Characterization of Conserved Toxicogenomic Responses in Chemically Exposed Hepatocytes across Species and Platforms
Bibliographic record
Abstract
BACKGROUND: Genome-wide expression profiling is increasingly being used to identify transcriptional changes induced by drugs and environmental stressors. In this context, the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation system (TG-GATEs) project generated transcriptional profiles from rat liver samples and human/rat cultured primary hepatocytes exposed to more than 100 different chemicals. OBJECTIVES: To assess the capacity of the cell culture models to recapitulate pathways induced by chemicals in vivo, we leveraged the TG-GATEs data set to compare the early transcriptional responses observed in the liver of rats treated with a large set of chemicals with those of cultured rat and human primary hepatocytes challenged with the same compounds in vitro. METHODS: We developed a new pathway-based computational pipeline that efficiently combines gene set enrichment analysis (GSEA) using pathways from the Reactome database with biclustering to identify common modules of pathways that are modulated by several chemicals in vivo and in vitro across species. RESULTS: We found that some chemicals induced conserved patterns of early transcriptional responses in in vitro and in vivo settings, and across human and rat genomes. These responses involved pathways of cell survival, inflammation, xenobiotic metabolism, oxidative stress, and apoptosis. Moreover, our results support the transforming growth factor beta receptor (TGF-βR) signaling pathway as a candidate biomarker associated with exposure to environmental toxicants in primary human hepatocytes. CONCLUSIONS: Our integrative analysis of toxicogenomics data provides a comprehensive overview of biochemical perturbations affected by a large panel of chemicals. Furthermore, we show that the early toxicological response occurring in animals is recapitulated in human and rat primary hepatocyte cultures at the molecular level, indicating that these models reproduce key pathways in response to chemical stress. These findings expand our understanding and interpretation of toxicogenomics data from human hepatocytes exposed to environmental toxicants.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".