Selective Induction of Glutathione S-transferases in Round Spematids by the Chemotherapeutic Regimen for Testicular Cancer in the Brown-Norway Rat.
Bibliographic record
Abstract
Advances in treatment for testicular cancer, including the co-administration of bleomycin, etoposide, and cis-platinum (BEP), have brought the cure rate to over 90% but lead to transient or permanent loss of fertility. We showed recently that the administration of BEP to male rats affects sperm chromatin integrity. Using this model, we analyzed the gene expression profile in round spermatids after treatment. Brown-Norway rats were treated for 9 weeks with vehicle (0X) or BEP at a dose equivalent to 0.3X or 0.6X of the human dose; for the 0.6X dose, BEP-treated rats were gavaged each week on days 1-5 with 1.8 mg/kg cis-platinum and 9 mg/kg etoposide and injected ip with bleomycin (0.9 mg/kg) on day 2; half of these doses were used for the 0.3X dose. At the end of the treatment, round spermatids were isolated on a BSA gradient. RNA was extracted and probed on Rat230-2.0 Affymetrix arrays. Gene expression in control and BEP-treated spermatids was compared using Genespring 7.2 by ANOVA (p<0.05) followed by multi comparison Newman-Keuls tests (p<0.05); changes were considered significant when the difference in expression level was ≥ 1.5 fold. Using the NETAFFX analysis center, we analyzed the expression of phase I and phase II drug metabolising enzymes. Many of these enzymes were expressed in round spermatids; this includes 9 of the 23 NADPH-cytochrome P450s (CYP), 4 of 6 N-acetyltransferases (NAT), 3 of 11 sulfotransferases (SULT), 9 of the 12 aldehyde dehydrogenases (ALDH) and all 16 of the glutathione S-transferases (GST) present on the array. Interestingly, the number of isozymes expressed and the overall relative expression values were higher for GSTs than any other enzyme family studied. Although no effect was found after the 0.3X treatment, significant increases were observed after the 0,6X treatment in 8 GSTs (GSTα2, α4, μ1, μ2, μ3, π1, π2 and microsomal GST1) and 2 ALDHs (Aldh1a1 and Aldh2). Thus, the expression of 50% of the GST family members present on the arrays was increased after treatment. The increased expression of GSTμ and GSTπ was further confirmed by RT-PCR (n=6) and Western blot (n=4). Together, these results suggest that GSTs play a prominent role among male germ cell drug metabolism enzymes and that their expression is selectively induced by BEP treatment. GSTμ and GSTπ are involved in drug resistance mechanisms. We hypothesize that BEP induction of GST expression may lead to the survival of damaged cells and production of abnormal sperm. Supported by CIHR, FRSQ and The Cole Foundation.
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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 | 0.000 |
| 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) | 0.000 | 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".