Aging Causes Alterations in the Base Excision Repair Pathway in Pachytene Spermatocytes in the Brown Norway Rat.
Bibliographic record
Abstract
With a current trend of increasing paternal age, there is a concern about a higher risk for the development of complex multi-gene diseases in newborns. Recent studies have established increased incidences of autism and schizophrenia with advancing paternal age. There is a strong correlation between the age of the male partner and decreased sperm quality and structural aberrations of chromatin and DNA in spermatozoa. It is known that the production of reactive oxygen species (ROS) increases with age in the testis. The Base Excision Repair (BER) pathway is the main operator in the removal of oxidative DNA damage and removes aberrant bases in DNA induced by hydrolysis, ROS or other metabolites. We hypothesize that with age the ability to repair oxidative stress-induced DNA damage is impaired in male germ cells. To test this, pachytene spermatocytes and round spermatids were isolated from Brown Norway rats at 4 months of age (young) and 18 months (aged) using the STA-PUT velocity sedimentation technique, achieving >80% purity. RNA was extracted from these two cell populations and gene expression was assessed using Affymetrix rat 230 2.0 whole rat genome microarrays. Raw data were analysed using Genespring v10 (Agilent Technologies) and Pathway Studio. Of the probe sets with significantly altered expression there appeared to be changes in the oxidative stress response and DNA repair in the pachytene spermatocytes but not in the round spermatids. Further analysis in the pachytene spermatocytes emphasized that genes involved in the BER pathway were specifically altered. We found that Ogg1 was overexpressed and Ape1, Fen1 and Xrcc1 were down regulated. Quantitative RT-PCR analysis showed at least a 1.5 fold change in these genes in the old in comparison to the young. We also identified Ogg1 protein in the early spermatocytes, elongating spermatids and the peritubular myoid cells using immunohistochemistry. The Ogg1 protein appeared to be more highly expressed in those testes from the aged rats. In the BER pathway Ogg1 encodes the enzyme responsible for the initiation of the inscision of 8-oxoguanine, a mutagenic base byproduct resulting from exposure to ROS. In conclusion, aging causes altered expression of genes involved the BER pathway. The fact that Ogg1 is upregulated and the others downregulated suggests that the initiation of the pathway is enhanced but that the subsequent repair of the damaged site is impaired. This work was supported by a grant from CIHR. (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 | 0.001 | 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".