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Hx and Principles

Background risk for a congenital anomaly 3%
Causes of Malformations 1) Genetic (28%) 2. Toxicants (3%) 3. Uterine factors and twinning (3%) 4. Multifactorial (23%) 5. Unknown (43%)
Teratogen definition Any environmental agent such as a drug, chemical, infection, or pollutant which potentially harms the developing fetus
Wilsons Principles of Teratology biologic explanation for the mechanism of action of the teratogen
There are 4 basic manifestations of abnormal development 1. Pregnancy loss 2. Malformations 3. Growth retardation 4. Functional deficits
Types of reproductive toxiticity 1. Alterations in libido, fertility, menstruation 2. Gene mutations or chromosome breaks 3. Pregnancy Loss 4. Fetal malformations 5. Fetal growth retardation 6. Behaviorial teratogenesis 7. Transplacental carcinogenesis
Paternal exposures 1. Sperm develop over a 90 day period 2. Possible effects include: DNA mutations or chromosome breaks 3. Alterations to fertility 4. Excreted in semen, absorbed by woman, directly affects fetus, may affect methylation; Poorly studied
With this genetic basis, phenytoin will lead to embryopathy Deficient epoxide hydrolase
Which this genetic basis, alcohol will lead to FAS Alleles of ADH and ALDH
With this genetic basis, smoking can cause oral clefts TGF alpha alleles
With this genetic basis, retinoic acid may lead to embryopathy Distribution of cell receptor
Nature of damage depends on timing of exposure 1. Period when a structure is sensitive to insult...leads to permanent damage 2. Generally just prior to or during appearance of the structure in the embryo 3. Functional maturation may take longer than structural development
Gestational age and teratogenic exposure: days 0 to 15 Miscarriage, fetal death
Gestational age and teratogenic exposure: days 15 to 60 Fetal death, major malformations, growth retardation, impaired IQ
Gestational age and teratogenic exposure: days 60 to 80 Fetal death, vascular disruption caused by hypocia, hemorrhage and tissue loss
Gestational age and teratogenic exposure: second and third trimester Stillbirth, growth retardation, impaired IQ
Syndrome of outcomes is specific to the toxicant Likely due to access of chemical to susceptible tissues, metabolic pathways, receptors in particular structures
Thalidomide Phocomelia
Alcohol Characteristic facies, growth retardation, functional deficits
Shepard's Criteria for Teratogenicity (3) 1. The agent must be present during the critical periods of development 2. The agent should produce congenital defects in an experimental animal 3. Proof should be obtained that the agent acts in an unaltered state on the embryo-fetus
Karnofsky's Law Anything at the right time of pregnancy, at the right dosage, in the right species of animal can be teratogenic
Created by: KChatham