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The First 4 Days: How the Mother's Diet Rewires the Embryo with Small RNAs
Last reviewed: 18.08.2025
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The diet of the expectant mother can begin to affect the child literally in the first four days after conception - even before implantation. A study in Nature Communications showed that with a high-fat diet, the "composition" of small non-coding RNA (sncRNA) in the uterine-tubal fluid in mice changes; these molecules reach the early embryo, disrupt its metabolic programs and lead to delayed fetal growth, lower birth weight and length, and then to metabolic disorders in the offspring. Implantation does not suffer - the "tuning" of development and the placenta suffers.
Background of the study
Over the past two decades, the idea of DOHaD (Developmental Origins of Health and Disease) has shifted the focus of perinatal science: the long-term health of the offspring is programmed already in the earliest stages - from the formation of gametes to the first days of embryogenesis. The "periconceptional" window before implantation is especially vulnerable: this is when the zygote genome (ZGA) is switched on, epigenetic marks (DNA methylation, histone modifications) are actively rewritten, and the first cellular "decisions" of fate are made. Any fluctuations in the mother's environment during these days - nutrition, metabolic status, inflammation - can theoretically leave a disproportionately long trace in the growth of the fetus and the risks of adulthood.
A key but long-underestimated mediator of this connection is the mother's reproductive fluids: tubal and uterine. They are not just "transport" and nutrition for the early embryo, but an active environment for the "uterus↔embryo" dialogue, where, in addition to ions, amino acids and proteins, nucleic acids circulate that can penetrate the blastocyst and change its programs. It has been previously shown that endometrial miRNAs from the uterine fluid can stimulate blastocyst adhesion, and in paternal sperm, small RNAs (in particular, tRNA derivatives) transmit the "memory" of a high-fat diet to the offspring. However, the composition and dynamics of the small RNA pool in the mother's uterine/tubal fluid before implantation, and most importantly, its sensitivity to short-term dietary shifts, remained virtually unexplored.
The current work in Nature Communications closes this gap technologically and conceptually. Using PANDORA-seq, a method for “panoramic” sequencing of small non-coding RNAs, the authors mapped the sncRNA repertoire in the tubal and uterine fluid of mice on days 1–4 post-fertilization and found that tsRNA and rsRNA (derivatives of tRNA and rRNA) dominate, with pronounced diurnal dynamics, rather than miRNA. Critically, brief exposure to a high-fat diet on these four days alone significantly shifts the tsRNA/rsRNA balance and modifications in the uterine fluid. This creates a biologically plausible channel through which the mother’s “nutritional signal” can reach the embryo even before implantation.
The authors then test causality: it is shown that such “shifted” sncRNAs from uterine fluid (obtained against the background of HFD) are capable of disrupting the expression of blastocyst metabolic genes and, without affecting the fact of implantation itself, worsening the growth of the embryo and placenta, reducing the weight/length of newborns and increasing the risk of metabolic disorders in the offspring - an effect reproduced by direct transfection of the embryo with the corresponding sncRNAs. Against the background of many epidemiological observations on the relationship between nutrition in early pregnancy and risks in children, this work adds the missing molecular link: uterine small RNAs as “couriers” of the mother’s dietary status to the embryo in the very first days of development.
What did the scientists do?
The researchers used their proprietary “comprehensive” PANDORA-seq technology to map small RNAs in the uterine (UF) and tubal (OF) fluids of mice before implantation. They found that tsRNA and rsRNA are the big players, accounting for ~80% of the total sncRNA pool; microRNAs make up a fraction of a percent.
- Key observations in fluid biology:
- The sncRNA profile changes dynamically from day 1 to day 4: uterine fluid contains more rsRNA and less tsRNA than tubal fluid.
- Under the influence of a high-fat diet (HFD) in the mother, this balance shifts, especially sharply on the 4th day in the uterus (tsRNA falls, rsRNA rises).
- RNA modifications and sncRNA sequences themselves also change - not just their proportions.
What about the embryo and the babies?
When these “shifted” sncRNAs enter the embryo, they rewire the expression of metabolic genes in the blastocyst. As a result, implantation occurs, but by midgestation the embryo and placenta develop poorly; newborns have lower weight and length, and metabolic disorders appear later. And this is not just an association: transfection of early embryos with sncRNAs isolated from uterine fluid (obtained in the presence of HFD) mimics the effects of a living model.
- Sequence of events (simplified):
- Mom eats fat out the window before implantation →
- In the uterus/tube, the tsRNA/rsRNA pool changes →
- These sncRNAs enter the embryo →
- The blastocyst's metabolic "regulators" are disrupted →
- The growth of the embryo/placenta slows down, and the offspring experiences metabolic risks.
Why is this important?
The periconception window is short and vulnerable: it is then that the zygote's genome is switched on, epigenetic marks are rewritten, and the first "fateful" decisions of cells are made. The work adds a missing link to the concept of DOHaD (the origin of diseases in early development): uterine small RNAs act as "couriers" of the mother's metabolic status to the embryo. This explains why even very brief changes in nutrition around conception can have a long-lasting effect.
- What's new in this particular article:
- It is shown for the first time that uterine/tubal fluid is rich in tsRNA/rsRNA and that its composition is sensitive to maternal diet within days.
- Causal effect proven: injection of sncRNA from uterine fluid into the embryo “after HFD” reproduces the phenotype.
- It has been shown that the consequences are “delayed”: implantation is not impaired, but the growth and metabolism of the fetus/offspring are.
How it was done (briefly about the methods)
Mice were placed on a high-fat diet for the first 4 days of pregnancy, OF/UF was collected, sncRNA was sequenced (PANDORA-seq), and then assessed:
- Gene expression in blastocysts,
- Embryo/placental growth in mid-gestation,
- Birth weight/length and metabolic health of offspring,
- And functional tests were carried out by transfecting embryos with isolated sncRNA.
Where are the boundaries and what's next?
This is mouse work: translating the findings to humans requires caution, and the mechanisms of action of specific tsRNA/rsRNA and their “targets” in the embryo have yet to be sorted out. But the idea of a mother-to-embryo signaling pathway via sncRNA is now supported by causal data. The next step is to look for sncRNA biomarkers in human reproductive fluids and test whether the risk can be modified by gentle dietary interventions before implantation.
- What I would like to see in future research:
- Maps of specific tsRNA/rsRNA targets and their effects on blastocyst metabolism.
- Observational and interventional human studies around IVF/natural conception.
- Testing whether dietary interventions in the 'zero window' reduce the risk of growth retardation/metabolic failure.
Practical takeaway "here and now"
While clinical recommendations remain unchanged, the signal is clear: nutrition in the days around conception is no small thing. A diet with an emphasis on whole foods and moderate fats in the periconception window is not only about the “chances of pregnancy,” but also about the metabolic health of the future child. And molecular “mail” from the uterus – tsRNA and rsRNA – is probably one of the ways this connection is realized.
Source: Pan S. et al. Maternal diet-induced alterations in uterine fluid sncRNAs compromise preimplantation embryo development and offspring metabolic health. Nature Communications, published August 16, 2025. https://doi.org/10.1038/s41467-025-63054-5