3. 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 conceptusdo not come to term

4. 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 salicylateExample 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 placentaltransfer. It replaceswarfarin which cross readily and is a potentteratogenin first trimester (nasal hypoplasia) Example 3:viral particles, very large but cross by special mechanisms egRubella (human),panleucopenia(cats)

6. ‘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 % malformation 910111213141516 days 10 Rat embryos Brief pulse of teratogen at 10 days: 35% brain 33% eye 24% heart18% skeletal 6% urogenital0% palate Gestation How would pattern change at day 12?

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

10. CROOKED CALF DISEASE Pasture may contain plants withteratogeniceffects (1) Western states of USA Lupinspecies containing alkaloids such asanagyrine Critical period 40–70 days gestation Joint abnormalities

11. CYCLOPIA IN LAMBS Pasture may contain plants withteratogeniceffects (2) Idaho Skunk cabbage or corn lily (Veratrium californicum) contains alkaloidcyclopamine Critical period: 14 days (cyclopia), 30 days (limb defects) 11 year investigation by US Department of Agriculture Affects sonic hedgehog signalling pathway Shhmutations can also producecyclopia Holoprosencephaly–forebrain does not divide into two lobes

12. CYCLOPIA Pasture may contain plants withteratogeniceffects (3) The head of acyclopic lamb: fused cerebral hemispheres, one central eye, no pituitary Gilbert 2006 A humanfoetuswith a proboscis-like nose above a single median eye. (Teratogenicorigin unknown)

13. Some farm pesticides are shown to beteratogenic Parbendazole(abenzimidazole) 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-teratogenicrelatives(see Pharmacology–year 3) PARBENDAZOLE AS ANTIHELMINTHIC

14. Therapeutic agents can beteratogens(1) 13-cis-retinoicacid 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 transretinoicacid (derived from Vitamin A) binds to nuclear receptors that control HOX gene expression Antagonism affectsrostralcaudal axis determination, limb development and cranial neural crest development VITAMIN A ANTAGONIST

15. Therapeutic agents can beteratogens(2) There have been two humanteratologicalcatastrophes– 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

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

17. CONCLUSION–CHEMICAL TERATOGENS A complex chemical world makes it a dangerous place for embryos Butteratogenicrisk 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, anti- histamines, antibiotics, steroids, anti-malarials, pesticides

18. 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 myelinationand hair development (‘fuzzy lamb’ and ‘hairy shaker’ are synonyms) Panleucopeniavirus (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