1. What is a Teratogen? Definition:
A teratogen is an environmental agent that can adversely affect the unborn child, thus producing a birth defect
An agent that causes specific anatomical derangements or functional losses when present during a specific window on the timescale of development.

2. Teratology TERATOS (Gk) = Monster
In ancient times a malformed birth was often seen as a prophecy or of mystical significance.
It still can be!
The study of abnormal development in embryos and the causes of congenital malformations or birth defects

3. But we have scientific explanations (in some cases)
Birth trauma (1%)
Maternal metabolism (1%)
Maternal infection (2%)
Drugs, chemicals,
Radiation (2%)
Cytogenetic
(4%)
Inherited (20%)
Unknown (70%)
97% NORMAL
3% DEFECTIVE
But –
these are births. It is estimated that perhaps half of human
conceptus
do not come to term
BIRTHS

4. The placenta is an imperfect barrier•
Amnion sac originally thought of as a completely protected envi
ronment •
Now realised that materials/chemicals can cross placenta to a g
reater or
lesser degree •
Small non -
polar molecules cross easily •
Large polar molecules cross poorly but rate still may be signif
icant
salicylate
Example 1:
Acetyl
(aspirin), mostly charged at pH 7 but
uncharged crosses placenta rapidly
Example 2:
Heparin, used as an anti -
coagulant in pregnant women
because size and polarity limit placental
transfer
. It replaces
warfarin
which cross readily and is a potent
teratogen
in first trimester (nasal
hypoplasia )
Example 3:
viral particles, very large but cross by special mechanisms eg
Rubella (human),
panleucopenia
(cats)

6. Brief pulse of teratogen at 10 days: 35% brain 33% eye
Pattern of effects depends on precise date in the organogenesis calender
‘Abruptly, as organogenesis begins, the embryo becomes susceptible to teratogenic agents, usually reaching a peak corresponding to the structural formation of the target organ’ (Wilson 1973)
Rat embryos
Brief pulse of teratogen at 10 days:
35% brain 33% eye
24% heart 18% skeletal
6% urogenital 0% palate 40 30
% malformation 20 10 8 9 10 11 12 13 14 15
16 days
Gestation
How would pattern change at day 12?

7. Timing
The fetal brain develops throughout pregnancy and can be affected at any time.
Exposure to a teratogen during the two weeks following conception is unlikely to cause birth defects.
The effect of teratogens depends upon the timing of exposure. 
The first trimester of pregnancy is the critical period of organ and limb development in the fetus. 

8. Photo Courtesy of: http://www.csulb.edu/~kmacd/361-6-Ch1.htm

11. TERATOGENIC AGENTS
PHYSICAL INSULT
Ionising radiation (nuclear waste, medical X -
rays)
Pressure of rectal palpation (c. 38 days, Holstein -
Friesian)
Pressures of defective uterine positioning
(??
Radiofrequency
fields from phone masts??)
CHEMICALS
Toxic plants
Farm pesticides
See following
Therapeutic agents
VIRUSES
Bluetongue (sheep)
Bovine viral diarrhoea (cattle)
Border disease (sheep)
See following
Panleucopenia
virus (cats)
(Rubella (humans))

12. Therapeutic agents can be
teratogens
(1)
VITAMIN A ANTAGONIST • 13 -
cis -
retinoic
acid as antagonist •
Used in a cream to treat severe acne in humans •
Single dose at critical period can produce birth defects (30% vs
3% baseline) •
accumulates in fat and persists •
All trans
retinoic
acid (derived from Vitamin A) binds to nuclear
receptors that control HOX gene expression •
Antagonism affects
rostral
caudal axis determination, limb
development and cranial neural crest development

13. Therapeutic agents can be
teratogens
(2)
THALIDOMIDE •
There have been two human
teratological
catastrophes –
Rubella and thalidomide •
Thalidomide was introduced as a sedative in the 1950’s •
Adult toxicity had been shown to be negligible •
Embryo toxicity in rodent species tested was negligible •
Single exposures during 28 -
49 days in pregnant women gave
almost 100% defective births •
Phocomelia
(seal limb) –
short or absent long bones in limbs

14. Therapeutic agents can be
teratogens
(3)
THALIDOMIDE
Abnormalities in forelimb, lower jaw, ear
and tail in 100 day Rhesus monkey
foetus
following treatment of pregnant
mother with 30 mg/kg thalidomide on day
26 of pregnancy. Normal
on right
Wilson (1973)
Absence of arms 38 -
42 days
(absence of legs 39 -
45 days)
Gilbert (2006)

15. CONCLUSION –
CHEMICAL TERATOGENS •
A complex chemical world makes it a dangerous place for embryos •
But
teratogenic
risk is usually not known for a specific animal and is
very variable across the mammals •
The lack of specific knowledge about the impact of new chemical s
makes pregnancies (including human pregnancy) almost experimenta l
in nature! •
Continued worries about aspirin, caffeine,
tranquilisers
, anti -
histamines, antibiotics, steroids, anti
malarials
, pesticides

16. Birth defects can arise from infective agents•
Relatively few examples probably because of placental barrier
Mostly virus but some protozoa
General points •
Bluetongue (sheep) –
abnormal brain development as a result of
maternal infection or maternal vaccination with attenuated virus
Examples •
Border disease Sheep) -
abnormal brain development, nerve
myelination
and hair development (‘fuzzy lamb’ and ‘hairy shaker’ are
synonyms) •
Panleucopenia
virus (cats) -
cerebellar hypoplasia
, defective balance
and coordination •
Rubella (German measles)(humans) –
50% defective births when
maternal infection occurred in first month leading to deafness,
blindness and heart defects .
20000 infants affected (USA 1964)

17. Congenital Infections
HIV
The biggest risk to the fetus is for transmission of the virus to fetus
Treatment during pregnancy can greatly reduce the risk to the baby.
Rubella
A.K.A. German Measles, may result in the baby being born blind, deaf, mentally disabled, have heart defects
Syphilis
STD, ½ of infected pregnancies will spontaneously abort
Baby may be born premature, have enlarged liver or spleen, deaf, blind, MR, skin rash, jaundice
Toxoplasmosis
Common infection caused by microscopic worms
Can cause developmental disabilities, deafness, blindness

18. Physical Agents X-Rays Hyperthermia
Possible effects on the newborn include: slow growth, developmental disabilities, sterility, possible cancers later in life
Hyperthermia
Refers to an abnormally high body temperature (fever, prolonged exposure to extreme heat source, heavy exercising)
Baby is more likely to form neural tube defects, including spina bifida (incompletely formed spinal cord, may result in paralysis)

19. Maternal Health Factors
Maternal Diabetes
Delivery complications due to large baby
Stillbirth
Spontaneous abortion
Maternal PKU
Increased risk for mental retardation
Low birth weight, other birth defects

20. Chemicals, Drugs, & Medications
Alcohol
Leading known preventable cause of MR and birth defects
Low birth weight
Heart, joint, & eye defects
Still birth
Fetal Alcohol Syndrome

21. Chemicals, Drugs, & Medications
Cigarette Smoke
Nicotine
Fetal Distress
Abnormal heart rate
Low birth weight
Stillbirth
Sponataneous abortion
Death during first few weeks
Lasting effects
Smaller size, poor reading skills, poor school adjustment

22. Chemicals, Drugs, & Medications
Cocaine
Baby will be born addicted to cocaine
When no longer being given drugs, baby will go through stress, high-pitched crying, shaking, poor feeding, fever
Low birth-weight or premature birth
Grow slowly, malformed internal organs
Behavior worsens as they get older
Mothers addicted to crack usually have poor health and nutrition

23. Chemicals, Drugs, & Medications
Always discuss any medications with doctor prior to taking them
Aspirin
Prolonged labor
Bleeding in mother and baby

24. Proven Human Teratogens: Proven to cause major birth defects…
Alcohol
Angiotensin converting enzyme inhibitors (ACEI) (captopril, enalapril, lisinopril)
Carbamazepine
Cocaine
Coumarin anticoagulants
Diethylstilbestrol
Folic acid antagonists: Aminopterin and methotrexate
Hydantoins (phenytoin and trimethadione)
Isotretinoin (13-cis-retinoic acid)
Lithium
Misoprostol
Tetracyclines
Thalidomide
Valproate
For details on each of these drugs, go to

25. Possible Teratogenic Drugs:
D-penicillamine-
High doses are associated with connective tissue disorders.
Methimazole-
Thought to be associated with scalp defects.
Diazepam-
During first trimester exposure, there seems to be a slight increase in the incidence of cleft palate and lip.