The Threshold of Spermatogonial Stem Cell Numbers That Allows Male Fertility Restoration in Mice after a Treatment with an Alkylating Agent, Busulfan.
Bibliographic record
Abstract
As the cancer survival rate has been increasing steadily in recent years, the risk of infertility induced by anti-cancer regimen has become a significant concern for the quality of post-cancer life. Spermatogonial stem cells (SSCs) constitute the foundation of spermatogenesis and represent a crucial resource for the male fertility restoration. Using the mouse as a model, we investigated in this study the cytotoxic effect on SSCs of an alkylating agent, busulfan, and correlated the kinetics of SSC loss and proliferation with those of male fertility loss and restoration. We treated male transgenic mice, which carry LacZ in all male germ cells, with busulfan at three doses (15, 30 and 45 mg/kg) and examined their fertility by mating with intact females at different times post treatment. We measured SSC numbers by a transplantation assay using immunocompatible recipient mice. Colonies of donor-derived spermatogenesis were visualized by incubating recipient testes with 5-bromo-4chloro-3-indolyl β-galactosidase (X-gal) to determine the number of functional donor SSCs at each time point. We also measured testis weights and sperm counts and assessed spermatogenic recovery in histology. We found that fertility was lost within 4 weeks after treatment, regardless of busulfan doses. However, most SSCs were lost (>95%) in a dose-dependent manner within 3 days after treatment. Male fertility was restored in 12 weeks following treatment with 15 mg/kg busulfan, while 26 and 30 weeks were required when the males received 30 and 45 mg/kg busulfan, respectively, demonstrating a dose-dependent effect on SSC recovery. Interestingly, however, SSC numbers reached 30% of the before-treatment level by 4 weeks prior to the time of fertility restoration, regardless of busulfan doses (i.e., 8, 22, and 26 weeks with 15, 30, and 45 mg/kg busulfan, respectively). In agreement with these results, testis weights and spermatogenic recovery showed a dose-dependent effect of busulfan and its preferential killing of SSCs. The results of sperm counts showed that 17.5% of the before-treatment sperm number is required to grant fertility in mice, below which mice remained infertile. These results demonstrate that the loss and restoration of fertility after busulfan treatment are a direct consequence of SSC loss and proliferation. Importantly, the fact that the SSC numbers at 4 weeks before fertility recovery are nearly identical across the busulfan doses used indicate that there is a threshold in SSC numbers that allows the restoration of male fertility, which is 30% of the initial SSC numbers. In addition, these results set 17.5% of sperm count as a critical size of sperm population that allows male fertility in mice. (poster)
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 source (direct Gemma or distilled Codex), 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".