Transgenerational impact of grand‐paternal lifetime exposures to both folic acid deficiency and supplementation on genome‐wide DNA methylation in male germ cells
Bibliographic record
Abstract
BACKGROUND: DNA methylation (DNAme) erasure and reacquisition occur during prenatal male germ cell development; some further remodeling takes place after birth during spermatogenesis. Environmental insults during germline epigenetic reprogramming may affect DNAme, presenting a potential mechanism for transmission of environmental exposures across multiple generations. OBJECTIVES: We investigated how germ cell DNAme is impacted by lifetime exposures to diets containing either low or high, clinically relevant, levels of the methyl donor folic acid and whether resulting DNAme alterations were inherited in germ cells of male offspring of subsequent generations. MATERIALS AND METHODS: Female mice were placed on a control (FCD), 7-fold folic acid deficient (7FD) or 10- to 20-fold supplemented (10FS and 20FS) diet before and during pregnancy. Resulting F1 litters were weaned on the respective diets. F2 and F3 males received control diets. Genome-wide DNAme at cytosines (within CpG sites) was assessed in F1 spermatogonia, and in F1, F2 and F3 sperm. RESULTS: In F1 germ cells, a greater number of differentially methylated cytosines (DMCs) were observed in spermatogonia as compared with F1 sperm for all folic acid diets. DMCs were lower in number in F2 versus F1 sperm, while an unexpected increase was found in F3 sperm. DMCs were predominantly hypomethylated, with genes in neurodevelopmental pathways commonly affected in F1, F2 and F3 male germ cells. While no DMCs were found to be significantly inherited inter- or transgenerationally, we observed over-representation of repetitive elements, particularly young long interspersed nuclear elements (LINEs). DISCUSSION AND CONCLUSION: These results suggest that the prenatal window is the time most susceptible to folate-induced alterations in sperm DNAme in male germ cells. Altered methylation of specific sites in F1 germ cells was not present in later generations. However, the presence of DNAme perturbations in the sperm of males of the F2 and F3 generations suggests that epigenetic inheritance mechanisms other than DNAme may have been impacted by the folate diet exposure of F1 germ cells.
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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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".