Regioselective In Vitro Toxicity of Aromatic Hydroxylated Metabolites of 6PPD-Quinone
Bibliographic record
Abstract
6PPD-Q undergoes rapid enzymatic reactions within salmonids to form two major hydroxylated metabolites, one alkyl and one aryl. While alkyl-OH-6PPD-Q has been confirmed to be nontoxic, the toxicity of aryl-OH-6PPD-Q remains unknown. We herein synthesized three aryl-OH-6PPD-Q isomers and tested their in vitro toxicity in a coho salmon (O. kisutch) embryo (CSE-119) cell line. Para-aryl-OH-6PPD-Q was determined to be the isomer formed in vivo with comparable toxicity (EC50 = 5.4 µg/L) to parent 6PPD-Q. The toxicity of aryl-OH-6PPD-Q isomers is highly regioselective, with reduced toxicity observed for meta-aryl-OH-6PPD-Q (EC50 = 32.8 µg/L), while ortho-aryl-OH-6PPD-Q did not exhibit toxicity up to 100 µg/L. The structure-related toxicity trend of ortho- and para- aryl-OH-6PPD-Q was also observed for their methoxy analogues, demonstrating that the regioselective toxicity should not be attributed to the desolvation energy of -OH. Instead, DFT calculations suggest that the reduced toxicity of ortho-aryl-OH-6PPD-Q could be due to its relatively high torsional energy (7.1 kcal/mol) compared to other isomers. In summary, this study highlighted the regioselective toxicity of aryl-OH-6PPD-Q isomers, where steric repulsion and rotational restrictions could possibly play an important role.
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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 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.001 |
| Bibliometrics | 0.000 | 0.002 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 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; both teacher heads agree on what is shown here.
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".