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Applications for estimation of in vivo toxicity point of departure for discovery stage molecule predictive safety assessment

ABSTRACT: Applications for estimation of in vivo toxicity point of departure for discovery stage molecule predictive safety assessment

PROVIDER: PRJNA1122150 | ENA |

REPOSITORIES: ENA

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Applications for estimation of in vivo toxicity point of departure for discovery stage molecule predictive safety assessment

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

PrePhage safety

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Exploring the Effects of Experimental Parameters and Data Modeling Approaches on In Vitro Transcriptomic Point-of-Departure Estimates

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

A Rat Liver Transcriptomic Point of Departure Predicts a Prospective Liver or Non-liver Apical Point of Departure.

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.

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Multiomics Point of Departure (moPOD) Modeling Supports an Adverse Outcome Pathway Network for Ionizing Radiation

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A microRNA or messenger RNA point of departure estimates an apical endpoint point of departure in a rat developmental toxicity model.

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.

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Transcription profiling of brain tissue from mice after safety or fear conditioning

Project description:safety versus fear conditioning. Mice were trained with 4 unpaired (Safety) or paired (Fear) CS-US presentations over 3 days. Mice were killed by decapitation 4hrs after the last training session.

2008-11-28 | E-MEXP-1358 | biostudies-arrayexpress

Evaluation of a non-animal toolbox informed by adverse outcome pathways (AOPs) for human inhalation safety

Project description:Concentration- and time- response and human lower EpiAveolar™ respiratory tract tissues comparison of transcriptional responses following 12-day exposure with different test materials. Differential expression and pathway analyses were performed to estimate the lowest transcriptional point of departure (PoD) - minimum effect concentration when a biological perturbation as estimated by gene expression changes could be identified.

2025-01-19 | E-MTAB-14272 | biostudies-arrayexpress

Short-term transcriptomic points-of-departure are consistent with chronic points-of departure for three organophosphate pesticides across mouse and fathead minnow.

Project description:Short-term transcriptomic points-of-departure are consistent with chronic points-of departure for three organophosphate pesticides across mouse and fathead minnow.

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Comparing transcriptomic points of departure to apical effect concentrations for larval fathead minnow exposed to chemicals with four different modes of action

Project description:It is postulated that below a transcriptomic-based point of departure, adverse effects are unlikely to occur, thereby providing a chemical concentration to use in screening level hazard assessment. The present study extends previous work describing a high throughput fathead minnow assay that can provide full transcriptomic data after exposure to a test chemical. One day post-hatch fathead minnows were exposed to ten concentrations of three representatives of four chemical modes of action: organophosphates, ecdysone receptor agonists, plant photosystem II inhibitors, and estrogen receptor agonists for 24 hours. Concentration response modeling was performed on whole body gene expression data from each exposure, using measured chemical concentrations when available. Transcriptomic points of departure in larval fathead minnow were lower than apical effect concentrations across fish species but not always lower than toxic effect concentrations in other aquatic taxa like crustaceans and insects. The point of departure was highly dependent on measured chemical concentration which were often lower than the nominal concentration. Differentially expressed genes between chemicals within modes of action were compared and often showed statistically significant overlap. In addition, reproducibility between identical exposures using a positive control chemical (CuSO4) and variability associated with the transcriptomic point of departure using in-silico sampling were considered. Results extend a transcriptomic-compatible fathead minnow high throughput assay for possible use in ecological hazard screening.

2024-10-18 | GSE252223 | GEO

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