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Teratogen

external, environmental agent that can cause birth defects to an embryo after maternal exposure

4 properties of teratogens

1. external, environmental agents
2. can cross placenta
3. disrupt embryonic development
4. cause non-inheritable defects that are present at birth

What percentage of birth defects are caused by teratogens?

7%

What are the 2 main periods of gestation and what are their time frames?

1. Embryogenesis (0-8 weeks)
2. Fetogenesis (9-40 weeks)

During which period of gestation are embryos most vulnerable to teratogens?

3-8 weeks (embryogenesis stage) - organogenesis in particular is occurring at this time

What is the total duration of the gestation period?

38 weeks

Why are embryos less susceptible to teratogens in the first 2 weeks of embryogenesis?

Up until the 8 cell stage, if a blastomere is damaged or removed from the embryo it will still be viable. This is because the blastomeres at this stage are totipotent so they can compensate for the missing blastomeres

Define fetogenesis

Period of growth and remodeling of fetus. Occurs from 9 weeks until birth. Embryo is less susceptible to teratogens at this time

How does Preimplantation Genetic Diagnosis (PGD) work? What does it prove?

PGD is a screening procedure where we remove 1 or 2 blastomeres from an 8 cell embryo (blastocyst) in order to perform genetic testing. If we then transfer this embryo to the mother for gestation, the embryo goes on to make a normal infant
This shows us that up until this stage the blastocyst retains powerful regulatory ability and can recover from the loss of blastomeres b/c all remaining blastomeres are totipotent.

If a teratogen affects the embryo at the 2 cell stage, what are the 2 responses possible?

1. Entire embryo is killed off (b/c not much there) - call cannot recover
2. A few blastomeres are killed - cell can recover due to totipotency of remaining blastomeres

When does organogenesis occur?

3-8 weeks of gestation

What are some of the major organs that form during 3-8 weeks of gestation

CNS, Heart, Eyes, Ears, Facial primordia, Upper and Lower Limbs & External Genitalia

When does internal genitalia form? When does external genitalia form?

Internal = 12 weeks
External - 3-8 weeks

During 3-8 weeks of the embryonic period, what 3 processes are at their peak?

1. Cell Division
2. Cell Differentiation
3. Morphogenesis

What does the type of abnormality depend on?

Which organs are most susceptible at that time - each organ has a critical period when development can be disrupted

Can a teratogen affect different organ systems?

Yes - if they are developing at the same time then both are vulnerable to the presence of the teratogen

Until what point are cleavage cells considered totipotent?

Blastocyst stage (8 cells)

What occurs at the blastocyst stage?

The first differentiation of the embryo into 2 tissues:
1. Inner cell mass --> makes embryo proper
2. trophoblast --> makes placenta
These cells are no longer considered totipotent

What are inner mass cells able to do? What are they not able to do?

Considered pluripotent b/c they are able to form all cells in the body but they CANNOT form trophoblast cells.

Which of the 2 cell groups that characterize the blastocyst are used to make embryonic stem cells? Why?

Inner mass cells - b/c they are pluripotent and retain the ability to make all the cells in the body

Define neuralation

Formation of the nervous system
Embryo forms the neural tube which will eventually become the brain and spinal cord

What is the critical period of the brain?

3-16 weeks

Which organ system shows the longest period of sensitivity to disruption?

CNS - constantly forming and remains susceptible throughout development and for about 1-2 years after birth

What does the anterior end of the neural tube go on to form?

Brain

What does the posterior end of the neural tube go on to form?

Spinal cord

Which end of the neural tube fuses first?

Anterior --> posterior

At what point in gestation does neuralation begin?

3 weeks

What are somites? What do they go on to form?

Block of mesoderm which go on to form:
1. Dermis
2. Skeletal muscle
3. Vertebrae

What does the neural tube form from?

Area on the surface of the ectoderm.

Describe the 3 steps of neuralation

1. Formation of the neural plate
2. Neural plate invaginates (folds inward) to form a longitudinal groove, forming 2 neural folds
3. The 2 neural folds meet in the center and fuse to form a tube that separates from the overlying layer of the ectoderm

How is the ectoderm formed?

Gastrulation
Epiblast had migration & invagination of 2 cells to the surface, first forming the endoderm and mesoderm. Remaining cells on the side = ectoderm

What condition occurs if the posterior end of the nerual tube fails to fuse? What are the symptoms of this condition?

Spina bifida - infant is born with an open neural tube
Abnormalities depend on how much is left open
Basic symptoms: impairment of legs, loss of bowel control, bladder problems

What condition occurs if the anterior end of the neural tube fails to fuse? What are the symptoms of this condition?

Anencephaly
Infant will have no brain - this is lethal

What are some of the prominent features of the embryo at the end of organogenesis? (There are 7 in total)

1. Eyes with defined eyelids
2. External ears
3. Broad and flat nose
4. Neck
5. Large, rounded head - almost half the size of the body
6. Limbs are longer and have joints
7. Toes of each side touch - "praying feet"

At the end of organogenesis, what 2 things are present in the fetus?

1. Formed all major organs
2. Shows typically human features - especially in face

Does the embryo ever become separated from the placenta during development?

No - separation from the placenta results in death of embryo

What form the largest group of teratogens?

Drugs & environmental chemicals

What was the drug Thalidomide used for? What were its results?

Thalidomide was a mild sedative prescribed for pregnant women to combat morning system
Resulted in birth defects of limbs and ears

When is the embryo most susceptible to dangerous effects of Thalidomide?

3-5 weeks

What are the 5 birth defects that Thalidomide caused?

1. Limb abnormalities
2. Ear abnormalities
3. Heart defects
4. Malformed intestines
5. Malformed Kidneys

Where was Thalidomide first used? Was it ever used in the U.S?

Germany
No- applied for license but it was refused

Why did Dr. Kelsey refuse to clear the drug? What did

Inadequate testing b/c:
1. Lacked details of clinical and animal studies
2. Lacked testing with pregnant animals

What is the landmark malformation of Thalidomide?

Phocomelia

Define phocomelia and its morphological characteristics

Defect where the upper portion of the limb (s) are poorly developed or absent
Results in seal-like flipper appearance of the limb b/c the hand or foot attaches to the shoulder or hip by a short, flipper-like stump

Amelia

absence of 1 or more limbs

What are the 5 factors that affect the susceptibility of an embryo to a teratogen?

1. Dose
2. Duration of exposure
3. Stage of embryonic development
4. Mother's genotype
5. Embryo's genotype

Are all species sensitive to Thalidomide?

No - mice and rats were not sensitive at all
Problem b/c they are a major animal model used in testing of new drugs

Is Thalidomide always teratogenic?

No - only from 3-5 weeks of gestation
At this point even very small amounts are teratogenic

Why does Thalidomide prevent the proper formation of limbs?

B/c it is teratogenic at 3-5 weeks of gestation which is the very beginning of limb bud formation
Thalidomide blocks blood vessels

Is Thalidomide still used today?

Yes - Used to treat:
1. Side-effect of leprosy
2. type of cancer (multiple myeloma)

What has been done to prevent fetal exposure to Thalidomide due to its new therapeutic uses?

S.T.E.P.S = System for Thalidomide Education and Prescribing Safety
All doctors, pharmacists, and patients who use drug must enroll
Women must use 2 types of contraception when using Thalidomide and take regular pregnancy tests

What are the 3 defects caused by women exposed in utero to Diethylstilbestrol?

1. Abnormal development of the female reproductive tract (i.e. abnormal vagina, uterus and fallopian tubes)
2. Slight increase in rare vaginal cancer
3. Slight increase in breast cancer

Why is DES a teratogen? When does it have teratogenic effects?

DES is a chemical that disrupts development by interfering with the normal function of estrogen in the body
It acts during first 12 weeks of gestation when the Mullerian ducts are being formed

What are the 5 results of Fetal Alcohol Syndrome (FAS)?

1. Pre and postnatal growth deficiencies
2. CNS abnormalities
3. Mental retardation
4. smaller head and brain size
5. characteristic facial features

When is the embryo sensitive to alcohol?

First month of pregnancy

What causes FAS?

Chronic use of alcohol during the first month of pregnancy

What is key in diagnosing FAS?

characteristic facial features

What are the 5 characteristic facial features of an infant with FAS?

1. Indistinct philtrum
2. thin upper lip
3. flat nose
4. reduced midface region
5. short eye slits

What is Fetal Alcohol Effects (FAE)?

Children have some of the neurological impairments from alcohol exposure but do not show FAS facial features

What area of the brain is affected by maternal alcohol exposure?

Presumptive forebrain - excessive cell death
Result in lack of this tissue later

Cranial-facial model

A mouse model developed to understand the effects of alcohol on the face and nervous system

What happens to mice who are exposed to alcohol in utero?

Results in similar defects as humans in their:
1. facial features
2. early brain formation - excessive cell death in presumptive forebrain

What is FASD?

Fetal Alcohol Spectrum Disorder - includes FAS & FAE

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