Serotonin synthesis protects the mouse colonic crypt from DNA damage and colorectal tumorigenesis
Bibliographic record
Abstract
Abstract Serotonin (5‐HT) signaling pathways are thought to be involved in colorectal tumorigenesis (CRT), but the role of 5‐HT synthesis in the early steps of this process is presently unknown. In this study, we used carcinogen treatment in the tryptophan hydroxylase 1 knockout (Tph1KO) and transgenic (Tph1 fl/fl Villin Cre ) mouse models defective in 5‐HT synthesis to investigate the early mutagenic events associated with CRT. Our observations of the colonic crypt post‐treatment followed a timeline designed to understand how disruption of 5‐HT synthesis affects the initial steps leading to CRT. We found Tph1KO mice had decreased development of both allograft tumors and colitis‐related CRT. Interestingly, carcinogenic exposure alone induced multiple colon tumors and increased cyclooxygenase‐2 ( Ptgs2 ) expression in Tph1KO mice. Deletion of interleukin 6 ( Il6 ) in Tph1KO mice confirmed that inflammation was a part of the process. 5‐HT deficiency increased colonic DNA damage but inhibited genetic repair of specific carcinogen‐related damage, leading to CRT‐related inflammatory reactions and dysplasia. To validate a secondary effect of 5‐HT deficiency on another DNA repair pathway, we exposed Tph1KO mice to ionizing radiation and found an increase in DNA damage associated with reduced levels of ataxia telangiectasia and Rad3 related ( Atr ) gene expression in colonocytes. Restoring 5‐HT levels with 5‐hydroxytryptophan treatment decreased levels of DNA damage and increased Atr expression. Analysis of Tph1 fl/fl Villin Cre mice with intestine‐specific loss of 5‐HT synthesis confirmed that DNA repair was tissue specific. In this study, we report a novel protective role for 5‐HT synthesis that promotes DNA repair activity during the early stages of colorectal carcinogenesis. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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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 | 0.001 | 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".