Adverse effects of paternal chemotherapy exposure on the progeny brain: intergenerational chemobrain
Bibliographic record
Abstract
// Anna Kovalchuk 1, 2 , Yaroslav Ilnytskyy 2 , Rafal Woycicki 2 , Rocio Rodriguez-Juarez 2 , Gerlinde A.S. Metz 1, 3 and Olga Kovalchuk 2, 3 1 Canadian Center for Behavioural Neuroscience, Department of Neuroscience, University of Lethbridge, Lethbridge, AB, T1K3M4, Canada 2 Department of Biology, University of Lethbridge, Lethbridge, AB, T1K 3M4, Canada 3 Alberta Epigenetics Network, Calgary, AB, T2L 2A6, Canada Correspondence to: Gerlinde A.S. Metz, email: gerlinde.metz@uleth.ca Olga Kovalchuk, email: olga.kovalchuk@uleth.ca Keywords: chemotherapy, brain, transcriptome, epigenetics, transgeneration effects Received: January 18, 2016 Accepted: April 27, 2017 Published: January 23, 2018 ABSTRACT Recent advances in cancer treatments have led to significant increases in cure rates. Most cancer patients are treated with various cytotoxic chemotherapy regimens. These treatment modalities are mutagenic and genotoxic and cause a wide array of late-occurring health problems, and even exert a deleterious influence on future offspring. The adverse effects from exposed parents on offspring are referred to as transgenerational effects, and currently little is known about chemotherapy-induced transgenerational effects. Furthermore, transgenerational effects have not been studied in the brains of progeny of exposed parents. In this study, we analyzed the existence and molecular nature of transgenerational effects in the brains of progeny of animals exposed to three common chemotherapy agents: cyclophosphamide (CPP), procarbazine (PCB) and mitomycin C (MMC). For the first time, our results show that paternal exposure to chemotherapy drugs causes transgenerational changes in the brain of unexposed progeny. Although no DNA damage was observed in terms of γH2AX levels, some alterations were found in levels of PCNA, protein involved in DNA repair, replication and profileration. Furthermore, there were changes in proliferation and apoptosis proteins BCL2 and AKT1, the proteins associated with DNA methylation, DNMT1 and MeCP2. Some altered expression trends were noted in proteins involved in myelin biogenesis, MBP and MYT1L. Moreover, global transcriptome profiling revealed changes in over 200 genes in the whole brains of progeny of animals exposed to CPP, and the changes in the levels of FOXP2 and ELK1proteins were confirmed by western blot analysis. These findings suggest that paternal chemotherapy significantly affects offspring brain development and may affect brain functioning. This research provides a key roadmap for future investigations of the novel phenomenon of transgenerational effects of chemotherapy in the brain of progeny of exposed parents.
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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) | 0.001 | 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".