Proliferating primary hepatocytes from the pUR288 <i>lacZ</i> plasmid mouse are valuable tools for genotoxicity assessment in vitro
Bibliographic record
Abstract
Safety assessments of substances with regard to genotoxicity are generally based on a combination of in vitro and in vivo tests. These tests are performed according to a (tiered) test strategy whereby a positive result in vitro usually triggers further testing in vivo. A low specificity and high frequency of irrelevant positive results associated with most in vitro mammalian cell genotoxicity assays necessitates the design and validation of suitable alternatives. As such, we examined the feasibility of culturing primary hepatocytes from the pUR288 lacZ reporter mouse, and moreover, using established cultures to reliably assess genotoxic activity in vitro. Initial studies characterizing the metabolic capacity of proliferating lacZ primary hepatocytes indicated that these cells retained at least some activities important for xenobiotic metabolism: cytochrome P450 1A1 enzyme activities were markedly increased in the hepatocytes after exposure to benzo[a]pyrene, and also UDP-glucuronosyl transferase and glutathione-S-transferase activities, both Phase II enzymes, were detected. Increasing levels of phosphorylated p53 at residue serine 389 after ultraviolet treatment indicated a properly functioning p53, one of the criteria for an effective new test system. Four genotoxic substances with different mechanisms of genotoxicity, i.e., benzo[a]pyrene, bleomycin, etoposide, and cyclophosphamide, were tested in the lacZ rescue assay. For etoposide and cyclophosphamide, the induction of mutant colonies was rather low. Exposure to benzo[a]pyrene and bleomycin, however, yielded a clear concentration-dependent induction of the lacZ mutant frequency. Based on our preliminary observations, proliferating lacZ primary hepatocytes are a promising new tool for the assessment of genotoxic hazard.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".