Development and Ageing Flashcards
mode of early embryo nutrition
histiotrophic (digest maternal tissues and use uterine secretions from uterine glands as nutrition)
2nd trimester embryo swithc to what kind of nutrition
haemotrophic
why placenta is called haemochorial type placenta
maternal blood directly contacts the fetal membranes (chorionic villi)
in what week is fetal demand on oxygen low
week 0-13
why chorionic villi becomes more branched as time goes by
increase SA based in maternal blood for exchange
role of syncytiotrophoblast
invasion into endometrium to take secretions from uterine glands
what are the 3 phases of chorionic villi development
primary
secondary
tertiary
primary phase of chorionic villi development
outgrowth of cytotrophoblast ad branching of these extension
secondary phase of chorionic villi development
growth of fetal mesoderm into primary villi
tertiary phase of chorionic villi development
growth of umbilical artery and vein into villus mesoderm to provide vasculature
describe the structure of terminal villus microstructure
Convoluted knot of vessels and vessel
dilation
whole structure coated with trophoblast
why terminal villus microstructure has slow blood flow
enable exchange between maternal and fetal blood
what is terminal villus microstructure coated with
trophoblast
function of spiral arteries
provide the maternal
blood supply to the endometrium
what forms the endovascular extra-villus trophoblast (EVT)
EVT cells coating the villi invade down into maternal spiral arteries to form endovascular EVT
what grows down to form spiral arteries
invasion of trophoblast cells
what is the conversion of spiral artery in spiral artery remodelling
turns from high resistance and low capacity to low resistance and high capacity after fully converted
How does spiral artery
re-modelling occur?
- EVT cell invasion triggers endothelial cells to release chemokines, recruiting immune cells.
- Immune cells invade spiral artery walls and begin to disrupt vessel walls.
- EVT cells secrete break down normal vessel wall extracellular matrix and replace with a
new matrix known as fibrinoid to give structure to vessel - Remodelling: remove smooth muscle, immune cell and have EVT cells invasion
what happens if there is failed conversion in spiral artery remodelling
smooth muscle remains,
immune cells become embedded in vessel wall and vessels blocked/occluded by RBCs
pro-inflammatory and high resistance
consequences of failed spiral artery remodelling
lead to perturbed flow and local hypoxia, free radical damage and inefficient delivery of substrates
into the intervillous space.
* Retained smooth muscle may allow residual contractile capacity -> perturb blood delivery to the intravillous space.
* Atherosclerosis can occur in basal (non-spiral) arteries
that would not normally be targeted by trophoblast.
what pathologies are unconverted spiral arteries vulnerable to
intimal hyperplasia
atherosclerosis
what is pre-eclampsia
New onset hypertension (in a previously normotensive
woman) BP ≥140 mmHg systolic and/or ≥90 mmHg diastolic
* Occurring after 20 weeks’ gestation
symptoms of pre-eclampsia
sudden onset of HTN
oedema
abdo pain
headache
visual disturbances, seizures, breathelessness
what happens to fetus in pre-eclampsia
reduced fetal movement
what happens to amnionic fluid volume in pre-eclampsia
reduced
how to check amnionic fluid in PE
USS
how to consider early or late onset of PE
Early onset: <34 weeks
Late onset: >34 weeks
what are the PE early onset placenta changes
Changes in placental structure
Reduced placental perfusion
what are the PE late onset placenta changes
less overt/ no placental changes
is early onset PE associated with fetal or maternal symptoms
both
is late onset PE associated with fetal or maternal symptoms
mostly maternal
which is more common, early or late onset of PE
late
what are the PE risks brought to mother
damage to kidneys, liver, brain and
other organ systems
Possible progression to eclampsia
(seizures, loss of consciousness)
HELLP syndrome: Hemolysis, Elevated Liver Enzymes, Low Platelets, Placental abruption (separation of the
placenta from the endometrium)
what are the PE risks brought to fetus
Pre-term delivery
Reduced fetal growth (IUGR/FGR)
Fetal death
what is HELLP syndrome
Hemolysis, Elevated
Liver Enzymes, Low Platelets
normally where does EVT invasion of spiral artery pass through in maternal side
EVT invasion of maternal spiral
arteries through decidua and into
myometrium
then EVT becomes endovascular EVT and spiral arteries are high in capacity
in PE, what doesn’t go into myometrium
spiral arteries
where is decidua
contact between foetus and myometrium
what happens to EVT invasion in early PE onset
EVT invasion of maternal spiral
arteries is limited to
decidual /endometrial layer.
Spiral arteries are not extensively
remodelled
what happens to placenta perfusion in early PE onset
placenta perfusion restricted
cause placental ischaemia
what is PLGF
placental growth factor
function of PLGF
VEGF related, pro-angiogenic
factor released in large amounts
by the placenta
where is PLGF released
placenta
what is Flt1
soluble VEGFR1
what does Flt1do in PE
Soluble receptor for VEGF-like
factors which binds soluble
angiogenic factors (VEGF, PLGF) to limit their bioavailabilitiy
what happens to Flt1 in PE
excess production of Flt-1 by distressed placenta leads to reduction of available pro-angiogenic factors in maternal circulation, resulting in endothelial dysfunction
in healthy placenta why we need to release PLGF and VEGF
Releases PLGF and VEGF into the maternal circulation.
These growth factors bind
receptors on the endothelial surface to promote vasodilation, anti-coagulation and
‘healthy’ maternal endothelial cells.
in PE placenta what does it release
soluble Flt1 (sFlt1)
what does sFlt1 do in PE
acts as a sponge – mopping up PLGF and VEGF and stopping them binding to the endothelial surface receptors. In the absence of these signals (PLGF, VEGF),
the endothelial cells become
dysfunctional.
what do extracellular vesicles (EV) contain in terms of cargos
mRNAs, proteins and microRNAs (miRNAs)
how can extracellular vesicles influence cell behavior
can cause cell signalling locally and at distance
what are the Changes observed in EV number and composition in PE (3)
- Overall increase in EVs in the maternal circulation
- Increase in endothelial-derived EVs (indicative of maternal circulation defects)
- Decrease in placenta-derived EVs
what are extracellular vesicles
tiny lipid-bilayer laminated vesicles released by almost all cell types
what is the possible mechanism of how extracellular vesicles contribute to PE
- Placental ischaemia induces
trophoblast cell (syncytiotrophoblast) apoptosis and EV
release - These enter the maternal circulation
- Act on endothelial cells to induce
endothelial dysfunction, inflammation and
hypercoagulation - Collectively these may contribute to PE
why can EV fuse with cell membrane to deliver cargos
have lipid bilayers
what are the 3 ways SDEVs can cause PE after entering maternal circulation
- endothelial dysfunction
- systemic inflammation
- hypercoagulation disorders
what do human endothelial cells inhibit the production of in PE
production of eNOS (endothelial nitric oxide synthase)
cause inhibition of vasorelaxation & vasodilation
what is the current theory of causes of later onset PE
existing maternal genetic pre-disposition to cardiovascular disease,
which manifests during the ‘stress-test’ of pregnancy.
what are genetic factors causing abnormal placentation
maternal and fetal SNPs
what are maternal / environmental factors causing abnormal placentation
smoking
DM
hyperglycaemia
chronic hypertension
AKI/renal disease
what are immunological factors causing abnormal placentation
placental Th1 Predominance
Immunogenic HLA-C on trophoblast
decidual NK cell
what are some systemic vascular dysfunction in PE
- proteinuria/ glomerular endotheliosis
- hypertension
- visual disturbances / headache/ cerebral edema and seizures (eclampsia)
4.HELLP syndrome,, coagulation abnormalities
what can be used to test for PE
PLGF levels alone or sFlt-1/PlGF ratio
what can be used to predict PE
cell free RNA from liquid biopsy
OR
small molecule metabolites in urine
when is clinical diagnostics useful to identify women that are at risk of PE early in pregnancy
after 20 weeks gestation
what is small for gestation age meaning
Fetal weight: <10th centile (or 2 SD below pop norm)
Severe SGA: 3rd centile or less
what are the 3 subclasses of small for gestational age (SGA)
- Small throughout pregnancy, but otherwise health
- Early growth normal but slows later in pregnancy
(FGR/IUGR) - Non-placental growth restriction (genetic,
metabolic, infection)
difference between SGA and IUGR/FGR
*SGA considers only the fetal/neonatal weight without any consideration of the in-utero growth and physical characteristics at birth.
* IUGR is a clinical definition of fetuses/neonates with clinical features of malnutrition and in-utero growth restriction, irrespective of weight percentile
what is symmetric and asymmetric IUGR
symmetrical IUGR: all parts of the baby’s body are similarly small in size. asymmetrical IUGR: the baby’s head and brain are the expected size, but the rest of the baby’s body is small.
difference in period of insult of symmetric and asymmetric IUGR
symmetric: earlier gestation
asymmetric: later gestation
difference in incidence rate of total IUGR cases of symmetric and asymmetric IUGR
symmetric: 20-30%
asymmetric: 70-80%
difference in cell number of symmetric and asymmetric IUGR
symmetric: reduced
asymmetric: normal (hv correct body plan)
difference in cell size of symmetric and asymmetric IUGR
symmetric: normal
asymmetric: reduced (smaller fetus)
difference in head and chest circumference of symmetric and asymmetric IUGR
symmetric: <3cm
asymmetric: >3cm
difference in prognosis of symmetric and asymmetric IUGR
symmetric: poor
asymmetric: good
what are the cardiovascular implications of FGR/IUGR
- fetal cardiac hypertrophy
- re-modelling of fetal vessels due to chronic vasoconstriction
what are the respiratory implications of FGR/IUGR
poor maturation of lungs during fetal life, leading to bronchopulmonary dysplasia and respiratory compromise
what are the neurological implications of FGR/IUGR
long term motor defects and cognitive impairments
What challenges could the fetus face in utero that might have lasting impact on its health?(6)
Fetal infection in utero
Maternal nutrition (under/over)
Maternal illness
Maternal stress
Maternal medication
Environmental factors/exposures
what is the Developmental Origins of Health and Disease (DOHaD) hypothesis
programming adult health in early life
risk of coronary events was more strongly related to the rate of change of childhood BMI, rather than to the BMI attained at any particular age of childhood.
how undernutrition in utero/ overnutrition as a child affects development of a child according to DOHaD hypothesis
increased risk of metabolic syndrome
leads to increased risk of cardiovascular events
what is the name given to developmental adaptations taken to prepare the fetus for its future environment
predictive adaptive responses (PARs)
what is definition of PARs (predictive adaptive responses)
developmental adaptations taken to prepare the fetus for its future environment
do PARs benefit foetus immediately
no
don’t benefit the fetus immediately, but are taken in anticipation of the environment they will be exposed to.
what is the main idea of DOHaD
programming in utero
what happens when there is a mismatch between PARs and actual environment
mal-adapted
contribute to disease risk later in life
what can environmental exposures associate with when fetus develop into adult
Cardio-vascular disease
Type 2 diabetes
Lung disease
Cancer risk
Neurological, special sense and intellectual development
Allergic and auto-immune diseases
what factors in growth and development in utero contributes to diseases in adult life
foetal gene expression
maternal health and environment
fetal nutrient
endocrine milieu
placental vascular supply
adult exposure
amplification in infancy
what are the 3 major challenge mechanism could the fetus face in utero that might have lasting impact on its health?
Hormonal effects (especially glucocorticoid exposure)
Epigenetic modifications
Irreversible developmental changes in organ size/structure
what is Fetal glucocorticoid exposure is usually regulated by
placental 11Beta- HSD2 enzyme
role of placental 11Beta-HSD2 enzyme
regulate Fetal glucocorticoid exposure
consequence of reduced 11BHSD2 expression
greater fetal glucocorticoid exposure
cause changes in fetal growth (cell number, gene expression, organ structure etc) , development and metabolism
consequence of increased maternal glucocorticoids
greater fetal glucocorticoid exposure
cause changes in fetal growth (cell number, gene expression, organ structure etc) , development and metabolism
examples of Epigenetic changes modify the expression of genes without modifying DNA sequence
DNA methylation, post-translational (protein) modification of histones, and non- coding RNAs
effect of DNA methylation to gene
switch off gene
consequences of modifying types or levels of epigentic marks
altered or dysregulated gene expression
what are the Key windows of epigenetic reprogramming during development are points of vulnerability (5)
- gametogenesis
- early development
- organogenesis and foetal growth
- post-natal growth
- adulthood and ageing
what happens in epigenetic reprogramming
- writing gametic epigenome
- erasure of gametic identity
- writing epigenome in each cell type during cell differnetiation for aquisition of a specific expression profile and cell identity
which are the 3 key windows of epigenetic reprogramming during contribute to developmental vulnerability
- gametogenesis
- early development
- organogenesis and fetal growth
why gametogenesis are important
health of parents will affect quality of sperm and egg which influence fetus later health and life
what happens in gametogenesis in terms of parent specific epigenetic marks
parent-specific epigenetic marks are established during the development of sperm and oocytes
what happens in early development of gamete
embryos undergo widespread erasure and re-patterning of epigenetic marks during which these gamete-specific marks are erased and new epigenetic profiles established.
what happens in organogenesis and fetal growth
epigenetic marks influence timing and onset of cell-type-specific gene expression, influencing how cells differentiate
what happens in fetal hypoxia
reduced nephron numbers -> increased risk of hypertension/renal disease in adulthood
what happens in fetal undernutrition
reduced beta cell mass/altered muscle insulin sensitivity -> impaired glucose control in adulthood
what are primordial germ cells (PGCs)
embryonic precursor cells of oocytes and spermatozoa
what happens to primordial germ cells (PGCs) in embryogenesis (2)
- undergo epigenetic reprogramming
- These cells then give rise to sperm and egg – which transmit these epigenetic marks to the next generation
what impacts gamete quality (6)
- DNA integrity
- ROS generation
- lipid composition
- spindle integrity
- epigenetic status
- seminal plasma concentration
what affects embryo development (3)
epigenetic remodelling
metabolic status
TE/ICM cell number
what affects uterine environment (4)
- vascular remodelling
- seminal plasma mediated interactions
- inflammatory and immunological responses
- maternal environmental stressor
what affects adult health (4)
- gamete quality
- cardio-metabolic disease risk
- reproduce fitness
- inter/transgenerational programming
what affects fetal growth (4)
- predictive adaptive responses (PARs)
- organ biometry
- placental function and adaptions
- maternal responses to pregnancy
which factor override fetal genetic factors in determining prenatal growth
maternal factors
does paternal genetic factors have large or small effect on birth
little
which genetic prenatal factor is important in determining birth size
maternal size
which endocrine factors are major prenatal hormones influencing growth(2)
IGF-1
IGF-2
what does IGF-2 important for in prenatal stage
embryonic growth
what is IGF-1 important for in prenatal stage
later fetal and infant growth
in postnatal stage which hormone is major hormone controlling growth after birth
human growth hormone (hGH)
what is commonest cause of placental insufficiency
intrauterine growth restriction (IUGR)
what provides all nutrients to growing fetus in prenatal
placenta
in prenantal stage what influences fetus’ nutritional availability
maternal diet
what contributes to limited growth potential in post natal stage
starvation
what are the 2 main internal environmental factor that affects fetus growth in prenatal stage
Uterine capacity
placental sufficiency
what environmental factors affect postnatal growth (4)
Socioeconomic status
Chronic disease
Emotional status
Altitude (mediated by lower oxygen saturation levels)
ratio of head: body at birth vs adult
1:3 vs 1:7
4 phases of growth
Fetal
Infantile
Childhood
Pubertal
when does cranial suture open and close
open at birth, close by 18months
what affects infantile growth (3)
nutrition
good health and happiness
thyroid hormone
what affects fetal growth (1)
uterine environment
what affects childhood growth (4)
gene
growth hormone
thyroid hormone
good health and happiness
what affects pubertal growth
testosterone and oestrogen
growth hormone
which is the fastest growth period over life-course
fetal phase
which of the growth phase accounts for largest % of adult height
childhood
what does growth mainly driven by during fetal life
hyperplasia
how many cycles of cell division before birth
42
how many cycles of cell division occur from birth to adulthood.
5
how does fetus size grow over gestation
double
when is infantile phase
0-18 months
what is growth is infantile phase largely depend on
nutrition
when is childhood growth phase
18months -12yo
what contributes to growth in childhood phase (3)
nutrition
health
endocrine growth regulation
what is other name of pubertal phase
pubertal growth spurt
what hormones rises in pubertal phase
sex hormones
which hormone do sex hormones boost during pubertal phase
hGH production
how many cm for XY boys and XX girls increase over 304 years during pubertal phase
25 for XY
20 for XX
when is neonatal phase
new born
(first 4 weeks after birth)
when does mini puberty occur
neonatal phase
in terms of reproductive hormone, what happens in fetal phase
development of sexual organs and GnRH network
when does sexual maturation occur
adolescence
for fetus, when there is high oestrogen exposure, does it affect follicle formation
no, follicle formation still normal
what happens in mini puberty
HPG axis is transiently activated after birth (mini-puberty), after release from restraint by placental hormones
how gonadotrophin secretion changes in mini puberty
Gonadotrophin secretion commences towards the end of the first trimester, peaks mid-pregnancy, then declines
differences in XY and XX in reproductive hormones after birth
both will increase uptake but in XX oestradiol fluctuates
importance of mini puberty in males
Elevated sex steroids in males during mini-puberty
important for normal gonadal development (testicular tissue and penile development)
importance of minipuberty in female infants
less clear
Important for patterning and development of mammary tissue(?)
how Elevated sex steroids in minipuberty may also influence programming of body composition and linear growth
High testosterone levels in boys during minipuberty, may partly explain the higher growth velocity observed in boys compared to girls
what triggers puberty
Release of neurokinin KNDy neurons may regulate release of Kisspeptin peptides, which act on GnRH neurons to promote pulsatile GnRH release
mutation in what affect puberty timing
KISS1R
what does consonance mean
The developmental events of puberty typically follow a predictable pattern
Compliance with this sequence is consonance
what are the 4 developmental domains
gross motor skills
fine motor skills
speech, language, hearing skills
social behavior and play skills
examples of gross motor skills
raises head
sit without support
crawl
cruises ard furniture
walks unsteadily
walk steadily
examples of fine motor skills
follow object to move head
reaches out for toys
palmar grasp
transfer toy from hand to hand
mature pincer grip
make marks with crayon
ability to draw without seeing it is done
copy drawing
examples of language skills
make noises
turn to soft sounds out of sight
use sound indiscriminately/discriminately
make 2-3 words and then more
talk constantly
example of social behavioral skills
smiles responsively
put food in mouth
waves
drink
hold spoon and feed
play
