Unit 5: Implications of Developmental Biology

Lecture 1
Teratogenesis: Types and Teratogenic agents

Teratogenesis; Definition
Teratology is the study of abnormal development in embryos and the causes of congenital malformations
or birth defects. Such defects arise during embryonic development. It results due to interference in
embryonic processes which leads to chaotic development, thus forming an abnormal embryo called a
‘terata’ or ‘monster’, meaning malformed infants.
The formation of ‘terata’ is called tratogenesis.
These anatomical or structural abnormalities are present at birth although they may not be diagnosed until
later in life. They may be visible on the surface of the body or internal to the viscera.
Congenital malformations account for approximately 20% of deaths in the perinatal period.
Approximately 3% of newborn infants have major malformations and another 3% have malformations
detected later in life. The congenital malformations constitute the fifth biggest cause of perinatal
mortality in India.

Fig: Examples of some birth defects

Causes of Teratogenesis
Factors causing birth defects are called teratogens or teratogenic agents
Abnormal development may be caused by certain genetic errors, from environmental errors or some
unknown factors which affect the developmental process.
There are a variety of causes of congenital malformations including:
1) Genetic factors (chromosomal abnormalities as well as single gene defects)- Genetic mutations,
chromosomal defects and aneuploidy etc. are called malformation.
2) Environmental factors (drugs, toxins, infectious etiologies, mechanical forces) - Many birth defects
reported are due to prenatal exposure to radiation, environmental factors, drugs and chemicals etc. and
are called disruptions.
3) Multifactorial etiologies including a combination of environmental and genetic factors. The graph
below) divides these etiologies by percentages.

Types of Teratogenesis
.The teratogenesis, on the basis of their origin can be classified as:

• Genetic teratogenesis (Malformations)

• Environmental teratogenesis (Disruptions)
• Multifactorial teratogenesis
Genetic teratogenesis:
Such defects are caused by change in the genetic make-up, ie., genetic mutations, chromosomal defects,
aneuploidy, etc.
Examples:

• Downs syndrome – Caused by chromosome 21 trisomy

 • Anencephaly (absence of forbrain)
• Hydrocephaly (enlarged head)
• Aniridia (absence of iris) – Caused due to mutation of the PAX 6 gene
• Piebaldism (unpigmented or white patch of skin or hair) – Caused due to a dominant mutation in
a KIT gene located in the long arm of chromosome 4. The KIT gene encodes a protein that is
expressed in the neural crest cells, precursors of the blood cells and germ cells. It enables cell’s
proliferation in the haematopoiesis, spermatogenesis, angiogenesis and melanogenesis etc.
• Cleft lip and cleft palate (opening or splits in the roof of the mouth and lip)
• Cardiac abnormalities, etc.
Death of the early embryo is common due to chromosomal abnormalities as they interfere with normal
development.
Environmental teratogenesis:
Almost any environmental factor can be teratogenic. The factor may be biological or non-biological.
Based on their nature, the factors (teratogens) can classified as:
a) Biological (Bacteria, virus, protozoa, and other parasites)
b) Non-Biological (temperature and radiation)
c) Chemical (drugs, pesticides and nutritional imbalance)
The agents for the disruptions are called teratogens.
Table: List of Teratogenic agents
List of Teratogenic agents as per FDA
Teratogens
The effects of teratogens on the embryo depends on:
1. Dose of teratogen: Teratogens affect the embryo at dose levels. At a very low dose it may be
ineffective whereas a high dose may have a lethal effect.
2. Period of embryonic development: Most teratogen produce their effects only during certain
critical period of development especially during organogenesis.

In human development, the sensitive period lies between weeks 3 and 8.

The critical period varies in different organs.
Example:
Heart – during 3rd and 4th week
External genetilia – between 8th and 9th week
Brain and skeleton – they are sensitive from 3rd week to end of pregnancy

Fig. Sensitivity to Teratogen during pregnancy

Classification of Teratogens
The teratogens are classified as:
1. Natural teratogens
2. Pharmaceutical teratogens
3. Endocrine disruptors
4. Industrial teratogens/heavy metals
5. Microbial teratogens
 6. Recreational teratogens
7. Metabolic conditions
Natural Teratogens:
They are further classified as
a. Chemical teratogens
b. Ionizing radiations
a. Chemical teratogens:
Some plant chemicals can be highly teratogenic. Few examples are:

• Skunk cabbage (Veratrum calcifornicum) or wild corn produce alkaloids jervine and cyclopamine
which can cause severe abnormalities like neurological damage and cyclopia (fusion of two eyes)
in the fetus of the cattle and sheep which feeds on it. The alkaloids inhibit cholesterol synthesis in
the developing fetus by inhibit SHH genes which play important role in cell growth, cell
differentiation, pattern formation of the body and development of brain, spinal cord,eyes, limbs
and other parts of the body.
• Plant product Quinine from quinona plant, also causes congenital malformations in embryo such
as deafness
b. Ionizing teratogens:
Exposure to radiation cause chromosomal breakage and alter the structure of DNA leading to mutations.
Radiation on fetus affects cell division, causing malignancy and cell death.
- A small dose of 10 rads may inhibit implantation causing abortion.
- A single dose of 360 rads of X rays can kill a fetus by 14th week of gestation.
Some other teratogenic effects of radiations are:
- Microcephaly
- Hydrocephaly
- Microphthalmia
- Optic atrophy
- Germ cell mutation
- Cataract, etc.
2. Pharmaceutical teratogens:
Many drugs that are used to control diseases in adults may have deleterious effects on fetus. Few
examples are:
a. Thalidomide
b. Ratinoic acid
c. Valporic acid
d. Warfarin

a. Thalidomide:
Brand name- Immunoprin
Used as – Anticonvulsive drug to control anxiety and insomnia.
- Given as mild sedative
- Was also given to control morning sickness during late 1950s, resulting in malformed
infants
Effects – It affects different structures at different time of development
- Phocomelia (long bones of the limbs are reduced in length or are absent.
- Malformed intestine
- Hearing defects
- Renal abnormalities
Critical period – Drug is teratogenic if given during20-36 days after conception
Mechanism – Different theories are proposed by different workers.
- Most common theory suggests that the neural crest cell migration is affected.
- Another theory indicates reduction in the size of the ganglia and their neurons or inhibition of
cell-cell interaction and lower number of cell adhesion molecules.
b. Retinoic acid
Low level of retinoic acid is secreted by certain cells and is essential for anterio-posterior axis
formation and limb development. It acts as a teratogen at very high concentration
Used as - It is a component of drug Accutane (13 cis- retinoic acid)
Effects – Exposure during pregnancy to retinoic acid in higher contentration causes multiple defects
in the infants. Some of them are:
- Craniofacial changes such as small jaws,
- Cleft palate
- Neural tube defect
- Cardiovascular malformations
- Absence or malformation of ears
- Thymic deficiency
- Kidney alterations
- Low IQ

Critical period – between 3-5 weeks of pregnancy. The critical exposure time for humans are
restricted from 20- 35 days.

Mechanism - Biologically active retinoic acid binds with its receptor which attaches to the DNA
enhancers like retinoic acid response elements which are present in some Hox genes. It inhibits the
migration nd proliferation of the neural crest cells.

c. Valproic acid:
Used as – anticonvulsant drug to control epilepsy
Effects – High dose of the drug during pregnancy causes bone defects. The affected children are born
with
- Lumbosacral spina bifida
- Midfacial hypoplasia
 - Deficient orbital ridge
- Prominent forehead and
- Decreased postnatal growth
- It also affects fetal metabolism required for neural tube formation
Mechanism: It is shown to decrease the level pf paired box (Pax1) transcription in chick somites causing
malformation of vertebrae and ribs. Pax gene codes for tissue specific transcription factors.
d. Warfarin:
Brand Name – Coumadin
Used as – anticoagulant by patients to treat thrombosis, pulmonary embolism, atrial fibrillation and
valvular heart disease
Effects – If administered during pregnancy it results in malformed infants showing following
abnormalities:
- Hypoplastic nose
- Eyes abnormalities
- Mental retardation
- Brachydactyly
- Central nervous disorders if taken at the later stages of pregnancy
Mechanism: Causes alteration in the post translational carboxylation of protiens which may result in
defects of skeletal system
3. Endocrine disruptors
These chemicals affect the functioning of the hormones of the body and results in the defects in fetus.
The encocrine function is disrupted in various ways:
a. By binding to hormone receptors:
Example- Diethylstilbestrol (DES)- It is non-steroidal synthetic estrogen (analogue of estradiol)
It was used to prevent miscarriage and premature labor during 1940-1978.
Effects: It resulted in cervical cancer of rare type in female fetus. It also caused mullerian
duct abnormalities leading to defective reproductive tract. DES also affects the male
genitalia and cause cryptorchidism.
Mechanism: DES binds to estrogen receptors and alters expression of Hoxa-10 gene in the
differentiation of the mullerian duct. Hoxa-9, 10, 11 and 13 are regulated by estrogen and
progesterone.

b. By blocking hormone receptor:

Example: Finasteride
Drug used to prevent baldness and enlargement of prostate gland (benign prostrate
hyperplasia)
Mechanism: The drug blocks the conversion of testosterone to dihydrotestoterone which is
essential for formation of external genital, prostate differentiation and descent of testes.

c. By hormone transport and elimination:

Examples:
 i) Polychlorinated biphenyl (PCB) – affects thyroid function causing birth defects.
ii) Atrazine - It is a herbicide which increases the synthesis of estrogen. Can cause preterm
delivery and retards intrauterine growth
iii) Bisphenol – Compound used for making plastics. In utero exposure causes embryonic
mammary gland to make more estrogen
iv) Bisphenol A (BPA) – causes low sperm counts in males and predisposition of breast cancer
in females

4. Industrial Teratogens:
Examples: Heavy metals such as lead, mercury, arsenic, zinc, cadmium
Source: Found in high concentrations in drinking water, vegetables, air in the polluted cities. Also
components of some cosmetics
Effects:
Lead: It is a cumulative poison and it mimics the role of calcium in body.
Critical period of exposure of lead is 12-14 weeks of gestation in humans. It accumulates in fetal
brain causing neurological defects. Also impairs the cell adhesion during development of nervous
system and alters neuronal migration. Lead exposure can cause preterm delivery, decreased
postnatal growth and increased risk of neonatal death.
Mercury: Commonly accumulates as methyl mercury in the body which is extremely toxicto
humans as it accumulates in the fetal tissues after traversing through placenta.
Arsenic: It is a potent teratogen causing a spectrum of defects like malformation in urinogenital
system, skeletal system and micromelia.

5. Microbial Teratogens:
Infectious microbes act as the teratogens and are leading cause of neonatal morbidity and
mortality. The general teratogenic symptoms involve premature birth, growth retardation,
neurological abnormalities, damage to eye, liver, heart and ear and bone lesions.
Some common teratogenic microbes are:
a. Rubella virus (cause - German Measles)
Teratogenic effects: abnormal babies are born to women suffering from measles during the
first five weeks of gestation. Abnormality includes
- Microphthalmia
- Cataract
- Glaucoma
- Cardiac malfunction
- Hearing loss and
- Mental retardation

b. Cytomegalovirus (CMV) Herpes simplex (Causes herpes)

- If infected with CMV in early gestation period fetus is aborted.
- Infection in later gestation leads to blindness, deafness, cerebral palsy and mental
retardation.
- Herpes virus also has similar teratogenic effects.

c. Toxoplasma gondi
 It is a protozoan parasite which spreads by cat. Man is the intermediate host.If a pregnant
woman is infected by this protozoan, the parasite can cross the placenta and cause
embryopathy. It may result in
- Hydrocephaly
- Microphthalmia
- Chorioretinitis
- Brain lesions and
- Multiple organ damage in the fetus.
The fetal damage is maximum if the mother is infected in third trimester resulting in 60% of
infected newborns.

d. Trepanoema pallidium (Causes Syphilis, an STD)

- Early infection to pregnant females often results in spontaneous miscarriage. Children
born with infection are anemic and suffer from condition called congenital syphilis.
- They suffer from seizures, spleen and liver malformations, skin lesions, nasal discharge
and joint pains.
- Infections during late pregnancy results in deafness, cardiovascular defects, dental and
bone abnormalities.
-
6. Recreational teratogens:
Alcohol, tobacco, cocaine, cigarette and heroin are considered as recreational teratogens. They
reduce the fetal and postnatal growth and increase the infant mortality.

a. Alcohol:
• Alcoholic females give birth to defective babies, a condition referred as fetal alcohol
syndrome (FAS).
• Alcohol enters through the placenta to the fetal circulatory system and causes
abnormalities.
• Ethanol induces hypoxia and fetal malnutrition by reducing the placental blood flow to the
fetus causing vasoconstriction.
• Malformations due to FAS in fetus include:
- Microcephaly
- Decreased philtrum size (the pair of ridges that run between the nose and mouth above
the centre of the upper-lip)
- Narrow upper lip
- Low nose bridge
- Micropthalmia
- Cardiovascular disorders
- Maxillary hypoplasia
• The affected children are mentally retarted with low IQ and behavioral abnormalities
• Alcohol may impair neural crest cell migration or may cause cell death by lytic
mechanism.

b. Tobacco

• Women who smoke during pregnancy are more likely to have spontaneous abortions or
premature delivery.
 • Nicotine in tobacco impairs the flow of fetal blood through placenta resulting in chronic
hypoxia and malnutrition leading to embryonic defects.
• The babies of soker mothers are smaller in size with less birth weight.
• There is reduction of head size and development of certain facial abnormalities.

c. Cocaine or benzoylmethylecgonine and other such drugs

• Cocain is an alkaloid that is extracted from plant Erythroxylum coca which is endogenous
to South America, Mexico, Indonesia and West Indies,
• It causes birth defects by disrupting placental blood vessel thereby inducing fetal hypoxia
and malnutrition.
• Fetus exposed to cocaine show structural abnormalities such as
- Retarded growth,
- Microcephaly
- Urinogenital abnormalities, neuronal and behavioral defects.
• There is also an increased risk of premature delivery, spontaneous abortion and fetal
death.

7. Metabolic conditions:
Certain pre-existing metabolic disorders also subject a risk of abnormality in fetus.

a. Diabetes:
• Some of the defects associated with insulin dependent diabetes are:
- Multiple congenital malformations such as cardiac and skeletal defects
- Alteration in central nervous system
- Caudal dysgenesis
• Diabetes also increases the risk of still birth and neonatal death

b. Nutritional Stress:
• Nutritional stress may also affect the fetus by compromising its immune system.
• The growth of the fetus is affected if the mother is not fed well during her pregnancy.
• The infant born is more prone to infections and diseases.
• Nutritional deficiency of iodine in food may cause abnormality in the neural development.

Genetic –environmental interaction

Susceptibility to teratogens depends on two factors:
1. The genetic constitution of the female
2. Interaction with environmental factors
Recent studies have shown that different alleles in human populations can influence harmfulness of a
substance to the fetus. For example, if the expecting mother is a heavy smoker, and has a particular allele
(A2) of the gene for growth factor TGF – β, then the risk of embryological abnormalities is more. This
indicates that the teratogenic influence depends on the genotype of the individual and its expression is
also influenced by the environment. Its teratogenic effect also depends on the age of the fetus.
Preventive measures
Prevention can be done at primary and secondary levels.
Primary prevention: It is done at the time of conception or immediately after conception and is continued
throughout the gestation period to maintained the pregnancy. The major preventive measures are:

• Optimal time (age) of reproduction

• Exclusion of possible teratogens (alcohol),
• Good nutrition including vitamins
• Good treatment of chronic diseases, careful medication
• Genetic counseling if required (in case of old age pregnancies)
Secondary Preventions: This is generally required when the expecting mother is exposed to teratogens.
The maintenance and continuation of the pregnancy depends on the degree of exposure and damage done.
Medical examination is an essential component of secondary prevention. It involves:

• Prenatal diagnosis of severe anomalies.

• According to the local laws – in the Czech Republic the women can ask for termination of
pregnancy for “genetic reasons“ up to the end of 24th week if a severe anomaly of the fetus has
been proven.
Secondary prevention is the reason why the number of severe anomalies in births is quite low.