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)

BIRTHS

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

•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

The placenta is an imperfect barrier

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)

At early stages, cells are pluripotent and cells can replace damaged cells

At late stages, organ systems have formed and cellular differentiation is occurring

Organogenesis is susceptible to teratogensis

Footnote: Some organogenesis is late and some teratogens act late eg cerebellum, palate, urinary and reproductive

Gestation

Sen

sitiv

ity

Birth

EMBRYONIC FOETAL

ORGANOGENESIS

BLASTULATION

HISTOLOGICALDIFFERENTIATION

MATURATIONOF FUNCTION

‘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)

Pattern of effects depends on precise date in the organogenesis calender

8

20

30

40

% m

alfo

rmat

ion

9 10 11 12 13 14 15 16 days

10

Rat embryos Brief pulse of teratogen at 10 days:35% brain 33% eye24% heart 18% skeletal6% urogenital 0% palate

Gestation

How would pattern change at day 12?

Embryos can be vulnerable to low concentrations of teratogen

100

% e

f fe c

t

Log [Dose]

Teratogenic effect

Embryolethality

Maternaltoxicity

Footnotes:1. Teratogens usually have a general toxicity2. But: distinguish between general toxicity and specific formation of defects3. 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

• 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).

Summary of features of teratogen

PHYSICAL INSULTIonising 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??)

TERATOGENIC AGENTS

CHEMICALSToxic plantsFarm pesticides See followingTherapeutic agents

VIRUSESBluetongue (sheep)Bovine viral diarrhoea (cattle)

Border disease (sheep) See following

Panleucopenia virus (cats)(Rubella (humans))

CROOKED CALF DISEASE

Pasture may contain plants with teratogenic effects (1)

• Western states of USA

•Lupin species containing alkaloids such as anagyrine

• Critical period 40 – 70 days gestation

• Joint abnormalities

CYCLOPIA IN LAMBS

Pasture may contain plants with teratogenic effects (2)

• 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

CYCLOPIA

Pasture may contain plants with teratogenic effects (3)

The head of a cyclopic lamb: fused cerebral hemispheres, one central eye, no pituitaryGilbert 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 (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)

PARBENDAZOLE AS ANTIHELMINTHIC

Therapeutic agents can be teratogens (1)

• 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

VITAMIN A ANTAGONIST

Therapeutic agents can be teratogens (2)

• 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

THALIDOMIDE

THALIDOMIDE

Absence of arms 38-42 days(absence of legs 39-45 days)Gilbert (2006)

Therapeutic agents can be teratogens (3)

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 rightWilson (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 experimenta l in nature!

• Continued worries about aspirin, caffeine, tranquilisers , anti-histamines, antibiotics, steroids, anti-malarials , pesticides

Birth defects can arise from infective agents

• Relatively few examples probably because of placental barrier

• Mostly virus but some protozoa

General points

• 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)

• Bluetongue (sheep) – abnormal brain development as a result of maternal infection or maternal vaccination with attenuated virus

Examples