development in health and disease

Question 1

how many embryos implant in the uterus

Answer 1

fertility studies that less than half of cleavage-stage embryos implant in the uterus
- only about 40% of implanted embryos survive to term

Question 2

birth defect rate

Answer 2

about 2.5% of babies are born with a recognizable birth defect

Question 3

what are the three major pathways leading to abnormal development

Answer 3

(1) genetic mutations
(2) environmental mechanism
(3) stochastic events

Question 4

pleiotropic

Answer 4

single genes that cause multiple defects when mutant

Question 5

mosaic pleitropy

Answer 5

occurs when a gene is required in multiple cells/tissues for their development

Question 6

relational pleiotropy

Answer 6

occurs when a gene is required in one cell type or tissue, but defects cause developmental abnormalities in other tissues

Question 7

genetic heterogeneity

Answer 7

when defects in different genes cause the same phenotype

Question 8

phenotypic heterogeneity

Answer 8

when a single gene defect causes different phenotypes in different individuals, it is called phenotypic heterogeneity

Question 9

teratogens

Answer 9

exogenous (external) agents that cause developmental defects
- drugs, chemicals, microorganism
- cause the most damage during the embryonic period

Question 10

Thalidomide

Answer 10

given to pregnant women to relieve nausea, causes ear and limb defects

Question 11

embryonic v fetal periods

Answer 11

EMBRYONIC ; most development occurs here, 3-8 weeks, the susceptibility phase–> teratogens cause the most damage during this period

FETAL; primarily a growth period

Question 12

largest class of teratogens

Answer 12

-drugs and chemicals

Question 13

cyclopamine

Answer 13

-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

Question 14

nicotine

Answer 14

from tobacco smoke impairs lungs and brain development

Question 15

zika virus

Answer 15

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

Question 16

zebrafish

Answer 16

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

Question 17

alcohol

Answer 17

alcohol is the most common teratogen affecting newborn human babies

Question 18

fetal alchohol syndrome

Answer 18

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

Question 19

fetal alchohol spectrum disorder

Answer 19

-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

Question 20

Mouse as a model for FAS

Answer 20

• 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

Question 21

retinoid acid can be teratogenic

Answer 21

• 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

Question 22

Some teratogens alter physiological endocrine signaling

Answer 22

• 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

Question 23

endocrine disruptors

Answer 23

• 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

Question 24

DES and Wnt signaling inhibition

Answer 24

• 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

Question 25

Bisphenol A

Answer 25

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

Question 26

Bisphenol effects

Answer 26

• 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

Question 27

BPA exposure in utero may predispose women to breast cancer later in life

Answer 27

• 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

Question 28

Endocrine disruptors cause epigenetic changes that are retained over generations

Answer 28

• 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