Folate Deficiency Alters the Sperm Epigenome and Reproductive Outcomes.
Bibliographic record
Abstract
Data from epidemiological and animal studies suggests that the paternal epigenetic contribution in sperm may serve as a route to altered offspring phenotypes. However to date there is little to no evidence of direct effects of diets on the sperm epigenome or consequences for the offspring. Epigenetics refers to heritable changes in gene expression that are regulated by DNA methylation and the covalent modification of histones. Given that dietary folate can alter the supply of methyl donors, we hypothesized that male germ cells may be sensitive to dietary folate and that this may manifest as altered epigenetic programming and have downstream consequences for spermatogenesis and reproductive outcomes. The objective of this study was to determine the impact of exposure to a low folate diet, beginning during embryonic development through to adulthood on spermatogenesis, the sperm epigenome, fertility, and offspring. Inbred C57/BL6 mice were fed either a folate-sufficient (FS, 2 mg of folate/kg of diet), or a folate-deficient diet (FD, 0.3 mg of folate/kg of diet). Adult FS (n=54) and FD (n=49) males remained on the diets for either 2 or 4-4.5 months and were assessed for fertility parameters and overall health. In adults, spermatogenesis and sperm counts were not altered by diet nor were body, testis and epididymis weights. Epigenetic programming was disturbed in the sperm of folate depleted mice. Histone H3 methylation was significantly reduced in sperm from FD versus FS mice. Notably histone H3 methylation has been shown to mark genes for embryonic development. Genome wide DNA methylation (MeDIP-chip) analysis revealed alterations at more than 50 gene promoter regions. Bisulfite sequencing confirmed that 6 of these regions including genes implicated in developmental processes had significant decreases in DNA methylation at specific CpG locations in the sperm of FD males (n=5 for both groups). FD (n=29) and FS (n=27) males were then mated to females on control diets and pregnancy outcomes at embryonic day 18.5 were analyzed. Embryonic loss was 2 fold greater in the litters sired by FD vs FS mice and developmental abnormalities were observed in 27% of the litters sired by FD mice vs 3% for those sired by FS mice. This is the first study to show that diet can alter the sperm epigenome and suggests that an altered sperm epigenome leads to negative pregnancy outcomes. This research was supported by NSERC, and the Réseau Québécois en Reproduction (RQR-FQRNT).
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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 | 0.001 | 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".