Teratology

Question 1

Birth Defect and Failed Pregnancy Stats

Answer 1

 30-70% of fertilized eggs are lost before implantation
 31% of eggs are lost post-implantation
 < 20-30% of human zygotes and < 1/2 half of all pregnancies result in normal, healthy babies
 50% of birth defects are by unknown causes

Question 2

Impact of Birth Defects

Answer 2

– 7.5x increased risk of subsequent siblings having birth defect
o Individual themselves – dependence on others; psychological issues
o Parents – financial burden, high divorce rate
o Siblings – psychologic and behavioral problems

Question 3

Critical Periods in Teratogenesis

Answer 3

o With time, embryonic potency decrease while cell differentiation increases
o After fertilization but before implantation  highly resistant to toxic agents
 Cells are totipotent so they will replace cells that die
o Embryonic Period (first 8 weeks)
 Major events of differentiation/organogenesis take place critical period of development
 Most teratogenic drugs exert their main effects during this period due to vulnerability
 Once organ systems have developed, toxic agents can affect further tissue development  functional deficits not major malformations
o Fetal Period (week 9 to term) – growth and maturation of organ systems
 Reduced sensitivity to teratogens  results in growth retardation of already formed organ

Question 4

Embryonic Cell Regulation

Answer 4

o Tissue interactions occur via intercellular signals; unidirectional towards more differentiation
o Internal Rearrangement – if something goes wrong during development the embryo can slow development down and work to repopulate cells where cell death has occurred

Question 5

Developmental Plasticity

Answer 5

– epigenetics - ability of a single gene to express more than one phenotype based on environmental conditions  basis of metabolic syndrome

Question 6

Trisomy 21, 18, 13

Answer 6

 Trisomy 21 – Down Syndrome – 75% spontaneously abort; survivors live into fifties
• Result: mental deficiency, brachycephaly, flat nasal bridge, Simian crease (hand)
 Trisomy 18 – Edward Syndrome – 50% spontaneously abort; most die by 6 months
• Result: mental deficiency, micrognathia, malformed ears, flexed digits; prominent occiput (bulging of posterior side of skull)
 Trisomy 13 – Patau Syndrome – 50% spontaneously abort; most die by 6 months
• Result: mental deficiency, CNS malformations, cleft palate, polydactylyl

Question 7

45X

Answer 7

 Turner Syndrome/45, X – 1% survive; paternal X is missing

• Result: NO secondary female sex characteristics, webbed neck, lymphedema

Question 8

47 XXX; 47XXY; 47xYY

Answer 8

 47, XXX – normal female appearance; fertile; 20% mentally retarded
 47, XXY – Klinefelter Syndrome – males; small testes; aspermatogenesis; long legs; intelligence deficit; gynecomastia
 47, XYY – normal male appearance; tall; aggressive

Question 9

Triploidy and Tetraploidy

Answer 9

 Triploidy (3N) – intrauterine growth retardation, small trunk, large head; caused by dispermy; lives birth very rare
 Tetraploidy (4N) – abort very early; caused by failure of cytoplasmic cleavage or chromosomal segregation at 1st mitotic cleavage

Question 10

Translocation and Terminal Deletions

Answer 10

o Translocation -nonhomologous DNA swapping associated w/ radiation, drugs, chemicals, viruses
 Effects depend on nature of translocation
• Balanced = no DNA lost  less severe; Unbalanced = DNA lost  severe
o Terminal Deletions - Cri du chat syndrome – deletion of short arm of chromosome 5; microcephaly, severe mental retardation, heart anomalies

Question 11

Duplications, Inversions, Isochromosomes

Answer 11

o Duplications – duplicated region exists as repeat within chromosome or as separate fragment; more common than deletions but less harmful (no loss of DNA)
o Inversions – segment of chromosome is reversed
 Paracentric – confined to single arm
 Pericentric – both arms including centromere; more severe
o Isochromosomes – centromere divides transversely instead of longitudinally; most common = X

Question 12

Holoprosencephaly, Achondroplasia, Cystic Fibrosis

Answer 12

o Holoprosencephaly – Sonic Hedgehog (SHH) – dominant – multiple point mutations
 Failure of forebrain to completely separate into 2 lobes
 Wide range of brain, skull, and facial defects
o Achondroplasia – FGFR3 – dominant – point mutation – dwarfism
o Cystic Fibrosis – CFTR – recessive – small deletion – causes lung/GI problems

Question 13

Fetal Hydantoin Syndrome

Answer 13

– may have genetic predisposition for susceptibility or resistance
o Fetal Hydantoin Syndrome – caused by drugs Phenytoin and Dilantin– prescribed for epilepsy
 Defect in enzyme epoxide hydrolase – cant breakdown one of drugs toxic intermediates
 Result: microcephaly, altered face, underdeveloped nail, IUGR

Question 14

Toxicants in Embryo vs. Adult

Answer 14

o Embryo - Gestational age has importance; multiple sites to act
o Adult – Dose is important – exposure must exceed certain threshold level

Question 15

Embryo/Fetal Toxicity in Presence of maternal toxicity

Answer 15

o Aminopterin, methylmercury, polychlorinated biphenyls (PCBs)

Question 16

Embryo/Fetal Toxicity in Presence of Maternal Stress

Answer 16

o Steroid hormones, ethanol, cigarette smoking

Question 17

Embryo/Fetal Toxicity without Maternal Effects

Answer 17

o Thalidomide, Accutane, diethylstilbesterol, ionizing radiation

Question 18

Pre-Eclampsia

Answer 18

– occurs mid/late pregnancy
 Blood vessels constrict in uterus to increase BP in mother; decrease blood to fetus
 Associated with low levels of VEGF in maternal blood
 Periconceptual multivitamins associated with decreased incidence of preeclampsia
 More common during 1st pregnancy and family history

Question 19

Diabetes

Answer 19

– risk of birth defects increase if glucose levels poorly controlled
 macrosemia (large baby), sacral agenesis, holoprosencephaly (failure forebrain to divide)

Question 20

Hyperthermia

Answer 20

– body temperature > 101F/39.5C due to fever, exercise, hot tub/sauna
 Increased risk of neural tube defects (spinal bifida  anencephaly)
 Critical period = 3-4 weeks gestation when neural tube is closing

Question 21

Phenylketonuria

Answer 21

– defect in phenylalanine metabolism; control through diet

 Leads to abnormal brain development, heart defects, behavior problems

Question 22

Septate Uterus

Answer 22

– uterine constraint is most common cause of deformation; occur late fetal period
 Can cause club foot, hip dislocation, skull deformation, defects limbs/face

Question 23

Amniotic Bands

Answer 23

– fibrous band from anion tears encircle body parts, especially limbs/digits
 Leads to impaired growth and amputations

Question 24

Oligohydraminos

Answer 24

– low level of amniotic fluid (<500ml) due to renal agenesis or amnion leak
 Can lead to fetal loss, deformations, and lung defects

Question 25

Paternal Exposure-Associated Anomalies and Routes

Answer 25

o 3 routes: germ cell mutagenesis, toxicants in semen, workplace chemical exposure brought home
o Prader-Willi Syndrome – 15q deletion in paternal-derived chromosome
 Associated with paternal hydrocarbon exposure with or without 15q deletion
 Result: hypothalamic dysfunction, hyperphagia, obesity

Question 26

Rubella Virus/German Measles

Answer 26

– 1st infectious agent associated w/ congenital anomalies
 Sensitive period: first 5 weeks
 TRIAD – cataract, hearing defect, patent ductus arteriosus

Question 27

Cytomegalovirus

Answer 27

– most common viral infection at birth in US
 Accounts for highest number of US children who are born with or who develop long-term medical conditions each year
 Silent teratogen – most adults don’t know when they have it
 Often show no signs at birth but develop symptoms during first few years of life
 Result: deaf, vision impairment, mental disability, impaired liver function, poor growth

Question 28

Toxoplasm gondii

Answer 28

– protozoan; exposure via raw meat and cat feces
 Earlier the exposure  greater the risk
 Symptoms at birth : eye infections, enlarged liver/spleen, jaundice
 Later Effects: visions impairment, hearing loss, learning disabilities

Question 29

Treponema pallidum

Answer 29

– treatment before 16 weeks prevents birth anomalies
 Asserts its affects AFTER 16 weeks gestation
 Results: stillbirth/neonatal death, dental anomalies, deaf, mental retardation, skin/bone lesions, meningitis

Question 30

Methylmercury

Answer 30

 Mercury waste was dumped into bay and contaminated shellfish eaten by humans
 Adult Result: “itai-itae” (ouch-ouch) disease; convulsions, psychosis, coma, death
 Fetus: neurologic and behavioral disturbances around 6 months old
 **Theory: interferes with neuronal cell proliferation and migration

Question 31

Halogenated Aromatic Hydrocarbons

Answer 31

 PCDFs is main cause
 Premature, low birth weight, neonatal death, growth abnormalities, neurological damage, hyperpigmentation, chloracne, gum and dental disorders, sperm defects

Question 32

Fetal Alcohol Syndrome

Answer 32

– diagnosis that refers to a set of specific physical/mental birth defects stemming from in-utero alcohol exposure
 Mental retardation, small head, facial abnormalities, growth deficits, microcephaly, heart/liver/kidney defects, vision/hearing problems
 Mechanism: excessive cell death, decreased cell proliferation, altered cell migration, loss of cell adhesion, altered differentiation  all lead to DECREASED BRAIN MASS
 Most severe effects take place in 1st MONTH of pregnancy
 1:1000

Question 33

Fetal Alcohol Spectrum Disorders

Answer 33

• NOT a clinical diagnosis; refers to range of effects alcohol can have on fetus
   100% preventable; ~40,000 US babies annually (1:100 births)

Question 34

Thalidomide

Answer 34

– over counter sedative used to treat leprosy, cancer, blindness
 Reason for very rigorous restrictions on prescriptions nowadays  STEPS Program
 Sensitive period: weeks 4-5 during limb  inhibits tumor necrosis factor & angiogenesis
 Result: hands come out of shoulder (no limb formation = phocomelia)

Question 35

Retinoids

Answer 35

– treats severe cystic acne
 Defects: craniofacial, heart malformations, thymic, cleft palate, CNS, eye/ear
 Isotretinoin embryopathy – ears are upside down looking
 Mechanism: affects neural tube; critical period ~3-5 weeks; mainly effects HOX gene expression

Question 36

Phenocopy + Pathognomonic

Answer 36

 Phenocopy – multiple agents can cause same birth malformation
 Pathognomonic – agent causes a unique finding that you know a particular agent is what caused it
o Rarely the case with birth anomolies

Question 37

Testing Teratogens

Answer 37

o Animal developmental toxicity studies (rodent and non-rodent) – almost all drugs that are known human teratogens were ositive in animal studies
 Segment I Tests – tests animals before mating, through mating, up to implantation
• Searches for effects on fertilization and implantation
 Segment II Tests- implantation until hard palate closes
• Search for malformations/birth defects
 Segment III Tests – implantation and continue through birth/lactation/growth

Question 38

Prenatal Screening Methods

Answer 38

 Amniocentesis – 13-16 weeks; genetic/karyotypic analysis; 1:200 miscarriage
 Chorionic villus sampling-8-10 weeks; genetic/karytopic analysis; 1:100 miscarriage
 Ultrasound (NONINVASIVE) – observe/confirm malformations
• Nuchal translucency ultrasound – 9-13weeks looks for increased thickness of neural fold >3mm  correlates w/ trisomies 13/18/21; indicates lymphedema
 Maternal Serum (NONINVASIVE) – 13-16 weeks
• Look at levels AND ratios of alpha-fetoprotein (AFP), estriol, and beta-hCG
o High AFT = neural tube defects
o Emerging Technology – maternal blood has 6 fetal cells per ml that are distinguished by surface receptor sand methylation patterns  clone cells and perform karyotyping and genetic testing  promises high predictability without risk of miscarriage