Human Transcriptomic Integrated Approach for Testing and Assessment Oral Reference Dose for Steatosis
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PROVIDER: PRJNA557466 | ENA |
REPOSITORIES: ENA
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Project description:Integrated Approaches to Testing and Assessment (IATA) are emerging as a means to strategically assess and test chemicals for toxicity, using existing information, and helping to identify potential data gaps. Adverse Outcome Pathways (AOPs) have recently been shown to be a good starting point for IATA development. Our interest in IATAs and AOP Networks (AOPNs) focuses on developing efficient testing and risk assessment strategies for new materials, new chemical entities, and setting environmental cleanup goals. We combine the maths logic of causality, specifically the notion of sufficiency to infer an adverse outcome, with AOPNs to develop Minimally Sufficient Sets of Key Events (MinSSKEs). These MinSSKEs represent a set of key events (can just be one key event) that taken together allow assessors to predict if an adverse outcome is likely or not. For our case study we use the military explosive trinitrotoluene (TNT). TNT is a relatively data rich chemical where the US Environmental Protection Agency has set a reference dose of 0.0005mg/kg-day, based on a point of departure for liver toxicity in dogs of 0.5mg/kg-day (a lowest observed adverse effect level; LOAEL) with uncertainty of 1,000X. Our IATA measures gene expression for genes in involved in our AOPN for energy metabolism, steatosis and oxidative stress in human induced pluripotent stem cells differentiated to hepatocytes exposed to TNT. We used a Bayesian statistical approach to identify differentially expressed genes, and a nonlinear data-driven dose-response modeling approach (Good Risk Assessment Values for Environmental Exposures; GRAVEE) to estimate points of departure for reference dose estimation. We obtained an RfD of 0.12mg/kg-day, with a 90% credible interval spanning from 0.02-0.19mg/kg-day using our IATA approach. Our RfD is based on a POD of 1.22mg/kg-day with a 90% credible interval spanning from 0.24-1.94mg/kg-day, and uncertainty of 10X after applying the IRIS uncertainty factors. Our PODs are highly comparable, with a difference of only 0.72mg/kg-day (or 2.44x). Our RfDs differ by 240x, owing to the fact that we have only a 10x uncertainty factor for human variability, whereas the IRIS assessment uses 1000x uncertainty for 10x animal-to-human extrapolation, 10x LOAEL-to-NOAEL extrapolation, and 10x for subchronic-to-chronic extrapolation. In this case study, our IATA resulted in a highly similar POD compared to the IRIS assessment, and an overall decrease in the uncertainty factors that needed to be applied. Our IATA approach worked well in this instance, and demonstrated several advantages by focusing on using a human-relevant in vitro model, data-driven POD modeling, and a net decrease in the overall risk assessment uncertainty factors, while maintaining the uncertainty associated with the data.
2022-07-02 | GSE135117 | GEO
Project description:We demonstrate how a multidisciplinary approach encompassing cellular reprogramming, transcriptomics, proteomics, metabolomics, modeling, network reconstruction and data management can be employed to unveil the mechanisms underlying the progression of steatosis. Proteomics revealed reduced AKT/mTOR signaling in fibroblasts derived from steatosis patients and further establishes that the insulin-resistant phenotype is present not only in insulin-metabolizing central organs, e.g. the liver, but is also manifested in skin fibroblasts. Transcriptome data enabled the generation of a regulatory network based on the transcription factor SREBF1, linked to a metabolic network of glycerolipid and fatty acid biosynthesis including the downstream transcriptional targets of SREBF1 which include LIPIN1 (LPIN) and low density lipoprotein receptor (LDLR). Glutathione metabolism was among the pathways enriched in steatosis patients in comparison to healthy controls. By using a model of the glutathione pathway we predict a significant increase in the flux through glutathione synthesis as both gamma-glutamylcysteine synthetase and glutathione synthetase have an increased flux. The transcriptomes of dermal fibroblasts derived from two patients with steatosis (60 yr, male BMI 45.7 (H0008) and 33 yr, female, BMI 51.3 (H0007)) and control fibroblasts (19 yr, female, BMI 21, (H0002)) were analyzed. Total RNA obtained from dermal fibroblasts derived from two patients with steatosis (60 yr, male BMI 45.7 (H0008) and 33 yr, female, BMI 51.3 (H0007)) and control fibroblasts (19 yr, female, BMI 21, (H0002)).
2013-12-31 | E-GEOD-37689 | biostudies-arrayexpress
Project description:Reference testing - FVST, DTU, ENGAGE (E.coli, 2014-2015)
| PRJEB14641 | ENA
Project description:Testing the effect of specific macronutrient combinations on mouse metabolism in vivo, we determined that diets pairing starch as carbohydrate with oleate as fat (42%:42% kcal) induced significant white adipose tissue pathology and hepatic steatosis compared to other isocaloric combinations.
2017-09-01 | GSE93800 | GEO
Project description:CPEB4 prevents hepatic steatosis
| PRJNA322835 | ENA
Project description:We demonstrate how a multidisciplinary approach encompassing cellular reprogramming, transcriptomics, proteomics, metabolomics, modeling, network reconstruction and data management can be employed to unveil the mechanisms underlying the progression of steatosis. Proteomics revealed reduced AKT/mTOR signaling in fibroblasts derived from steatosis patients and further establishes that the insulin-resistant phenotype is present not only in insulin-metabolizing central organs, e.g. the liver, but is also manifested in skin fibroblasts. Transcriptome data enabled the generation of a regulatory network based on the transcription factor SREBF1, linked to a metabolic network of glycerolipid and fatty acid biosynthesis including the downstream transcriptional targets of SREBF1 which include LIPIN1 (LPIN) and low density lipoprotein receptor (LDLR). Glutathione metabolism was among the pathways enriched in steatosis patients in comparison to healthy controls. By using a model of the glutathione pathway we predict a significant increase in the flux through glutathione synthesis as both gamma-glutamylcysteine synthetase and glutathione synthetase have an increased flux. The transcriptomes of dermal fibroblasts derived from two patients with steatosis (60 yr, male BMI 45.7 (H0008) and 33 yr, female, BMI 51.3 (H0007)) and control fibroblasts (19 yr, female, BMI 21, (H0002)) were analyzed.
2013-12-31 | GSE37689 | GEO
Project description:Human skin-derived precursor cells (hSKP) are a post natal stem cell population isolated from the dermis. These cells acquire hepatic characteristics upon differentiation with hepatogenic factors. Differentiated hSKP show characteristics of hepatocyte precursor cells and respond to hepatotoxic compounds in a comparable way as human hepatocyte cultures. We used microarray analyses to evaluate the modulation of gene expression due to exposure to a steatosis-inducing compound. hSKP obtained from 3 different donors were firstly differentiated and cultivated in the presence or absence of sodium valproate (Na-VPA). Control and Na-VPA samples were collected after 24h exposure.
2015-01-30 | E-GEOD-62547 | biostudies-arrayexpress