The Effects of Paternal Exposure to Cyclophosphamide on the Rate of Spermatozoal Decondensation and the Patterning of Chromatin Remodeling in Early Postfertilization Zygotes.
Bibliographic record
Abstract
Following fertilization, the entry of the mature spermatozoon triggers the arrested oocyte to complete its second meiotic division; oocyte proteins are activated to induce sperm decondensation. Sperm decondensation is divided into four distinct stages: condensed, type a (partially decondensed), type b (totally decondensed) and type c (recondensed) nuclei. Once the spermatozoon has started decondensing, chromatin remodeling is initiated, during which protein exchange occurs and sperm specific proteins are replaced with maternal histones. Cyclophosphamide (CPA), an anticancer and immunosuppressive agent that causes DNA crosslinks and strand breaks, is studied as a model male mediated developmental toxicant. Paternal exposure to CPA results in time specific and dose dependent adverse effects on progeny outcome. The treatment of male Sprague Dawley rats with a chronic low dose of CPA, 6 mg/kg/day for 4 weeks, targets highly sensitive post meiotic male germ cells undergoing chromatin remodeling. The delivery of a properly packaged male genome to the oocyte is essential for early embryonic development. We hypothesize that paternal exposure to CPA during spermiogenesis leads to improper packaging of the male genome, disturbing chromatin decondensation and remodelling in early zygotes. Our objectives were first to determine when, during sperm decondensation, post-translational modified histones are present on the paternal chromatin in the control group and second to assess whether CPA treatment alters the time required for sperm decondensation or the patterning of chromatin remodeling. Control and CPA treated male Sprague Dawley rats were mated overnight to naturally cycling females; early zygotes were collected the following morning at 9 AM and prepared for analysis by immunofluorescence and confocal microscopy. The classification of sperm decondensation stages was determined by the chromatin compaction level of spermatozoa stained with propidium iodide. Sperm decondensation occurred first at the base, then the tip and finally in the center region of the sperm head. In zygotes sired by CPA-exposed males, the progression of sperm through these decondensation stages was accelerated significantly in type c sperm nuclei compared to the zygotes sired by control males. The pattern and distribution of modified histones during chromatin remodeling was assessed with H4ack12 and H3S10ph. We observed two distinct patterns of chromatin remodeling. H4ack12, a marker for open chromatin structure, had homogenous staining, whereas H3S10ph, a marker for condensed chromatin structure, displayed a ring-like staining around the sperm head. Chromatin remodeling varied significantly along the longitudinal section of spermatozoa within and between sperm decondensation stages but was not affected by paternal exposure to CPA. Thus, paternal exposure to CPA disturbs the compaction of chromatin structure of male germ cells, affecting the rate of sperm decondensation, without altering the distribution pattern of modified histones in early post-fertilized zygotes. Supported by CIHR. (platform)
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".