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Pregnancy Timeline by SemestersDevelopmental TimelineFertilizationFirst TrimesterSecond TrimesterThird TrimesterFirst Thin Layer of Skin AppearsEnd of Embryonic PeriodEnd of Embryonic PeriodFemale Reproductive SystemBeginning Cerebral HemispheresA Four Chambered HeartFirst Detectable Brain WavesThe Appearance of SomitesBasic Brain Structure in PlaceHeartbeat can be detectedHeartbeat can be detectedFinger and toe prints appearFinger and toe prints appearFetal sexual organs visibleBrown fat surrounds lymphatic systemBone marrow starts making blood cellsBone marrow starts making blood cellsInner Ear Bones HardenSensory brain waves begin to activateSensory brain waves begin to activateFetal liver is producing blood cellsBrain convolutions beginBrain convolutions beginImmune system beginningWhite fat begins to be madeHead may position into pelvisWhite fat begins to be madePeriod of rapid brain growthFull TermHead may position into pelvisImmune system beginningLungs begin to produce surfactant
CLICK ON weeks 0 - 40 and follow along every 2 weeks of fetal development


Breast milk develops baby's social brain

Oxytocin promotes social brain development...

Oxytocin is an important peptide hormone crucial to interpreting and reading another person's feelings, and establishing good communication skills. It is therefore considered indispensable to the development of the social brain. It is synthesized in the brain and secreted into our blood.

Mother's milk contains various nutrients which also includes oxytocin. Soon after birth however, a baby's digestive tract forms a barrier to avoid uptake of undesirable macromolecules, in a process called "gut closure." So it was thought that oxytocin could not freely permeate from baby's digestion into a baby's body with the restriction of gut permeability. Yet, oxytocin levels in babys blood after drinking mother's milk is elevated, suggesting somehow oxytocin can be transported across the gut barrer.

Breast feeding has been recommended by the World Health Organization (WHO) since 2007 because of its positive effects on babies' short-term and long term health,. However, breast-feeding for 12 months has been decreasing — while production of powdered milk has increased year after yearinto a 7 trillion dollar market worldwide.
In the United States, 13% of babies are born prematurely. The number of babies around the globe who are born prematurely or with a very low body weight is approximately 15 million annually. The importance is now recognized of giving those babies colostrum and raising them with mother's milk.

The importance of breast feeding is now well recognized. However, information about oxytocin, which is necessary for development of the social brain for communication with others, has been fragmentary. Oxytocin in the mother's blood is transferred to the milk. It was thought that the uptake of oxytocin from mother's milk through the digestive tract should take place although the underlying mechanisms remained unknown.

An international research team led by researchers of Kanazawa University, Japan, together with researchers from Hokkaido University, Japan, Krasnoyarusk State Medical University, Russia, and the University of California San Francisco, USA, investigated oxytocin uptake from the gut of neonatal mice and obtained the following results.

1. Postnatal day 1: mice that stayed with their mother for 20 min were found to have oxytocin concentrations in the blood higher than those pups that were fasted.

2. Postnatal day 1-5: mice orally fed with oxytocin showed an increase of oxytocin concentration in the blood up to the fifth day after birth, decreasing thereafter.

3. Mice administered oxytocin directly into their digestive tract also showed an increase of oxytocin concentration in the blood. Taking into account the increase in quantity of blood associated with increase in body weight, oxytocin in blood is considered reduced from postnatal days 5-7.

4. Oral administration of oxytocin solution to mice whose Receptors for Advanced Glycation End-Products (RAGE*) gene (Ager) was knocked out brought generated oxytocin concentration increase in the blood on postnatal days 1-3. However, sharply decreasing on postnatal day 4.

5. A clear difference between wild type mice and RAGE knockout mice was observed on postnatal days 4-6. This suggests that on postnatal days 1-3, gut closure is not completed and that oxytocin should be freely permeable from the gut in both the wild type and RAGE knockout mice. After complete gut closure, wild type mice expressing RAGE could ingest oxytocin. It was interpreted that on postnatal days 7-8 and thereafter, oxytocin was enzymatically cleaved but could not be absorbed in its intact form.

6. In addition, adult mice administered a 10-fold quantity of oxytocin orally or directly into their digestive tract, exhibited a significantly increased blood oxytocin level in wild type mice in a RAGE-dependent manner.

7. Mass spectrometry analysis confirmed that oxytocin was transported into the blood in its intact form.

8. Expression of RAGE molecules on the surface of intestinal epithelial cells was confirmed by an immunohistochemical study.

The work is published in the journal Nature. The oxytocin uptake pathway — from the gut into the blood after completion of gut closure — is still not known. However, the present study found, for the first time, that intestinal villiated epithelial cells express RAGE, which is responsible for absorption of oxytocin from the gut into the blood.
These findings indicate oxytocin can be orally administered as a medication and/or nutrient (supplement in milk).

Acronym of Receptors for Advanced Glycation End-Products. RAGE is a 55 kilodalton transmembrane receptor of the immunoglobulin superfamily. It is first discovered as a receptor for advanced glycation end-products (AGE), closely associated with senescence. RAGE is now recognized as a multi-ligand receptor and a member of pattern-recongition receptors. AGE-RAGE binding can induce oxidative stress and inflammation, which in turn causes tissue damages.
Plasma oxytocin (OT) originates from secretion from the pituitary gland into the circulation and from absorption of OT in mother’s milk into the blood via intestinal permeability. However, the molecular mechanism underlying the absorption of OT remains unclear. Here, we report that plasma OT concentrations increased within 10 min after oral delivery in postnatal day 1–7 mice. However, in Receptors for Advanced Glycation End Products (RAGE) knockout mice after postnatal day 3, an identical OT increase was not observed. In adult mice, plasma OT was also increased in a RAGE-dependent manner after oral delivery or direct administration into the intestinal tract. Mass spectrometry evaluated that OT was absorbed intact. RAGE was abundant in the intestinal epithelial cells in both suckling pups and adults. These data highlight that OT is transmitted via a receptor-mediated process with RAGE and suggest that oral OT supplementation may be advantageous in OT drug development.

Authors: Haruhiro Higashida, Kazumi Furuhara, Agnes-Mikiko Yamauchi, Kisaburo Deguchi, Ai Harashima, Seiichi Munesue, Olga Lopatina, Maria Gerasimenko, Alla B. Salmina, Jia-Sheng Zhang, Hikari Kodama, Hironori Kuroda, Chiharu Tsuji, Satoshi Suto, Hiroshi Yamamoto & Yasuhiko Yamamoto

Funding from Strategic Research Program for Brain Sciences by MEXT, Agency for Medical Research and Development (AMED), Industry-Academia Collaborative R&D Programs (COI) from MEXT.

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Nov 8, 2017   Fetal Timeline   Maternal Timeline   News   News Archive

Image of mouse intestinal villiated epithelial cells (nuclei, blue) and RAGE (green).
Image credit: Kanazawa University.

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