What is a Teratogen?

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. TeratologyTERATOS (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. Birth trauma (1%) Maternal metabolism (1%) 97% NORMAL Maternal infection (2%) 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 But we have scientific explanations (in some cases) BIRTHS

4. • 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 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) The placenta is an imperfect barrier • Amnion sac originally thought of as a completely protected envi ronment

6. 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% brain33% eye 24% heart18% skeletal 6% urogenital0% 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. 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.  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. Timing

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

11. 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)) 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??)

12. • 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 (1) VITAMIN A ANTAGONIST • 13 - cis - retinoic acid as antagonist

13. • 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 (2) THALIDOMIDE

14. 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) Therapeutic agents can be teratogens (3) THALIDOMIDE Absence of arms 38 - 42 days (absence of legs 39 - 45 days) Gilbert (2006)

15. • 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 CONCLUSION – CHEMICAL TERATOGENS

16. 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) Birth defects can arise from infective agents

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 • 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 http://www.nvp-volumes.org/p2_4.htm

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.