Influence of arylamine <i>n</i>‐acetyltransferase, sex, and age on 4‐aminobiphenyl‐induced in vivo mutant frequencies and spectra in mouse liver
Bibliographic record
Abstract
One model for cancer initiation by 4-aminobiphenyl (ABP) involves N-oxidation by cytochrome P450 CYP1A2 followed by O-conjugation by N-acetyltransferase(s) NAT1 and/or NAT2 and decomposition to a DNA-binding nitrenium ion. We recently observed that neonatal ABP exposure produced liver tumors in male but not in female mice, and that NAT deficiency reduced liver tumor incidence. However, ABP-induced liver tumor incidence did not correlate with liver levels of N-(deoxyguanosin-8-yl)-ABP adducts 24 hr after exposure. In this study, we compared in vivo ABP-induced DNA mutant frequencies and spectra between male and female wild-type and NAT-deficient Muta™Mouse using both the tumor-inducing neonatal exposure protocol and a 28-day repetitive dosing adult exposure protocol. ABP produced an increase in liver DNA mutant frequencies in both neonates and adults. However, we observed no sex or strain differences in mutant frequencies in neonatally exposed mice, and higher frequencies in adult females than males. Neonatal ABP exposure of wild-type mice increased the proportion of G-T transversions in both males and females, while exposure of Nat1/2(-/-) mice produced increased G-T transversions in males and a decrease in females, even though females had higher levels of N-(deoxyguanosin-8-yl)-4-ABP adducts. There was no correlation of mutant frequencies or spectra between mice dosed as neonates or as adults. These results suggest that observed sex- and NAT-dependent differences in ABP-induced liver tumor incidence in mice are not due to differences in either mutation rates or mutational spectra, and that mechanisms independent of carcinogen bioactivation, covalent DNA binding and mutation may be responsible for these differences.
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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".