Chapter 23: Development in Health and Disease

• How some agents cause disruptions in human fetal development: environmental agents

  • Zika virus
  • Water-soluble crude oil
  • Effects of alcohol on fetal brains
  • DES
  • BPA
• Some agents thought to cause disruptions in human fetal development

  alcohol, diethylstilbestrol (DES), Zika virus
• Karyotype/ing


  is the process by which photographs of chromosomes are taken in order to determine the chromosome complement of an individual, including the number of chromosomes and any abnormalities

  
• Karyotype/ing

  Humans (usually) have 46 chromosomes

  • These are arranged in 23 pairs of homologous chromosomes
  • Human chromosomes are designated 1-22, plus the sex chromosomes X/Y, XX-Female, Y-Male

  
• causes of down syndrome or Trisomy 21

  extra chromosome on pair 21
• Possible mechanism for Zika virus-induced cell death 

  (A)Zika infection up regulates the miR-9 microRNA, which is associated with cell death and decreased neuron formation. 

  (B) Subsequent down regulation of GDNF, a neural growth factor that is a target of miR-9. 
• Possible mechanism for Zika virus-induced cell death 

  Zika infection

  ↓

  miR-9 microRNA

  ↓///

  GDNF (X)

  ↓

  Degradation of Neural growth factor
• Possible mechanism for Zika virus-induced cell death 

  Research data shows, decrease in the cortical neurons in the Zika virus-infected brains. 

  Blue fluorescence is from DAPI, which stains DNA, and green fluorescence is from Tbr1, a marker of newborn neurons. 
• Water-soluble crude oil components from the Deepwater Horizon oil spill are teratogenic in zebrafish


  Compared with normal zebrafish of the same age, zebrafish embryos exposed to oil spill components produced larvae with severe developmental anomalies, 

  • including reduction in the size of head, gill, and thoracic cartilages (blue staining) associated with cranial neural crest cell migration.
• Effects of alcohol on fetal brains

  The brain from the infant with FAS is smaller, and the pattern of convolutions is obscured by glial cells that have migrated over the top of the brain...

  glial cells are supposed to be in interior not the exterior
• Effects of alcohol on fetal brains - Abnormalities of the corpus callosum seen by diffusion tensor imaging of myelinated neurons. 


  FAS - Neurons did not project through the posterior regions of the brain into the cortex of the parietal and temporal lobes.

  Normal - neurons would normally project through the posterior regions of the brain into the cortex of the parietal and temporal lobes.
• Alcohol-induced craniofacial and brain abnormalities in mice

  (B)Alcohol exposer caused the anterior neural tube failed to close, resulting in exencephaly, a condition in which the brain tissue is exposed to the exterior. Later in development, the exposed brain tissue will erode away, resulting in anencephaly.

   

  (C) Prenatal alcohol exposure can also affect facial development, resulting in a small nose and an abnormal upper lip (open arrow). These facial features are present in fetal alcohol syndrome.

  
• Alcohol-induced craniofacial and brain abnormalities in mice (3D-MRI)

  In the alcohol-exposed specimen, the olfactory bulbs (pink) are absent and the cerebral hemispheres (red) are abnormally united in the midline.

  
• Cell death caused by alcohol-induced superoxide radicals

  (A-normal) Head region of control day-9 mouse embryo. 

  (B-FAS) Head region of alcohol-treated embryo, showing areas of cell death (arrowheads). 

  (C-Rescue) Head region of embryo treated with both alcohol and superoxide dismutase, an inhibitor of superoxide radicals. The enzyme prevents the alcohol-induced cell death.

  
• Hoxa gene expression in the reproductive system of a normal embryonic female mouse

  • Hoxa9 expression extends throughout the uterus and through much of the presumptive oviduct.
  • Hoxa10 expression has a sharp anterior border at the transition between the presumptive uterus and the oviduct. 
  • Hoxa11 has the same anterior border as Hoxa10, but its expression diminishes closer to the cervix. 
  • Hoxa13 expression is found only in the cervix and upper vagina.

  
• In situ hybridization of a Hoxa10 probe shows that DES exposure represses Hoxa10


  (A) Normal embryonic female mice show Hoxa10 expression from the boundary of the cervix through the uterus primordium and most of the oviduct (cvx, cervix; md, Müllerian duct; ov, ovary). 

  (B) In mice exposed prenatally to DES, this expression is severely repressed.

  
• In situ hybridization of a Hoxa10 probe shows that DES exposure represses Hoxa10


  (C) In control female mice at 5 days after birth (when reproductive tissues are still forming), a section through the uterus shows abundant expression of Hoxa10 in the uterine mesenchyme. 

  (D) In female mice that are given high doses of DES 5 days after birth, Hoxa10 expression in the uterine mesenchyme is almost completely suppressed.
• Bisphenol A induces altered mammary gland development in rhesus monkeys. 


  Mammary gland from a fetus exposed in utero to BPA. Twice as many buds (incipient branches) are seen in the BPA-exposed tissue. 
• Bisphenol A induces altered mammary gland development


  The percentage of mouse mammary glands showing intraductal hyperplasia (a cancer-prone state) is significantly increased at postnatal day (PND) 50 in BPA-exposed animals.
• Genital anomalies can occur in women exposed to DES in utero 

  • adenosis of cervix and vagina (abnormal tissue)
  • tissue "hood" of cervix
  • cervial dysplasia (precancerous growth)
• Misregulation of Müllerian duct morphogenesis by DES 


  DES inhibits Wnt7a leading to repression of all Hoxa leading to improper cell specification