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Developmental Hazards <ul><li>lead to abnormal development </li></ul><ul><li>causes: </li></ul><ul><ul><li>genetic  </li><...
Screening for birth defects <ul><li>Amniocentesis: </li></ul><ul><ul><li>16th week of pregnancy </li></ul></ul><ul><ul><li...
Screening, cont’d. <ul><li>Alpha fetoprotein test: </li></ul><ul><ul><li>protein made in fetal liver </li></ul></ul><ul><u...
Chorionic villus sampling <ul><li>8-10 weeks of pregnancy </li></ul><ul><li>catheter inserted thru vagina, cervix to uteru...
Genetic factors: numerical abnormalities <ul><li>Monosomy </li></ul><ul><li>conceptus lacks 1 copy of a particular chromos...
Turner Syndrome <ul><li>XO  </li></ul><ul><li>ovaries underdeveloped </li></ul><ul><li>short stature </li></ul><ul><li>web...
Numerical abnormalities: Trisomy <ul><li>conceptus has 3 of 1 type of chromosome instead of a pair </li></ul><ul><li>due t...
Single gene defects <ul><li>individual has appropriate number </li></ul><ul><li>one has structural abnormality </li></ul><...
Single gene defects, cont’d. <ul><li>dominantly inherited: achondroplasia </li></ul><ul><ul><li>inheritance of 1 copy of m...
Genetic mutations, cont’d.. <ul><li>autosomal recessive : cystic fibrosis </li></ul><ul><li>both parents are “carriers” (c...
Extrinsic disruptions of dev. <ul><li>abnormalities can arise due to exogenous agents ( disruptions ) </li></ul><ul><li>ag...
Teratogenic agents: Retinoic acid <ul><li>major source of teratogens: chemicals in environment </li></ul><ul><li>some occu...
Retinoic acid, cont’d. <ul><li>anomalies similar to those observed in expts. with mice </li></ul><ul><li>effects probably ...
Thalidomide <ul><li>sedative; used for morning sickness </li></ul><ul><li>caused rare syndrome of congenital anomalies: </...
Thalidomide, cont’d. <ul><li>targets of thalidomide: </li></ul><ul><ul><li>downregulation of cell adhesion molecules in li...
Alcohol <ul><li>most devastating teratogen in our society </li></ul><ul><li>causes fetal alcohol syndrome </li></ul><ul><l...
Alcohol, cont’d. <ul><li>L1 mutations in humans > mental retardation </li></ul><ul><li>induces cell death in frontonasal p...
Environmental estrogens? <ul><li>xenoestrogens> weak estrogens ;androgen antagonists </li></ul><ul><li>xenoestrogens can i...
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Developmental Hazards

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Transcript of "Developmental Hazards"

  1. 1. Developmental Hazards <ul><li>lead to abnormal development </li></ul><ul><li>causes: </li></ul><ul><ul><li>genetic </li></ul></ul><ul><ul><li>environmental factors </li></ul></ul><ul><ul><ul><li>bacteria, viruses </li></ul></ul></ul><ul><ul><ul><li>drugs ingested by mother </li></ul></ul></ul><ul><ul><ul><li>radiation </li></ul></ul></ul><ul><li>estimated causes: </li></ul><ul><ul><li>6% due to chromosomal abnormalities </li></ul></ul><ul><ul><li>7% due to environmental factors </li></ul></ul><ul><ul><li>8% due to single gene defects </li></ul></ul><ul><ul><li>25% due to multifactorial inheritance </li></ul></ul><ul><ul><li>54% due to unidentified factors </li></ul></ul>
  2. 2. Screening for birth defects <ul><li>Amniocentesis: </li></ul><ul><ul><li>16th week of pregnancy </li></ul></ul><ul><ul><li>women over age 34 (or with history of heritable genetic disorders) </li></ul></ul><ul><ul><li>long needle pass thru abdominal wall to sample amniotic fluid </li></ul></ul><ul><ul><li>cells in fluid are cultured </li></ul></ul><ul><ul><li>in ~4 weeks, cells are examined and screened for genetic disorders (~40) </li></ul></ul><ul><ul><li>risks: 1.5% miscarriage rate </li></ul></ul><ul><ul><li>disadvantage: waiting period </li></ul></ul>
  3. 3. Screening, cont’d. <ul><li>Alpha fetoprotein test: </li></ul><ul><ul><li>protein made in fetal liver </li></ul></ul><ul><ul><li>high conc. in fetal blood, CSF </li></ul></ul><ul><ul><li>also detected in mother’s blood </li></ul></ul><ul><ul><li>high levels may indicate neural tube defect; low may indicate trisomy 21 </li></ul></ul><ul><li>Ultrasound: </li></ul><ul><ul><li>sound waves applied to abdomen; dense tissues reflect waves and are detected by receiver </li></ul></ul><ul><ul><li>size, dimension assessed </li></ul></ul><ul><ul><li>heart rate detected </li></ul></ul><ul><ul><li>presence of twins identified </li></ul></ul><ul><ul><li>assess organogenesis </li></ul></ul>
  4. 4. Chorionic villus sampling <ul><li>8-10 weeks of pregnancy </li></ul><ul><li>catheter inserted thru vagina, cervix to uterus </li></ul><ul><li>chorionic cells removed from placenta and analyzed </li></ul><ul><li>advantage: can be performed earlier than amnio; results obtained in 4-24 hours </li></ul><ul><li>disadvantages: risk of miscarriage; risk of improperly formed fingers or toes (6-11 times compared to amnio) </li></ul>
  5. 5. Genetic factors: numerical abnormalities <ul><li>Monosomy </li></ul><ul><li>conceptus lacks 1 copy of a particular chromosome </li></ul><ul><li>if it’s is an autosome, embryo usually aborts </li></ul><ul><li>can survive with 1 sex chrom </li></ul>
  6. 6. Turner Syndrome <ul><li>XO </li></ul><ul><li>ovaries underdeveloped </li></ul><ul><li>short stature </li></ul><ul><li>webbed neck </li></ul><ul><li>broad chest </li></ul><ul><li>cardio., kidney disorders </li></ul><ul><li>possible mental retardation </li></ul>
  7. 7. Numerical abnormalities: Trisomy <ul><li>conceptus has 3 of 1 type of chromosome instead of a pair </li></ul><ul><li>due to nondisjunction </li></ul><ul><li>types of autosomal trisomy: </li></ul><ul><li>trisomy 18; trisomy 13 > fatal during infancy </li></ul><ul><li>tris. 21 (Down Syndrome) </li></ul><ul><li>trisomy of sex chromosomes > Klinefelter syndrome (XXY): </li></ul><ul><ul><li>male phenotype </li></ul></ul><ul><ul><li>small testes (no sperm) </li></ul></ul><ul><ul><li>long limbs </li></ul></ul><ul><ul><li>rarely detected until puberty </li></ul></ul><ul><ul><li>mental retardation </li></ul></ul>
  8. 8. Single gene defects <ul><li>individual has appropriate number </li></ul><ul><li>one has structural abnormality </li></ul><ul><li>usually induced by environmental factor </li></ul><ul><li>phenotype depends on particular chromosome involved </li></ul><ul><li>can involve deletion or duplication </li></ul>
  9. 9. Single gene defects, cont’d. <ul><li>dominantly inherited: achondroplasia </li></ul><ul><ul><li>inheritance of 1 copy of mutant gene results in syndrome </li></ul></ul><ul><ul><li>short limbs </li></ul></ul><ul><ul><li>large head </li></ul></ul><ul><ul><li>hump-back; protrusion of abdomen </li></ul></ul>
  10. 10. Genetic mutations, cont’d.. <ul><li>autosomal recessive : cystic fibrosis </li></ul><ul><li>both parents are “carriers” (chrom. 7) </li></ul><ul><li>mucus in lungs and digestive tract is particularly thick and viscous </li></ul><ul><li>previously: death in childhood due to recurrent lung infections </li></ul><ul><li>new hope: gene therapy </li></ul><ul><li>1 in 20 caucasians is a carrier </li></ul><ul><li>1 in 2,000 children affected </li></ul>
  11. 11. Extrinsic disruptions of dev. <ul><li>abnormalities can arise due to exogenous agents ( disruptions ) </li></ul><ul><li>agents = teratogens </li></ul><ul><li>chemicals, viruses, radiation </li></ul><ul><li>often exert effects during critical periods of dev. </li></ul><ul><li>critical period = time of growth, formation </li></ul><ul><li>different organs have different critical pds.: </li></ul><ul><ul><li>heart > 3-4 weeks </li></ul></ul><ul><ul><li>external genitalia > 8-9 weeks </li></ul></ul><ul><ul><li>brain, skeleton > week 3 - end of pregnancy </li></ul></ul><ul><li>days 15-60 critical for most organ systems </li></ul>
  12. 12. Teratogenic agents: Retinoic acid <ul><li>major source of teratogens: chemicals in environment </li></ul><ul><li>some occur naturally; most are artificially introduced </li></ul><ul><li>excess retinoic acid can act as teratogen </li></ul><ul><li>reported cases: </li></ul><ul><ul><li>RA taken by women of childbearing age for treating severe cystic acne </li></ul></ul><ul><ul><li>study of 59 fetuses > 26 normal, 12 aborted spontaneously, 21 born with anomalies </li></ul></ul><ul><ul><li>anomalies: absent/defective ears and jaws, cleft palate, CNS abnormalities, aortic arch abnorm. </li></ul></ul>
  13. 13. Retinoic acid, cont’d. <ul><li>anomalies similar to those observed in expts. with mice </li></ul><ul><li>effects probably due to altered expression of Hox genes (directs neural crest cell migration): </li></ul><ul><ul><li>RA binds to cranial neural crest cells </li></ul></ul><ul><ul><li>arrests proliferation, migration </li></ul></ul><ul><li>teratogenic effect confined to “window period” (8-10 days in mice; 20-35 days in humans) </li></ul>
  14. 14. Thalidomide <ul><li>sedative; used for morning sickness </li></ul><ul><li>caused rare syndrome of congenital anomalies: </li></ul><ul><ul><li>phocomelia (long bones of limbs absent or deficient) </li></ul></ul><ul><ul><li>heart defects </li></ul></ul><ul><ul><li>absence of external ears </li></ul></ul><ul><ul><li>malformed intestines </li></ul></ul><ul><li>only one pill necessary to cause limb malformations! </li></ul><ul><li>illustrated limits of animal studies </li></ul>
  15. 15. Thalidomide, cont’d. <ul><li>targets of thalidomide: </li></ul><ul><ul><li>downregulation of cell adhesion molecules in limb bud? </li></ul></ul><ul><ul><li>decreased number of neurons in dorsal root ganglion </li></ul></ul>
  16. 16. Alcohol <ul><li>most devastating teratogen in our society </li></ul><ul><li>causes fetal alcohol syndrome </li></ul><ul><li>characteristics: </li></ul><ul><ul><li>small head size </li></ul></ul><ul><ul><li>indistinct philtrum, narrow upper lip, low nose bridge </li></ul></ul><ul><ul><li>small brain </li></ul></ul><ul><li>affects 1 out of every 500-750 children </li></ul><ul><li>mouse model developed w/ similar abnormalities </li></ul>
  17. 17. Alcohol, cont’d. <ul><li>L1 mutations in humans > mental retardation </li></ul><ul><li>induces cell death in frontonasal process, impairs neural crest migration </li></ul><ul><li>prevents L1 (CAM) from holding cells together </li></ul>
  18. 18. Environmental estrogens? <ul><li>xenoestrogens> weak estrogens ;androgen antagonists </li></ul><ul><li>xenoestrogens can interfere with development </li></ul><ul><li>examples: </li></ul><ul><ul><li>DDT > 90% decline in birthrate of alligators in Florida lake; decrease in masculiniz. of ext. genitalia </li></ul></ul><ul><ul><li>dioxin > reduces sperm counts in mice; smaller testes </li></ul></ul><ul><li>role in breast cancer? decreased sperm count? other birth defects? </li></ul><ul><li>others: polystyrene plastics; household cleaners </li></ul>

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