Developmental Hazards

1
Developmental Hazards

• lead to abnormal development
• causes
• genetic
• environmental factors
• bacteria, viruses
• drugs ingested by mother
• radiation
• estimated causes
• 6 due to chromosomal abnormalities
• 7 due to environmental factors
• 8 due to single gene defects
• 25 due to multifactorial inheritance
• 54 due to unidentified factors

2
Screening for birth defects

• Amniocentesis
• 16th week of pregnancy
• women over age 34 (or with history of heritable
  genetic disorders)
• long needle pass thru abdominal wall to sample
  amniotic fluid
• cells in fluid are cultured
• in 4 weeks, cells are examined and screened for
  genetic disorders (40)
• risks 1.5 miscarriage rate
• disadvantage waiting period

3
Screening, contd.

• Alpha fetoprotein test
• protein made in fetal liver
• high conc. in fetal blood, CSF
• also detected in mothers blood
• high levels may indicate neural tube defect low
  may indicate trisomy 21
• Ultrasound
• sound waves applied to abdomen dense tissues
  reflect waves and are detected by receiver
• size, dimension assessed
• heart rate detected
• presence of twins identified
• assess organogenesis

4
Chorionic villus sampling

• 8-10 weeks of pregnancy
• catheter inserted thru vagina, cervix to uterus
• chorionic cells removed from placenta and
  analyzed
• advantage can be performed earlier than amnio
  results obtained in 4-24 hours
• disadvantages risk of miscarriage risk of
  improperly formed fingers or toes (6-11 times
  compared to amnio)

5
Genetic factors numerical abnormalities

• Monosomy
• conceptus lacks 1 copy of a particular chromosome
• if its is an autosome, embryo usually aborts
• can survive with 1 sex chrom

6
Turner Syndrome

• XO
• ovaries underdeveloped
• short stature
• webbed neck
• broad chest
• cardio., kidney disorders
• possible mental retardation

7
Numerical abnormalities Trisomy

• conceptus has 3 of 1 type of chromosome instead
  of a pair
• due to nondisjunction
• types of autosomal trisomy
• trisomy 18 trisomy 13 gt fatal during infancy
• tris. 21 (Down Syndrome)
• trisomy of sex chromosomes gt Klinefelter syndrome
  (XXY)
• male phenotype
• small testes (no sperm)
• long limbs
• rarely detected until puberty
• mental retardation

8
Single gene defects

• individual has appropriate number
• one has structural abnormality
• usually induced by environmental factor
• phenotype depends on particular chromosome
  involved
• can involve deletion or duplication

9
Single gene defects, contd.

• dominantly inherited achondroplasia
• inheritance of 1 copy of mutant gene results in
  syndrome
• short limbs
• large head
• hump-back protrusion of abdomen

10
Genetic mutations, contd..

• autosomal recessive cystic fibrosis
• both parents are carriers (chrom. 7)
• mucus in lungs and digestive tract is
  particularly thick and viscous
• previously death in childhood due to recurrent
  lung infections
• new hope gene therapy
• 1 in 20 caucasians is a carrier
• 1 in 2,000 children affected

11
Extrinsic disruptions of dev.

• abnormalities can arise due to exogenous agents
  (disruptions)
• agents teratogens
• chemicals, viruses, radiation
• often exert effects during critical periods of
  dev.
• critical period time of growth, formation
• different organs have different critical pds.
• heart gt 3-4 weeks
• external genitalia gt 8-9 weeks
• brain, skeleton gt week 3 - end of pregnancy
• days 15-60 critical for most organ systems

12
Teratogenic agents Retinoic acid

• major source of teratogens chemicals in
  environment
• some occur naturally most are artificially
  introduced
• excess retinoic acid can act as teratogen
• reported cases
• RA taken by women of childbearing age for
  treating severe cystic acne
• study of 59 fetuses gt 26 normal, 12 aborted
  spontaneously, 21 born with anomalies
• anomalies absent/defective ears and jaws, cleft
  palate, CNS abnormalities, aortic arch abnorm.

13
Retinoic acid, contd.

• anomalies similar to those observed in expts.
  with mice
• effects probably due to altered expression of Hox
  genes (directs neural crest cell migration)
• RA binds to cranial neural crest cells
• arrests proliferation, migration
• teratogenic effect confined to window period
  (8-10 days in mice 20-35 days in humans)

14
Thalidomide

• sedative used for morning sickness
• caused rare syndrome of congenital anomalies
• phocomelia (long bones of limbs absent or
  deficient)
• heart defects
• absence of external ears
• malformed intestines
• only one pill necessary to cause limb
  malformations!
• illustrated limits of animal studies

15
Thalidomide, contd.

• targets of thalidomide
• downregulation of cell adhesion molecules in limb
  bud?
• decreased number of neurons in dorsal root
  ganglion

16
Alcohol

• most devastating teratogen in our society
• causes fetal alcohol syndrome
• characteristics
• small head size
• indistinct philtrum, narrow upper lip, low nose
  bridge
• small brain
• affects 1 out of every 500-750 children
• mouse model developed w/ similar abnormalities

17
Alcohol, contd.

• L1 mutations in humans gt mental retardation
• induces cell death in frontonasal process,
  impairs neural crest migration
• prevents L1 (CAM) from holding cells together

18
Environmental estrogens?

• xenoestrogensgt weak estrogens androgen
  antagonists
• xenoestrogens can interfere with development
• examples
• DDT gt 90 decline in birthrate of alligators in
  Florida lake decrease in masculiniz. of ext.
  genitalia
• dioxin gt reduces sperm counts in mice smaller
  testes
• role in breast cancer? decreased sperm count?
  other birth defects?
• others polystyrene plastics household cleaners