TERATOGEN
An agent that causes specific anatomical
derangements or functional losses when present
during a specific window on the timescale of
development.
HISTORICALLY
TERATOS (Gk) = Monster
In ancient times a malformed birth was often seen as a prophecy or of
mystical significance.
It still can be!
Villagers in the district of
Ramechhap in the Himalayas
have said six-month-old
Risab, who has a headless
"parasitic twin" attached at the
abdomen, is akin to the
elephant god, Ganesh, whose
various forms have between
two and 16 arms.
The Telegraph, August 2009.
But we have scientific explanations (in some cases)
Birth trauma (1%)
Maternal metabolism (1%)
97% NORMAL
Maternal infection (2%)
BIRTHS
Drugs, chemicals,
Radiation (2%)
3% DEFECTIVE
Cytogenetic (4%)
Inherited (20%)
Unknown (70%)
But – these are births. It is estimated that perhaps half of human
conceptus do not come to term
The placenta is an imperfect barrier
• Amnion sac originally thought of as a completely protected environment
• Now realised that materials/chemicals can cross placenta to a greater or
lesser degree
• Small non-polar molecules cross easily
• Large polar molecules cross poorly but rate still may be significant
Example 1: Acetyl salicylate (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)
Organogenesis is susceptible to teratogensis
FOETAL
Sensitivity
EMBRYONIC
At early stages, cells are
pluripotent and cells can
replace damaged cells
BLASTU
LATION
ORGANOGENESIS
MATURATION
OF FUNCTION
At late stages, organ
systems have formed and
cellular differentiation is
occurring
HISTOLOGICAL
DIFFERENTIATION
Gestation
Birth
Footnote: Some organogenesis is late and some teratogens act late
eg cerebellum, palate, urinary and reproductive
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
20
10
8
9
10
11
12
13
14
Gestation
How would pattern change at day 12?
15
16 days
Embryos can be vulnerable to low concentrations of teratogen
100
Embryo
lethality
Maternal
toxicity
% effect
Teratogenic
effect
Log [Dose]
Footnotes:
1. Teratogens usually have a general toxicity
2. But: distinguish between general toxicity and specific formation of defects
3. Maternal toxicity can be much lower. In some cases (eg thalidomide in humans),
there is no maternal toxicity
4. Teratogenicity can be very variable in different mammals
Summary of features of teratogen
• Act during a critical narrow period of development
• Often a small concentration sufficient to cause damage
• Variable effect in different species*
* - This makes the use of model animals for testing teratogencity a
problem (some laboratory rodent strains were completely resistant
to massive doses of thalidomide).
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
Therapeutic agents
See following
VIRUSES
Bluetongue (sheep)
Bovine viral diarrhoea (cattle)
Border disease (sheep)
Panleucopenia virus (cats)
(Rubella (humans))
See following
Pasture may contain plants with teratogenic effects (1)
CROOKED CALF DISEASE
• Western states of USA
• Lupin species containing alkaloids such
as anagyrine
• Critical period 40 –70 days gestation
• Joint abnormalities
Pasture may contain plants with teratogenic effects (2)
CYCLOPIA IN LAMBS
• Idaho
• Skunk cabbage or corn lily (Veratrium californicum) contains
alkaloid cyclopamine
• Critical period: 14 days (cyclopia), 30 days (limb defects)
• 11 year investigation by US Department of Agriculture
• Affects sonic hedgehog signalling pathway
• Shh mutations can also produce cyclopia
• Holoprosencephaly – forebrain does not divide into two lobes
Pasture may contain plants with teratogenic effects (3)
CYCLOPIA
The head of a cyclopic
lamb: fused cerebral
hemispheres, one central
eye, no pituitary
Gilbert 2006
A human foetus with a
proboscis-like nose above a
single median eye.
(Teratogenic origin unknown)
Some farm pesticides are shown to be teratogenic
PARBENDAZOLE AS ANTIHELMINTHIC
• Parbendazole (a benzimidazole) was used to treat nematode
infections in domestic animals
• Can cause skeletal, renal and vascular defects
• Critical period: 14 days
• Worry about residue risks to humans
• Replaced on market by non-teratogenic relatives (see
Pharmacology – year 3)
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
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
Therapeutic agents can be teratogens (3)
THALIDOMIDE
Absence of arms 38-42 days
(absence of legs 39-45 days)
Gilbert (2006)
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 foetus on right
Wilson (1973)
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 chemicals
makes pregnancies (including human pregnancy) almost experimental
in nature!
• Continued worries about aspirin, caffeine, tranquilisers, antihistamines, antibiotics, steroids, anti-malarials, pesticides
Birth defects can arise from infective agents
General points
• Relatively few examples probably because of placental barrier
• Mostly virus but some protozoa
Examples
• Bluetongue (sheep) – abnormal brain development as a result of
maternal infection or maternal vaccination with attenuated virus
• 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)