Characterizing the Ovotoxicity of Cyclophosphamide Metabolites on Cultured Mouse Ovaries
Bibliographic record
Abstract
Cyclophosphamide (CPA) is reported to target dormant primordial ovarian follicles in rodents and humans. However, mechanistic studies are complicated due to the complex ovarian structure. We present here the characterization of the sensitivity of ovaries to CPA metabolites and the timing of morphological alterations induced by phosphoramide mustard (PM) in an in vitro system. Intact mouse ovaries (postnatal-day-4) were cultured in vitro and exposed to multiple breakdown products of CPA on day 0 (d0). Tissues were cultured up to d8, and then follicle counts and immunohistochemistry were performed. 4-Hydroperoxy-CPA (4-HC), a precursor of an activated form of CPA, and PM depleted primordial and primary follicles (> or =1 microM and > or =3 microM, respectively, p < 0.05); acrolein had effects on follicle numbers only under continuous exposure (> =30 microM); carboxycyclophosphamide and 4-ketocyclophosphamide reduced primordial and small primary follicles only at high concentrations (100 microM). PM-induced follicle loss became significant (p < 0.05) by d1 or d2 following exposures to 10 microM or 3 microM PM, respectively, as determined by the numbers of pyknotic or TUNEL-positive follicles. Cellular targets were oocytes in the smallest follicles, but granulosa cells in large primary follicles. TUNEL staining was observed in both cell types, but caspase-3, a marker of apoptosis, was absent from primordial follicles. In addition, a pan-caspase inhibitor could not prevent follicle losses when administered prior to PM. Thus, brief exposures to 4-HC or PM are sufficient to induce permanent follicle loss in ovaries, and PM is likely the ultimate ovotoxicant. Furthermore, the cell death pathway is likely caspase-independent.
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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 | 0.001 |
| 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 | 0.002 |
| 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".