development in health and disease Flashcards
how many embryos implant in the uterus
fertility studies that less than half of cleavage-stage embryos implant in the uterus
- only about 40% of implanted embryos survive to term
birth defect rate
about 2.5% of babies are born with a recognizable birth defect
what are the three major pathways leading to abnormal development
(1) genetic mutations
(2) environmental mechanism
(3) stochastic events
pleiotropic
single genes that cause multiple defects when mutant
mosaic pleitropy
occurs when a gene is required in multiple cells/tissues for their development
relational pleiotropy
occurs when a gene is required in one cell type or tissue, but defects cause developmental abnormalities in other tissues
genetic heterogeneity
when defects in different genes cause the same phenotype
phenotypic heterogeneity
when a single gene defect causes different phenotypes in different individuals, it is called phenotypic heterogeneity
teratogens
exogenous (external) agents that cause developmental defects
- drugs, chemicals, microorganism
- cause the most damage during the embryonic period
Thalidomide
given to pregnant women to relieve nausea, causes ear and limb defects
embryonic v fetal periods
EMBRYONIC ; most development occurs here, 3-8 weeks, the susceptibility phase–> teratogens cause the most damage during this period
FETAL; primarily a growth period
largest class of teratogens
-drugs and chemicals
cyclopamine
-plant derivative
-causes cyclopia (a rare congenital disorder characterized by facial abnormalities. In this condition, the orbits of the eye are not properly divided into two cavities so that they can be seen either as a single eye field or two bilateral fields that are very close to each other) by blocking Shh signaling
nicotine
from tobacco smoke impairs lungs and brain development
zika virus
has been shown to infect and kill fetal brain neurons, leading to smaller brains and heads
- appears to be caused by viral activation of regulatory microRNAs, which activate cell death pathways and reduce stem cell proliferation
zebrafish
zebrafish development is strongly affected by exposer to water-soluble compounds originating from the Deepwater Horizon oil spill; these developmental defects are attributed to alteration of neural crest migration
alcohol
alcohol is the most common teratogen affecting newborn human babies
fetal alchohol syndrome
babies born with FAS exhibit small head size and several facial abnormalities
- occurs in 1/650 children in the US
- often exhibit reduced IQ and learning deficiencies
- represents a subrange as its a spectrum disorder
fetal alchohol spectrum disorder
-manu individuals with FASD exhibit learning disabilities or behavioral abnormalities but lack FAS-associated gross defects
-the timing and magnitude of alcohol exposure likely contributes to the spectrum of FASD phenotypes
Mouse as a model for FAS
- in mice, fetal alcohol exposure causes poor development of the nose and upper lip, and defects in neural tube closure and forebrain development
- one major effect is on the migration and survival of neural crest cells that form cranial and facial features
-alcohol likely has a variety of effects on cells
-alcohol is known to cause an increase in oxidants, which can kill cells - alcohol also down regulates Shh expression and the adhesion molecule L1, both of which have prominent roles in head and face development
retinoid acid can be teratogenic
- retinoid acid, is a critical regulator important for A/P axis development
- used as topic medication for acne despite knowing its a teratogen in animals –> that’s why warning against use while pregnant
- inadvertent exposure to RA in women leads to spontaneous abortion or babies born with craniofacial defects, associated with cranial neural crest
- exposure to high RA creates phenotypes that mimic RA loss, presumably to strong negative feedback that degrades RA
- glyphosphate-based herbicides are becoming more prevalent in our food chain, and these herbicides increase RA signaling
- glyphosate elicits cranial neural crest defects in Xenopus embryos and reduces Shh expression in chick craniofacial mesoderm
Some teratogens alter physiological endocrine signaling
- can act as an endocrine disruptor
- diethylstilbestrol (DES) is a drug given to “ease” pregnancy but it can interfere with female reproductive tract development, leading to infertility and other reproductive problems such as cervical tissue growth in the upper coochie and sometimes cancerous growth
- in mice, this alters Hoxa gene expression in mullein ducts and changes part of uterus into oviduct
endocrine disruptors
- chemicals that perturb endocrine signaling are endocrine disruptors
- they can…
(a) mimic natural hormones
(b) antagonize hormones
(c) alter the synthesis, elimination, or transport of hormones
(d) increase sensitivity to hormones
DES and Wnt signaling inhibition
- DES mimics the hormone estradiol and binds to the estrogen receptor
- this binding leads to inhibition of Wnt7a expression by genital tract epithelium
- Wnt7a normally promotes Hox gene function as well as Wnt5a expression by underlying mesenchymal cells
- Wnt5a is important to reinforce Wnt7a expression and promote normal development
Bisphenol A
BPA was synthesized as hormone analog that mimics estrogen
- best known as a component of food can liners and water bottles that leaches into the food and water
Bisphenol effects
- male sex reversal in frogs
- chromosome abnormalities
- increased rate of miscarriage
- abnormal fetal gonad development, prostate enlargement, low sperm count, behavioral changes
- reduced female fertility after exposure in utero
- abnormal uterine, vaginal, breast, and ovarian ducts
- placental abnormalities with reduced fetal growth
- interferes with methylation-based imprinting
BPA exposure in utero may predispose women to breast cancer later in life
- BPA exposure causes increased proliferation and duct growth compared to controls
- animals exposed to BPA get cancer more often than those not exposed
- animals exposed to BPA get cancer more often when exposed to secondary carcinogens
Endocrine disruptors cause epigenetic changes that are retained over generations
- F1 exposure in utero to endocrine disruptors causes testicular dysgenesis syndrome
- this syndrome can be inserted through at least three additional generations when looking at testicular morphology
- these changes have been associated with methylation pattern changes at more than 100 different gene promoters in sperm-producing cells
