Teratology: Genetic and Developmental Toxicity

• Teratology


  The study of causes and patterns of abnormal development
• Teratology


  • Focuses on congenital abnormalities and birth defects
  • Aims to understand abnormalities and prevent them
  • Guides safer pregnancy practices and public health policies
• Teratogens


  Agents causing developmental anomalies prenatally
• Congenital malformations

  Structural defects present at birth
• Major anomalies


  Congenital defects incompatible with survival or life-threatening
• 3% of live-born infants have a major anomaly
• Single minor anomalies present in 14% of newborns
• Types of developmental abnormalities

  • Malformation
  • Disruption
  • Deformation
  • Dysplasia
  • Syndrome
• Mechanisms of teratogenesis


  • Physical factors (radiation, hyperthermia)
  • Chemical agents (medications, drugs, pollutants)
  • Genetic predispositions
• Teratogens disrupt normal developmental pathways


  Through interference with cell signalling, stress responses, and direct damage to genetic material
• Teratogens can cause epigenetic modifications that alter gene expression regulation
• Dose-response relationships and genetic variability

  • Severity depends on dose and duration of exposure
  • Genetic variability affects susceptibility to teratogens

  
• Species-specific responses

  • Response varies between species, challenging extrapolation of animal study findings
• Wilson's principles of teratology

  • Susceptibility depends on genotype and environmental factors
  • Susceptibility varies with developmental stage at time of exposure
  • Teratogens act on developing cells and tissues in specific ways
  • Adverse influences depend on nature of developing tissues
  • Manifestations include death, malformation, growth retardation, and functional defect
  • Manifestations increase in frequency and severity with dosage
  • Teratogens act by various mechanisms
• Types of genetic damage


  • Mutations
  • Chromosomal aberrations
  • Impaired DNA repair mechanisms
• Methods for testing genetic toxicity

  • In vitro methods
  • In vivo methods
  • Biomarkers (e.g. Ames test)
• Fetal Alcohol Syndrome (FAS)


  Serious condition from prenatal alcohol exposure
• Fetal Alcohol Syndrome (FAS)


  • Behavioral issues like social problems, anxiety, addictive behaviors
  • Primary cause is alcohol consumption during pregnancy
  • Alcohol crosses placenta and affects fetal development
  • Risk increases with alcohol amount and frequency
  • No cure, but early intervention improves outcomes
• Fetal Alcohol Effects (FAE)


  Term for children exposed to alcohol in utero with some FAS symptoms but not meeting all criteria
• Fetal Alcohol Spectrum Disorders (FASD)


  Current term encompassing range of effects from prenatal alcohol exposure, including FAS, partial FAS, ARND, and ARBD
• Partial Fetal Alcohol Syndrome (pFAS)

  Some signs and symptoms of FAS, including growth deficiencies and facial abnormalities, but does not meet full FAS criteria
• Alcohol-Related Neurodevelopmental Disorder (ARND)

  Primarily cognitive and behavioral problems like learning disabilities, impulse control issues, memory and attention problems, without physical features of FAS
• Alcohol-Related Birth Defects (ARBD)

  Physical defects in organs like heart, kidneys, bones, resulting from prenatal alcohol exposure
• Diagnosis and intervention for FASD


  • Comprehensive evaluation required, including medical, developmental, and sometimes genetic assessments
  • Early diagnosis and intervention crucial for symptom management and improved outcomes
• Topical medications can also be teratogenic
• Folic acid


  A crucial B vitamin essential for DNA synthesis, repair, and methylation
• Folic acid deficiency


  Leads to health issues and genetic/developmental toxicity, especially in pregnancy
• Gene silencing


  Inappropriate silencing of genes, a mechanism of teratogenesis

  
• Folic acid

  Converts homocysteine to methionine, producing S-adenosylmethionine (SAM)
• Developmental defects linked to folic acid deficiency

  • Neural tube defects (spina bifida, anencephaly)
  • Congenital heart defects
  • Oral facial clefts (cleft lip and palate)
  • Low birth weight and preterm birth

  
• Folic acid intake and supplementation

  • Consume folate-rich foods like leafy greens, fruits, legumes, and fortified foods
  • People who can become pregnant should take daily folic acid supplements, especially pre-conception and during first trimester
  • Many countries have mandatory folic acid fortification of certain foods
• Thalidomide

  A drug with a history of causing severe birth defects

  
• Oral Facial Clefts


  Insufficient folic acid associated with higher risk of cleft lip and palate in newborns

  
• Low Birth Weight and Preterm Birth

  Adequate folate levels reduce risk of delivering low birth weight or preterm infants
• Dietary intake of folic acid

  • Consume folate-rich foods: leafy greens, fruits, legumes, fortified foods
• Folic acid supplementation


  • People who can become pregnant: Daily folic acid supplement, particularly pre-conception and during the first trimester
• Public health initiatives: Mandatory folic acid fortification of certain foods (e.g., bread, cereals) in many countries
• Thalidomide


  Marketed as a non-addictive alternative to barbiturates
• Thalidomide


  Initial studies emphasized safety

  
• Regulatory requirements in the 1950s

  Lacked comprehensive pre-market safety testing