But we have scientific explanations in some cases
But we have scientific explanations (in some cases) Birth trauma (1%) 97% NORMAL Maternal metabolism (1%) 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 p. H 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)
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 % malformation 40 30 20 10 8 9 10 11 12 13 14 Gestation How would pattern change at day 12? 15 16 days
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)
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