Introduction to teratology TERATOLOGY Teratology is the study of birth defects, and a teratogen is something that either induces or amplifies abnormal embryonic or fetal development and causes birth defects. TERATOLOGY How to recognize a teratogen? TERATOLOGY TERATOLOGY How to confirm a teratogen? TERATOLOGY Wilson’s Six Principles of Teratology as Presented in the Wilson and Fraser Handbook of Teratology (Wilson, 1977) 1. Susceptibility to teratogenesis depends on the genotype of the conceptus and the manner in which this interacts with environmental factors. 2. Susceptibility to teratogenic agents varies with the developmental stage at the time of exposure. 3. Teratogenic agents act in specific ways (mechanisms) on developing cells and tissues to initiate abnormal embryogenesis (pathogenesis). 4. The final manifestations of abnormal development are death, malformation, growth retardation, and functional disorder. 5. The access of adverse environmental influences to developing tissues depends on the nature of the influences (agent). 6. Manifestations of deviant development increase in degree as dosage increases from the noeffect to the totally lethal level. TERATOLOGY TERATOLOGY Teratogens around us physical ionizing irradiation (UV, RTG, , , ), temperature, mechanical factors (amnion bands, pes equinus, ...) chemical pharmacological drugs (antibiotics, antiepileptics, anticoagulans, cytostatics) solvents, alcohol, heavy metals, ... biological patogens (virus), disease of mother (diabetes, myasthenia gravis, PKU) TERATOLOGY • Growth retardation • Failure of histogenesis, organogenesis • Embryonic/fetal death TERATOLOGY Mechanisms of action? TERATOLOGY Classification criteria? TERATOLOGY FDA classification https://www.govinfo.gov/content/pkg/FR-2008-05-29/pdf/E8-11806.pdf TERATOLOGY TERATOLOGY TERATOLOGY Evidence for ZIKV induced microcephaly? TERATOLOGY Strength (effect size): A small association does not mean that there is not a causal effect, though the larger the association, the more likely that it is causal. Consistency(reproducibility): Consistent findings observed by different persons in different places with different samples strengthens the likelihood of an effect. Specificity: Causation is likely if there is a very specific population at a specific site and disease with no other likely explanation. The more specific an association between a factor and an effect is, the bigger the probability of a causal relationship.[1] Temporality: The effect has to occur after the cause (and if there is an expected delay between the cause and expected effect, then the effect must occur after that delay). Biological gradient: Greater exposure should generally lead to greater incidence of the effect. However, in some cases, the mere presence of the factor can trigger the effect. In other cases, an inverse proportion is observed: greater exposure leads to lower incidence. Plausibility: A plausible mechanism between cause and effect is helpful (but Hill noted that knowledge of the mechanism is limited by current knowledge). Coherence: Coherence between epidemiological and laboratory findings increases the likelihood of an effect. However, Hill noted that "... lack of such [laboratory] evidence cannot nullify the epidemiological effect on associations". Experiment: "Occasionally it is possible to appeal to experimental evidence". Analogy: The use of analogies or similarities between the observed association and any other associations. Reversibility: If the cause is deleted then the effect should disappear as well Bradford Hill criteria TERATOLOGY ZKV transmission TERATOLOGY ZKV mechanism of action TERATOLOGY • Teratology, teratogens  Wilson’s principles • Mechanisms of action  any embryology and/or cell biology textbook • Classification & examples  any embryology textbook, FDA (EU) categories • Identification, validation  ZIIKA forest virus story & Bradford Hill criteria Take home message TERATOLOGY Thank you for attention TERATOLOGY