Methoxyacetic Acid-Induced Spermatocyte Death Is Associated with Histone Hyperacetylation in Rats1
Bibliographic record
Abstract
We used high-density microarrays to evaluate the possible mechanisms by which 2-methoxyacetic acid (MAA) disrupts spermatogenesis. Levels of mRNA transcripts were determined in total RNA isolated from testes of MAA-treated (650 mg/kg i.p.) or concurrent control rats killed 4, 8, 12, or 24 h postexposure (PE). Germ cell death was examined in testis sections using in situ staining for DNA fragmentation. MAA treatment caused increased death of pachytene spermatocytes starting 8 h PE and increasing dramatically at 12 and 24 h PE. Microarray results indicated that at 4 h PE the transcript levels of seven different genes were significantly overrepresented in the testes of MAA-exposed animals. One gene (histone H1 zero [H1f0]) was significantly overrepresented in MAA-treated samples at 4, 8, and 12 h PE. Because expression of this gene has been associated with increased acetylation of core histones, we examined MAA-induced changes in the acetylation of histones H4 (HISTH4) and H3 (HISTH3) in testis nuclear protein. Western blots of acid-extracted testis nuclei indicated that the levels of tetraacetyl histone H4 (4acHIST1H4) and of diacetyl histone H3 (2acHIST1H3) were elevated by MAA treatment at 4, 8, and 12 h PE. Using the same antibodies, 4acHIST1H4 and 2acHIST1H3 were localized primarily to elongating spermatids in testis sections from control animals. At 4 h PE, staining for either histone modification was dramatically increased in spermatogonia and all primary spermatocyte populations except for dividing spermatocytes. MAA treatment of testis nuclear protein extracts from unexposed animals caused both a significant increase in histone acetyltransferase activity and a significant inhibition of histone deacetylase activity, suggesting that increased core histone acetylation results from a combination of these complementary modes of action. Our results indicate that exposure to MAA causes increased acetylation of core histones in several testis germ cell populations, including those in prophase of meiosis, a large proportion of which die rapidly following this treatment.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| 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) | 0.000 | 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 teacher head, 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".