The impact of cyclophosphamide on male germ cell quality and consequences on early post-fertilization events /
Bibliographic record
Abstract
Paternal exposure to therapeutic drugs or environmental chemicals can alter the genomic integrity of male germ cells, and consequently, be a source of detrimental effects on embryo development. Preconceptional exposure of male rats to the anticancer alkylating agent, cyclophosphamide, resulted in increased embryo loss, malformations and behavioral deficits in the offspring; these drug effects can be transmissible to subsequent generations. The goal of the studies presented in this thesis is to gain an understanding of the manner by which altered spermatozoal genomic integrity, acquired during preconceptional exposure to a DNA damaging agent, may lead to developmental instabilities in the early preimplantation embryo. Spermatozoa must be functional in order to effectively transmit genetic information to the oocyte. Motility is one component contributing to the ability of the spermatozoon to achieve proximity to and penetration of the oocyte for fertilization. Chronic cyclophosphamide exposure had little effect on the kinematic parameters constituting spermatozoal motion patterns. Drug-exposed spermatozoa are motile, and may thus be at an increased risk of transmitting an altered genomic complement to the embryo. An intact paternal genome is essential for normal embryogenesis. Using the rat sperm Y-4 fluorescence in situ hybridization assay, we determined that 9 weeks of chronic cyclophosphamide treatment, but not 6 weeks, significantly increased the frequency of numerical chromosomal abnormalities in epididymal spermatozoa. Epigenetic marks, characterized by various posttranslational modifications, also play an intricate role in chromatin dynamics during spermatogenesis and embryogenesis. Early post-fertilization, histone H4 acetylation and DNA methylation were dysregulated in both parental pronuclei in zygotes sired by cyclophosphamide-treated males. Intriguingly, posttranslational modifications important for DNA damage recognition are rapidly activated following fertilization by drug-exposed spermatozoa. Phosphorylated histone H2AX was dramatically increased in a biphasic manner in the paternal genome; Interestingly, poly(ADP-ribose) polymerase-1 was markedly elevated in both the paternal and maternal genome in zygotes fertilized by cyclophosphamide-treated males. Collectively, these studies demonstrate that male germ cell damage acquired during spermatogenesis can be transmitted to the embryo leading to aberrant epigenetic reprogramming and a dramatic induction of distinct modifications involved in DNA damage recognition in the 1-cell embryo. Importantly, we have highlighted the involvement of pronuclear cross talk as a unique phenomenon for both epigenetic reprogramming and DNA damage response in the zygote.
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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) | 0.002 | 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".