Embryology and Teratology Flashcards
teratogenesis
production of congenital birth defects in embryo or fetus
- malformations–> could be internal or external >200 different congenital abnormalites
leading cause of infant mortality in NA, why?
birth defects
- partly due to an improvements in obstetrical care so that other death rates are decreasing
- environmental toxins and drugs
malfunctions
non-reversible morphological defects present at birth
% of birth defects in live births
2-3%
birth defects count for __ of all deaths of children below 1 yr
more than 1/3, after the age of 2 the incident of BD goes up bc we discover BD in organs ( symptoms show later)
- 1/4 of deaths in children under 15 ( this is significant!!)
largest cause of birth defects
unknown causes (65-75%)
what % of BD is caused by known genetic causes
20-25%
other causes of BD
metabolic, infection, drug/chemical, chromosome aberration
less than ___ % of pregnancies result in a healthy, normal infant
50% –> including miscarriages
- majority is post-implantation loss (31%)
largest contributor to the 50% incident of unsuccessful pregnancy
post-implantation loss
- if uterus is not ready to receive the ovum, then the fertilized egg is shred
Each trimester has?
Particular nutritional needs and risk for development
organogenesis happens when? what is it?
- when is the organogenic period? what is it
organogenesis = 3-8 weeks after fertilization, which is the time when division and differentiation of the ovum occurs to form tissue and organs
- organogenic period 17-57 days post fertilization–> critical period with maximal cell division and differentiation ( hyperplasia - 17-8 weeks- time of max vulnerability for teratogenic effects)
teratogenic period
the organogenesis period may also be called the teratogenic period bc it is the most susceptible to birth defects
When does the neural tube close
within 28 days ( most women don’t know pregnant yet)
period of max cell division and differentiation
the organogenic period
- critical period ( organization, differentiating and organogenesis take place)
at the end of the organogenic period
the development the major fetal structures should be complete
hyperplasia
increase in cell number, happen 17 days to 8 weeks after fertilization, max time of vulnerability for teratogenic effects
what occurs day 17- 8 weeks
hyperplasia, could also be the organogenic period
max vulnerability to teratogenic effects
hyperplasia
after 8 weeks
hypertrophy (increase in cell size )
hyperplasia stops after 8 weeks, and now cells get bigger and form into more specialized organs and biochemical structures ( hyperplasia is the base foundation - building out of nothing - like. house- increasing cell size, after 8 weeks this is done and just need to add to the base structure- paint, add drywall –> increase cell size and improve function
higher risk for development of organ or biochemical malfunctions
during hypertrophy stage of development ( after 8 weeks )
pre-implantation –> before 1 week
increase in cell number but not cell size
- exposure to toxins has no effect or only a slight decrease in growth–> due to the fact that the fate of cells is not yet determined (pluropotency)–> they have great restorative capacity and low susceptibility to teratogens
interference with hyperplasia
permenant reduction in cell number which cannot be fixed later ( however before 1 week, exposure to toxins has little to no effect, bc cells are all pluripotent and could just generate, also more protection at this stage - not even in uterus yet
blastogenesis
zygote begins to cleave, increase cell number, producing the morula, then a cavity forms in the center of the morula, the entire structure is now called a blastocysts
blastocysts contain which two cell types
embryoblasts (inside) and trophoblasts (outside)
trophoblast cells secrete proteolytic enzymes which erode the epithelial lining, and allow for fluid and nutrients to be absorbed during the first days before placenta provides food for cells, these trophoblast cells are what well soon form to become the placenta
for the first 20-25 days what provides food for the embryo? what is this phase called? how does food enter?
histiotrophic nutrition phase–> fluid and nutrients absorbed by phagocytosis
histiotrophic phase
the first 20-25 days before the placenta has formed and fluid and nutrients are absorbed by trophoblast cells through phagocytosis to provide nutrients to the blastocyst
where do nutrients come from in the histiotrophic phase
the uterus lining “eating of the uterus”
- this is bc there is no placenta so must rely on the uterus for nutritional support
how does the placenta start forming
the trophoblast forms a cord of cells that extend into the endometrium and attach to start forming the placenta
how is pre-implantation characterized?
increase in cell number but not cell size
- low susceptibility to toxins
why is there low susceptibility to toxins in pre-implantation
cells are pluripotent so the ones that are harmed may just die off and can be rapidly replaced
- and there is less exposure as not in the uterus yet
describe the order from single celled zygote to gastrula
zygote, morula ( about 16-32 cells), blastula (about 100 cells), gastrula( day 14 when the embryobblast cells in the blastula start to differentiate into different cell types
what happens in gastrulation?
- embryo development at around 14 days ( differentiation into 3 layers) During gastrulation (day 2-3 weeks), VERY SUSEPTIBLE TO TERATOGENS 1. primitive streak 2. neurulation: ectoderm differentiates into the neural plate--> neural tube 3. mesoderm and endoderm cells migrate internally to form organs and tissues
the blastula folds in on itself to form three germ layers, the ectoderm, the mesoderm, and the endoderm, that will give rise to the internal structures of the organism. Starts with the formation of the invagination ( Hensons node) and moves gradually forming the primitive streak ( soon to be spinal cord)
definition of a blastula
After the cleavage has produced over 100 cells, the embryo is called a blastula. The blastula is usually a spherical layer of cells (the blastoderm) surrounding a fluid-filled or yolk-filled cavity (the blastocoel)
post- ovulation ( 16 days)
following implantation, gastrulation occurs
primitive streak
the faint streak which is the earliest trace of the embryo in the fertilized ovum of a higher vertebrate
- forms the future axis of the fetus and allows the three cells types to form
ectoderm
brain, CNS, skin
mesoderm
voluntary muscles, CVS, excretory organs
endoderm
digestive and Resp, glandular organs
when is VERY susceptible to teratogens
gastrulation, organogenesis
Neurulation
the ectoderm differentiates into the neural plate, forming the neural groove
precursors to CNS
crest cells
edges of the neural groove connect to form
the neural tube
when does gastrulation occur
2-3 weeks
post-ovulation ( 27-29 days)
- the heart is beating, shape is there, and major organ development begins
- smaller than an inch
- neural tube has segregated into head and postcranal regions
why does degeneration of nerve cells take place if neural tube doesn’t close by day 27
exposed to amniotic fluid
organogenesis time and type of growth
3 to 8 weeks
and soley hyperplasia
when is conceptus considered a fetus
at 8th week - all essential external and internal structures are present and the placenta has developed
fetal growth period
after 8 weeks
what is the only differentiation that takes place in fetal growth period
external genitalia
what will toxic exposure impact in the fetal growth period
growth and functional impairment - CNS and reproductive abnormalities and motor defect and behaviour defects
when do morphological defects primarily occur
embryonic period ( except the genitalia - fetal period)
Critical period: CNS`
the first one 3-5 weeks critical but also the longest one in terms of up until the end- can still have effect
Critical period: heart
2nd: 3 and half to 6
Critical period: ears and eyes
4-15 ears
4-8 eyes
Critical period: limbs
4-7
classes of teratogens
medications, social drugs, alcohol, environmental agents, fever or sustain high temps (sauna, hot) , infectious disease, chronic disease, nutritional def or excess
almost all drugs can cross the placenta?
yes
excess iodides effect
congenital goiter
mental and physical retardation
excess fluride
spina bifida
vitamin D
facial abnormalities
mental retardation
vitamin A
CNS abnormalities
incidence of BD with retinol intake study
women ingesting more than 10 000 had 2.5 higher risk of BD - closely related to time of intake in pregnancy ( first 6 weeks highest risk)
def in protein
microcephaly ( small head size)
vit A def
eye abnormalities nad microcephaly
vit D def
fetal rickets
Vit E def
congenital abnormalities
Vit K def
Coumadin syndrome (warfarin )
potassium def
kidney abnormalities
copper def
CT defect, brain and bone
zinc
NTD
folate antagonists (methotrexate)
30% risk of TND
characteristics of FAS
craniofacial dimorphism
growth retardation
decreased fat strokes
intellectual development
is FAS dose-response?
yes
difference between FAS and ARBD ( alcohol related BD)
diagnosis for FAS is 2 or 3 criteria of FAS whereas ARBD may be minor physical abnormalities, heart and lung malformation or microcephaly
CNS disturbances
decreased attention span, hyperactivity, decreased IQ
what are some main concerns of alcohol ingestion when pregnent
- alcohol crosses placenta freely
- 1/2 life is increased in fetus
- detoxification and clearance is less developed
-alcohol has calorie value so may decrease other sources calories - fetal hypoxia
- cell death
placenta toxicity
which two nutrients does alcohol affect
zinc and folic acid metabolism
anencephaly
- brain is exposed at birth
(most severe forms- very impaired or die early after birth _
what amounts are associated with learning difficulties
1 does or >5 drinks early in prep or 2 drinks later in pre
exencephaly
brain protrude out of skull
spina bifida
inability to walk, hold bladder, bowel functions or fatality
- can do surgery
- most common form
- usually in first month of gestation
etiolates of NTD
multifactorial inheritance
single gene disorders ( only 12% of NTD have an identifiable single gene defect)
aneuploidy
teratogens
severe OW
hot tubs or fever
folate def or folate metabolism disorders
findings from the study with folate
women who previously had a pregnancy with NTD ( cause more likely to have again) and found that folate helped more than a multivitamin
- folate supplement resulted in a 71% decrease in NTD
how many mg of folate is recommended to women with previous incident of NTD
4mg - then study stopped short for ethical reasons after seeing the effects of folate supplementation
what is homocysteine
an amino acid but not used for protein synth- it serves as an intermediate in the synthesis of methionine which is used for protein synth
what happens when SAM turns to SAH
the additional methyl group in SAM can be transferred to a substrate ( DNA, RNA, protein) and with methyltransferase it now becomes a methylated substrate which alters function! ( substrate may be a gene- epigenetic modifications)
with the methylation of a substrate what happens?
SAM ( s-adenosyl- methionine becomes s-adenosyl- homocysteine, which then is hydrolyzed into homocyteine
what does high levels of homocysteine indicate
an impatient in the metabolism of homocysteine (under normal conditions it is metabolized fast and kept in low concentrations)
how is homocysteine metabolized
2 pathways:
- B12 and folate dependent pathways
- and B6 dependent pathway
B12 and folate dependent pathway
metabolized and regenerated into methionine ( circular manner) using methionine synthase
enzyme for homocystiene to methionine
methionine synthase
B6 dependent pathway
homo is converted to cysteine via the transsulfuration pathway, using cystathionase
enzyme for transsulfuration b6 dependent pathway
cys-ta-thio-nase
most common cause of high levels of homocystiene
impairment in re-methylation pathway (caused by deficiency of folate)
what results in the inability to re-methylate homocysteine?
lack in 5-met-TH4-folate
what does 5-met-TH4-folate do?
donates a methyl group to homocystiene ( b12 is a cofactor to methionine synthase)
what enzyme is used to regenerate 5-me-TH4-folate? and how is its function impaired?
5-methylene tetrahydrofolate reductase
- a high intake of vitamin A suppresses this enzyme (which is how it is associated with NTD!!)
what happens with secondary accumulation of SAH (caused by accumulation of homocysteine)
decrease ( inhibition of ) in methyltransferase enzyme ( causing less DNA methylation and altered gene expression )
how is the effect of high levels of SAH exaggerated in organogenesis?
during organogenesis, gene expression is very high, if DNA is hypo-methylated, there may be issues with cellular differentiation and apoptosis
oxidative stress
damage to mito and nuclear DNA, affects protein structure and function, membrane lipids and signal transduction pathways
- it decreases the activity of methionine synthase by limiting the activity of B12
what does oxidative stress do to B12 ?
decreases availability and therefore decreases activity of methionine synthase
___% of the population is homozygous for a defect that increases the risk of low-tissue folate and high homocysteine levels
9-12%
mothers with NTD infants
low plasma folate, high homocysteine levels –> so defect in the folate-dependent homocysteine pathway
in born error in metabolism in families with NTD?
shortage of meth- tetrahedron-folate reductase - supplement fixes this ( normalize RBC and decrease homocysteine levels)
plasma homocysteine levels are ______% lower in pregnancy
30-60 % – maybe due to hemodilution
folic acid supplementation leads to ?
decrease in material and fetal homocystiene levels
risks associated with high homocysteine
preeclampsia, spontaneous abortion, miscarriages,
the higher the homocysteine levels in mother before conceiving the _____ the birth weight of baby
lower
there is a _______ correlation between pre-conception homocysteine levels and homocysteine during pregnancy
strong
- may be beneficial in identifying at risk mothers
does an increase in folate rich food increase concentration in RBC?
not much (6% difference from control) bc of variability in absorption and cooking decreases bioavailability! - need to supplement of fortified food
public awarness
few women know the importance of supplementing BEFORE
- 71% not taking supplements
- only 10% of non-preg women are taking in 400 micrograms/day
