The Effects of Paternal Exposure to Cyclophosphamide on the Rate of Spermatozoal Decondensation and the Patterning of Chromatin Remodeling in Early Postfertilization Zygotes.
Notice bibliographique
Résumé
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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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».