Applications for estimation of in vivo toxicity point of departure for discovery stage molecule predictive safety assessment
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1122150 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Utilization of in vitro (cellular) techniques, like Cell Painting and transcriptomics-based methods could provide powerful tools for risk assessment and regulatory decision-making. However, using these models generates challenges translating in vitro concentrations to corresponding in vivo internal exposures. We tested whether in vivo (rat liver) transcriptional and apical points of departure (PODs) could be accurately predicted from in vitro (rat hepatocyte or human HepaRG) transcriptional PODs or HepaRG Cell Painting PODs using PBPK modeling. We compared two PBPK models, ADMET predictor and the httk R package, and found httk to predict the rat hepatocyte no observed transcriptional effect level (NOTEL)-derived PODs more accurately. Our findings suggest that a rat liver apical and transcriptome POD can be estimated utilizing a combination of in vitro transcriptome-based PODs coupled with PBPK modeling for IVIVE.
2025-06-28 | GSE269501 | GEO
Project description:Multiple new approach methods (NAMs) are being developed to rapidly screen large numbers of chemicals to aid in hazard evaluation and risk assessments. High-throughput transcriptomics (HTTr) in human cell lines has been proposed as a first-tier screening approach for determining the types of bioactivity a chemical can cause (activation of specific targets vs. generalized cell stress) and for calculating transcriptional points of departure (tPODs) based on changes in gene expression. In the present study, we examine a range of computational methods to calculate tPODs from HTTr data, using six data sets in which MCF7 cells cultured in two different media formulations were treated with a panel of 44 chemicals for 3 different exposure durations (6, 12, 24 hr).
2023-12-05 | GSE249377 | GEO
Project description:Identifying a toxicity point of departure (POD) is a required step in human health risk characterization of crop protection molecules, and this POD has historically been derived from apical endpoints across a battery of animal-based toxicology studies. Using rat transcriptome and apical data for 79 molecules obtained from Open TG-GATES (Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System) (632 datasets), the hypothesis was tested that a short-term exposure, transcriptome-based liver biological effect POD (BEPOD) could estimate a longer-term exposure "systemic" apical endpoint POD. Apical endpoints considered were body weight, clinical observation, kidney weight and histopathology and liver weight and histopathology. A BMDExpress algorithm using Gene Ontology Biological Process gene sets was optimized to derive a liver BEPOD most predictive of a systemic apical POD. Liver BEPODs were stable from 3 h to 29 days of exposure; the median fold difference of the 29-day BEPOD to BEPODs from earlier time points was approximately 1 (range: 0.7-1.1). Strong positive correlation (Pearson R = 0.86) and predictive accuracy (root mean square difference = 0.41) were observed between a concurrent (29 days) liver BEPOD and the systemic apical POD. Similar Pearson R and root mean square difference values were observed for comparisons between a 29-day systemic apical POD and liver BEPODs derived from 3 h to 15 days of exposure. These data across 79 molecules suggest that a longer-term exposure study apical POD from liver and non-liver compartments can be estimated using a liver BEPOD derived from an acute or subacute exposure study.
| S-EPMC7357187 | biostudies-literature
Project description:Multiomics Point of Departure (moPOD) Modeling Supports an Adverse Outcome Pathway Network for Ionizing Radiation
| PRJNA854367 | ENA
Project description:Primary human pancreatic ductal organoids (HPDO) have emerged as a model to study pancreas biology and disease. Yet, donor material availability, and a lack of extensive benchmarking limits the range of applications. To address this gap, we established porcine pancreatic ductal organoids (PPDO) as a system from an easily obtainable source to model pancreatic ductal/progenitor biology. We benchmarked PPDO to HPDO and primary porcine pancreas using single-cell RNA sequencing (scRNA-Seq). We observed no overt phenotypic differences in PPDO derived from distinct developmental stages, with a WNT signaling enriched population characterizing PPDO. PPDO exhibited differentiation potential towards mature ductal cells and limited potential towards endocrine lineages. We used PPDO as a platform to assess the safety of FDA-approved drugs and showed conserved toxicity of statins and α-adrenergic receptor inhibitors between PPDO and HPDO cultures. Overall, our results highlight the PPDO as a model for mammalian duct/progenitor applications.
2025-09-10 | GSE307295 | GEO
Project description:Traditional developmental toxicity testing practice examines fetal apical endpoints to identify a point of departure (POD) for risk assessment. A potential new testing paradigm involves deriving a POD from a comprehensive analysis of molecular-level change. Here, the rat ketoconazole endocrine-mediated developmental toxicity model was used to test the hypothesis that maternal epigenomic (miRNA) and transcriptomic (mRNA) PODs are similar to fetal apical endpoint PODs. Sprague-Dawley rats were exposed from gestation day (GD) 6-21 to 0, 0.063, 0.2, 0.63, 2, 6.3, 20, or 40 mg/kg/day ketoconazole. Dam systemic, liver, and placenta PODs, along with GD 21 fetal resorption, body weight, and skeletal apical PODs were derived using BMDS software. GD 21 dam liver and placenta miRNA and mRNA PODs were obtained using three methods: a novel individual molecule POD accumulation method, a first mode method, and a gene set method. Dam apical POD values ranged from 2.0 to 38.6 mg/kg/day; the lowest value was for placenta histopathology. Fetal apical POD values were 10.9-20.3 mg/kg/day; the lowest value was for fetal resorption. Dam liver miRNA and mRNA POD values were 0.34-0.69 mg/kg/day, and placenta miRNA and mRNA POD values were 2.53-6.83 mg/kg/day. Epigenomic and transcriptomic POD values were similar across liver and placenta. Deriving a molecular POD from dam liver or placenta was protective of a fetal apical POD. These data support the conclusion that a molecular POD can be used to estimate, or be protective of, a developmental toxicity apical POD.
| S-EPMC9324934 | biostudies-literature
Project description:Primary human pancreatic ductal organoids (HPDO) have emerged as a model to study pancreas biology and disease. Yet, donor material availability, and a lack of extensive benchmarking limits the range of applications. To address this gap, we established porcine pancreatic ductal organoids (PPDO) as a system from an easily obtainable source to model pancreatic ductal/progenitor biology. We benchmarked PPDO to HPDO and primary porcine pancreas using single-cell RNA sequencing (scRNA-Seq). We observed no overt phenotypic differences in PPDO derived from distinct developmental stages, with a WNT signaling enriched population characterizing PPDO. PPDO exhibited differentiation potential towards mature ductal cells and limited potential towards endocrine lineages. We used PPDO as a platform to assess the safety of FDA-approved drugs and showed conserved toxicity of statins and α-adrenergic receptor inhibitors between PPDO and HPDO cultures. Overall, our results highlight the PPDO as a model for mammalian duct/progenitor applications.
2025-09-10 | GSE307148 | GEO
Project description:Primary human pancreatic ductal organoids (HPDO) have emerged as a model to study pancreas biology and disease. Yet, donor material availability, and a lack of extensive benchmarking limits the range of applications. To address this gap, we established porcine pancreatic ductal organoids (PPDO) as a system from an easily obtainable source to model pancreatic ductal/progenitor biology. We benchmarked PPDO to HPDO and primary porcine pancreas using single-cell RNA sequencing (scRNA-Seq). We observed no overt phenotypic differences in PPDO derived from distinct developmental stages, with a WNT signaling enriched population characterizing PPDO. PPDO exhibited differentiation potential towards mature ductal cells and limited potential towards endocrine lineages. We used PPDO as a platform to assess the safety of FDA-approved drugs and showed conserved toxicity of statins and α-adrenergic receptor inhibitors between PPDO and HPDO cultures. Overall, our results highlight the PPDO as a model for mammalian duct/progenitor applications.
2025-09-10 | GSE307147 | GEO