Identifying the Safe and Adequate Folic Acid Intake Range Using Biomarkers in 2 Mouse Models
Bibliographic record
Abstract
BACKGROUND: High intakes of folic acid (FA), the synthetic form of folate added to fortified foods and supplements, have been associated with adverse effects in studies in animals and humans, albeit inconsistently. Animal models are integral to investigating these relationships; however, it is unclear how commonly used FA doses in animal feeding studies relate to intakes in humans. OBJECTIVE: To identify adequate and excess FA intakes in mice based on biomarkers of inadequate [plasma homocysteine (Hcy)] and excessive [plasma unmetabolized FA (UMFA)] FA intakes. METHODS: Four-week-old male and female BALB/c and C57BL/6 mice were fed diets containing 0, 0.2, 0.5, 1, 2, 5, 20, or 40 mg/kg FA for 12 wk. Total folate in red blood cells (RBC) and plasma was measured biweekly. Plasma Hcy, plasma and liver folate vitamers including UMFA, total blood counts, and kidney pathology were assessed at necropsy. RESULTS: Sex and strain effects were evident for nearly all endpoints. Plasma Hcy reached baseline in mice fed FA as low as 0.2 mg/kg. Plasma and RBC total folate were dose responsive and took 2-4 and 10+ wk to reach homeostasis in plasma and RBC, respectively. Plasma UMFA was only higher in mice fed the 20 and 40 mg/kg FA; UMFA represented ∼50% of total folate in these mice. UMFA did not accumulate in liver in any mice. Other endpoints were not FA dependent. CONCLUSIONS: The AIN-93 diet, the most commonly used control diet, contains 2 mg FA/kg diet, which is higher than adequate. On the basis of increased UMFA, commonly used supplemental FA doses associated with adverse effects in mice are supraphysiological and likely do not reflect human exposures. Our findings suggest caution is warranted when interpreting findings in mice fed these very high FA doses.
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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 | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.003 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.002 |
| Bibliometrics | 0.005 | 0.001 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.003 | 0.003 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".