vivo model provides reasonable estimates of BMD values for traditional apical endpoints. This approach may be useful to prioritize chemicals for further testing while providing actionable data in a timely and cost-effective manner.
2020-05-12 | GSE147072 | GEO
Project description:New approach methods (NAMs) can reduce the need for chronic, animal-based toxicity and carcinogenicity bioassays. Here, we apply benchmark dose (BMD) response modeling (BMDExpress 2.3) to transcriptomic data after short-term exposures to three organophosphate pesticides (OPPs) to estimate chronic adverse effect levels in mouse. Specifically, mouse-liver were collected for RNA sequencing after 7-days of exposure, respectively, to several dose-levels of well-known OPPs: fenthion, methidathion and parathion. Transcriptional points-of-departure (TPODs) were compared to chronic, apical points-of-departures (APOD) for each OPP to inform more efficient means of estimating chemical potency and risk. The mouse-liver TPODs for fenthion, methidathion, and parathion were 0.009, 0.093, and 0.046 mg/Kg-day, respectively. These short-term TPODs reflected the relative potencies of the most sensitive, apical effects from the chronic studies with fenthion identified as the most potent OPP. Moreover, the TPODs were 2.3 to 17-fold more sensitive than the chronic APODs for mouse, suggesting utility in using short-term gene response for estimating long-term chemical risk. Further investigation into OPPs’ modes of action identified significant impacts on acetylcholinesterase mRNA abundance (FDR p-value <0.05, |FC|>2) as well as enrichment of canonical pathways (IPA, z-score>|2|) associated with organism death and neurological and immune dysfunctions, which have been known to be affected by OPPs. Despite bioassay-related differences, our results indicate the conservation of key events potentially important to OPPs biological activity and potency across species. While additional research is needed, these results build confidence in using short-term, molecular-based assays for the characterization of toxicity and risk, thereby reducing reliance on chronic, rodent-based studies.
2023-11-13 | GSE240853 | GEO
Project description:Postmenopausal females (50 85 years) representing a wide range of Bone mineral densities (BMDs) were consecutively registered, excluding persons who had diseases and medications known to affect bone remodeling. Low energy fracture(s) occurred in 32 (38 %). Trans-iliacal bone biopsies (84) were submitted to Affymetrix microarray expression analysis to study the relationship between BMD or osteoporosis and gene expression.
2009-11-12 | E-MEXP-1618 | biostudies-arrayexpress
Project description:Fluoxetine (FLX) is the most common selective serotonin reuptake inhibitor pharmaceutical used for the treatment of psychological disorders such as depression and anxiety. Increased prescription use of FLX by human populations has led to its pseudo-persistence in effluent-receiving waterways. Despite emerging concerns of FLX becoming a potential threat to the aquatic environment, there is currently limited information on effects of FLX on aquatic wildlife, including its specific mechanism of action and associated toxicity pathways in fish. The main goal of this study was to identify and validate key molecular toxicity pathways that are predictive of apical endpoints induced by exposure to FLX using the fathead minnow (Pimephales promelas), a model species common to North American freshwater systems. Adult fathead minnows were exposed to three concentrations of FLX (2.42, 10.7, and 56.7 µg/L) and a control for 21 days. After 96 hours, a subset of fish was sampled, and liver and brain tissue were collected to characterize molecular toxicity pathways using whole transcriptome and proteome analyses. In addition, at the end of the 21-day exposure, individuals were assessed for apical outcomes of regulatory relevance including histopathology and fecundity. Differential gene expression observed in the liver of fish exposed to the highest FLX treatment and revealed dysregulation of pathways associated with biosynthesis and metabolism of fatty acids, which may be an upstream molecular response that led to lipid-type vacuolation of hepatocytes, as observed in the histology analysis. Whole proteome analysis of the same fish revealed dysregulation of PPAR signalling, which may be associated with the enrichment of lipid-related pathways observed in the transcriptome. In addition, there was an indication of pathway enrichment of transcription- and translation-related pathways in the proteome. Common dysregulated genes in the brain of the treated fish were related to cellular signalling processes that are influenced by serotonin levels and shown to be involved in reproductive behaviour and, in turn, reproductive success. This was confirmed through a significant decrease in fecundity following the 21-day exposure. Pathways to measurable adverse outcomes are complex, however, this research does provide some important clues to the mechanistic toxicity that FLX inflicts.
2022-02-27 | GSE182913 | GEO
Project description:The number of legacy chemicals without toxicity reference values combined with the rate of new chemical development are overwhelming the capacity of the traditional risk assessment paradigm. More efficient approaches are needed to quantitatively estimate chemical risks. In this study, rats were dosed orally with multiple doses of six chemicals for 5 days, 2, 4, and 13 weeks. Target organs were analyzed for traditional histological and organ weight changes and transcriptional changes using microarrays. Histological and organ weight changes in this study and the tumor incidences in the original cancer bioassays were analyzed using benchmark dose (BMD) methods to identify noncancer and cancer points-of-departure. The dose-response changes in gene expression were also analyzed using BMD methods and the responses grouped based on signaling pathways. A comparison of transcriptional BMD values for the most sensitive pathway with BMD values for the noncancer and cancer apical endpoints showed a high degree of correlation at all time points. When the analysis included data from an earlier study with 8 additional chemicals, transcriptional BMD values for the most sensitive pathway were significantly correlated with noncancer (r = 0.827, p = 0.0031) and cancer-related (r = 0.940, p = 0.0002) BMD values at 13 weeks. The average ratio of apical-to-transcriptional BMD values was less than two suggesting that for the current chemicals, transcriptional perturbation did not occur at significantly lower doses than apical responses. Based on our results, we propose a practical framework for application of transcriptomic data to chemical risk assessment.
2013-04-22 | GSE45892 | GEO
Project description:To provide insights into the mode of action for Ni3S2 lung carcinogenicity by examining gene expression changes in target cells after inhalation exposure. Gene expression changes were determined in micro-dissected lung broncho-alveolar cells from Fischer F344 rats following inhalation of Ni3S2 at 0.0, 0.04, 0.08, 0.15, and 0.60 mg/m3 (0.03, 0.06, 0.11, and 0.44 mg Ni/m3) for one and four weeks (6 hours per day, 5 days per week). Results: Broncho-alveolar lavage fluid evaluation and lung histopathology provided evidence of inflammation only at the two highest concentrations, which were similar to those tested in the 2-year bioassay. The number of statistically significant up- and down-regulated genes decreased markedly from one to four weeks of exposure, suggesting adaptation. Cell signal pathway enrichment at both time-points primarily reflected responses to toxicity, including inflammatory and proliferative signaling. While proliferative signaling was up-regulated at both time points, some inflammatory signaling reversed from down-regulation at 1 week to up-regulation at 4 weeks. Conclusions: These results support a mode of action for Ni3S2 carcinogenicity driven by chronic toxicity, inflammation and proliferation, leading to mis-replication, rather than by direct genotoxicity. Benchmark dose (BMD) analysis identified the lowest pathway transcriptional BMD exposure concentration as 0.026 mg Ni/m3, for apoptosis/survival signaling. When conducted on the basis of lung Ni concentration the lowest pathway BMD was 0.64 µg Ni/g lung, for immune/inflammatory signaling. Implications: These highly conservative BMDs could be used to derive a point of departure in a nonlinear risk assessment for Ni3S2 toxicity and carcinogenicity.
2014-07-19 | GSE59593 | GEO
Project description:In this study, female fathead minnows (FHM) were exposed to waterbourne phenanthrene (201.8 µg/L) or a solvent control for 7 weeks. Fish were tested for behavioral differences in a modified behavioral test prior to euthansia. Hypothalami were excised and stored for microarray analyses.
2016-08-25 | GSE85993 | GEO