Barker’s Hypothesis.

Adverse events in fetal life can have lifelong effects on health and disease
processes later in life. What happens in fetal life may determine your health and well being down the
road. By understanding fetal development, we may be able to come up with strategies to prevent or
delay adverse events later in life. Epidemiology paper 25 years ago; he looked at correlations between
adult diseases and any lifestyle factors/anything he could identify to see if anything could be associated
with type II diabetes, stroke, heart attack. Surveyed a group of seniors in 60s or 70s in the UK. Found
that in addition to lifestyle factors/economic backgrounds, also able to obtain their birth records. Knew
birth weight and placental weight. The only significant correlation between incidences of disease was
with birth weight. If someone was born with a lower birth weight, more likely to have higher blood
pressure in 60s/70s. The relationship is a continuum. Increase in birth weight, decreases blood pressure.
The relationship is not linear; if the birth weight is above 9lbs, you have increased risk of high blood
pressure as well. Within the range of 5-8lb, there is an inverse relationship between birth weight and
blood pressure. This relationship is independent of all other factors like lifestyle/socio-economic factors.

Disease predisposition is determined even before you are born. Birth weight is more significant in
comparison to all other factors collectively. If someone is born prematurely, that person is more likely to
develop adult diseases as well due to complications from premature birth. Their organs aren’t
developed properly. After this paper was published, tremendous increase in this field. Correlation
doesn’t mean a causal relationship. Now want to determine is there a causal relationship between low
birth weight and predisposition to diseases later in life? Can only use animal models. Now we know
indeed this is a causal relationship. Doesn’t matter what type of insult you introduce (ie: restrict fetal
growth restriction) will develop obesity, diabetes, heart disease.

What is the molecular link or mechanism that is responsible for programming disease and health?

Fetal Sheep

Older literature almost exclusively performed in sheep. Because the size of sheep is similar to human.
Fetal rat and mice are too small. Another major advantage is that sheep are suitable for chronic studies.
In fetal studies we want to monitor blood hormone, gas, pH levels etc. in an invasive way for a long time.
For rats and mice this is very difficult. In fetal sheep, you can put in catheters and look at their hormonal
profiles over a long time. Sheep growth and development is very similar to humans. In terms of rats and
mice, they are postnatal developers in terms of brain development. Their brains are very immature at
birth. In humans and fetal sheep, brains are relatively mature at birth.

Length of Gestation

Sheep also have a longer gestational length. One day development in rats and mice is very significant
because the length of gestation is very short. Birth weight is similar to humans; litter size is also similar.

Mice are good because you can easily manipulate their genome; knockouts available for study. Cannot
easily do genetic modifications in sheep.

Intrauterine Environment
Fetus resides in a very safe environment. Like a fish in a fishtank. Surrounded by amniotic fluid. There
are a few layers of membranes. The chorion and the amniotic sac (containing the amniotic sac).

Implantation

Fertilization  Division  Blastocyst formation  ICM and Trophoblast. Trophoblast develops into
placenta. ICM into embryo.

Definition of the Placenta

Viviparous: born alive. Oviparous: hatched from an egg.

Placenta is the lifeline for the fetus. The exchange site for the fetus and the mother.

Placental Development

One umbilical vein and two umbilical arteries. Umbilical circulation is very different from systemic
circulation. In adults, arteries carry oxygenated blood and veins carry deoxygenated blood. In umbilical
circulation, it is the opposite. The umbilical vein carries oxygenated blood and the umbilical arteries
carry deoxygenated blood.

Placenta and Fetal Membranes

The position of the placenta.

Structure of Placental Villi

Fingerlike structure. If smooth, limited exchange. Fingerlike? Surface area is greatly increased. Facilitates
exchange.

The outer layer of the villi has a brush border membrane. At a gross anatomical level, fingerlike. At a
macroscopic level, the brush border membrane also increases surface area for physiological exchange.
The brush border is in direct contact with maternal blood.

Two cell types: syncitiotrophoblast is multinuclear cells. Terminally differentiated cells (cannot undergo
proliferation; only undergo apoptosis) responsible for physiological function in terms of producing
hormones (hCG) and growth factors; the outer layer of the villi. The inner layer is composed of
cytotrophoblasts. Precursor cells for syncitiotrophoblasts. When syncitiotrophoblasts undergo renewal
processes, they rely on cytotrophoblasts as they undergo differentiation into syncitiotrophobolasts.

Placental Function

Four functions: transport of nutrients, oxygen; removes waste; barrier to protect the fetus from
potential harmful exposure to environmental factors; produces hormones growth factors and enzymes.

Placental Barrier

3-6 layers, depending on the species.

Placental Types

Humans: only 3 layers. Hemochorial placenta. Hemo ie blood. In humans, the chorion epithelium is in
direct contact with the blood. Anything that crosses human fetus, has to cross 3 layers. Chorionic
epithelium, fetal connective tissue, fetal endothelium. Chorionic epithelium in direct contact with
maternal blood.

Cats: Endotheliochorial. Extra endothelial layer.

Sheep: Epitheliochorial. Epithelial layer.

Endocrine Functions

3 major classes: steroids, peptides, prostaglandins.

Profiles

hCG, Progesterone, Total Estrogen, Placental weight, HCS.

Hormonal profile mimics placental weight (other than hCG). This implies that the production of these
hormones is proportional to placental size. In humans, animal species where you can take a blood
sample, can use the hormonal profile as an indirect indicator of fetal development and well being.
Question: can you come up with a way to determine fetal health and well being, in a relatively non-
invasive way? One example is to take a look at one of the hormones which profiles mimics placental
weight. If hormone is relatively low in relation to predicted placental weight, you know there is
something wrong with the fetus.

hCG profile is very different. Peaks early on. Detect pregnancy by detecting hCG levels in urine. Only
produced during pregnancy. Can’t use estrogen or progesterone because they are produced in non
pregnant stages. Also use hCG because it peaks early on in pregnancy. Easy to detect. Can’t use any
other hormone because they are at such low levels early on.

Abnormal placental hormonal profile is an indication of abnormal fetal development. Abnormal fetal
development can lead to a predisposition to diseases earlier in life.

hCG

2 subunits. Alpha subunit common amongst all. Beta subunit differentiates different hormones in the
family. You can apply this knowledge to a pregnancy test. You need to detect the beta subunit of hCG.
Can’t detect alpha subunit because this will give you a false positive! It is also in LH, FSH, and TSH.

Placental Lactogen (PL) or CS

PL mRNA is 25% of total mRNA in the placenta! One single hormone’s mRNA accounts for 25% of total
mRNA produced by the placenta. This protein is highly produced. Production rate is so huge, this is used
as a potential indicator of placental function and fetal well-being. Looking at other hormones is not as
good as this one. One of the best indicators of placental function.
Synthetic Pathway

During pregnancy, the placenta produces steroids. Main difference between adrenal and placental
steroid production is that adrenal glands are capable of steroidogenesis without any other organs. The
placenta lacks certain enzymes. Relies on precursors from the mother or the fetus to make steroids.
Placenta can produce progesterone from cholesterol.

Placenta cannot synthesize E2/estriol from cholesterol. Relies on precursors from the fetus or the
mother. The precursor is DHEA. DHEA comes from the fetus and mother (adrenal).

Estriol production is different. Estriol production in the placenta totally relies on precursors from the
fetal liver. Exam question!

Steroids (Regulation)

3 major regulators/3 layers of regulation. Production rate is proportional to placental size, so it is a

major determinant. Substrate availability (universal). Doesn’t matter placental/adrenal/ovarian; the
limiting factor is substrate availability. The third level of regulation is the expression of steroidogenic
enzymes. The more you express the steroidogenic enzymes, the more steroid production.

Progesterone

Myometrium quiescence until just before birth.

Fetal Membranes

Two closely applied but separate membranes lining the uterine cavity surrounding developing embryo.

Inner: aminon; outer: chorion; outside chorion is the decidua. The decidua is the endometrium. Decidua
is a specialized structure only present during pregnancy. What lies outside the decidua is the
myometrium.

From outermost layer: myometrium, decidua, chorion, then aminon.

Amnion

At full term, the cavity contains 500-1000cc of fluid. Provides many functions for the fetus. Ruptures just
before birth. When the amnion ruptures, birth process is irreversible.

Functions to protect the fetus; separate the fetus from membranes; allows freedom of movement;
facilitates somatic growth and development; protects fetus from loss of heat and maintains fetal
temperature; serves as a source of oral fluid for fetus.

Chorion

On slide.