Topic 2: Pre-eclampsia and offspring Neurodevelopment Flashcards
risk factors for pre eclampsia
advanced maternal age, obesity, diabetes, chronic hypertension
symptoms of PE
Onset of chronic hypertension on or after 20 weeks gestation, commonly occurs with proteinuria, placental insufficiency, endothelial dysfunction, systemic inflammation, and organ damage
treatment for PE
delivery of placenta and baby
effects on mother if untreated?
liver, kidney, brain damage, eclampsia, death
what do children born to a mom with PE have an increased risk of developing later in life?
cardiovascular disease, obesity, asthma, and stroke
what risk is increased by 30-35% in babies born to a PE mother?
ASD ID and ADHD
what has been observed in neuroimaging studies?
altered regional but not total grey matter volumes, altered structural and functional connectivity, reduced white matter maturation
what has been observed in offspring of rodent models of PE
behavioural deficits, altered regional brain volume, reduced neurogenesis and oligodendroligogenesis, altered brain transcriptome
risk genes for PE
Not well understood, mostly genes involved in endothelial function like VEGF, or cytokine signalling like ERAP1
what are the risk genes for ASD?
complicated, Shank and neuroligin genes or TFs that regulate neurodevelopment like FoxP1 and MeCP2
birth complications of PE associated also with neurodevelopmental disorders
preterm birth, low birth weight, intrauterine growth restriction
name the potential mechanisms of the association of PE and neurodevelopmental disorders
epigenetics, microbiota, placental nutrient transfer, impaired angiogenesis, perturbed placental signaling systems, inflammation, oxidative stress
nutrient levels in PE new-borns
decreased nervonic acid (males esp.), lower DHA, higher total and specific amino acids, increased homocysteine levels, altered placental expression of certain transporters
describe two important events in PE that cause placental insufficiency
shallow trophoblast invasion and failure to remodel spiral arteries of the myometrium
what angiogenic factors (pro and anti) are impacted in PE
VEGF and PIGF are decreased — these are proangiogenic
s-Flt1 and sENG are increased — these are antiangiogenic
what are the consequences of impaired angiogenesis in the foetal brain
impaired development of cerebrovasculature leading to oxygen and nutrient deprivation to developing brain, also affects BBB development and permeability
prenatal stress and maternal immune activation, how does this impact the developing brain
women with pre-eclampsia exhibit higher levels of stress, placental HSD11B2 expression is decreased in PE placenta, not as much cortisol converted to inactive cortisone, cortisol enters fetal circulation
maternal immune activation is sustained activation of the immune system of the mother during pregnancy, increase in cytokines in both maternal and fetal circulation, elevated IL-6 associated w PE
describe the placental serotonin system
the placenta synthesizes 5-HT from maternal tryptophan at a time where the fetus has the 5-HT receptors but cannot make its own serotinin.
how is the placental serotonin system altered in PE
it is altered due to changes in tryptophan metabolism
placental neurotrophin system; describe, function, and PE effect
placenta makes and secretes neurotrophic factors like BDNF, NT-3, NT4, NGF
BDNF esp. is an essential regulator of neurodevelopment processes
PE: there is decreased BDNF and increased NGF in maternal and fetal circulation
in PE, cortisol is __, 5HT is ___
and BDNF is ____, and NGF is _____
in PE cortisol is increased, so is 5-HT, BDNF is decreased and NGF is increased
describe normal oxidative stress vs oxidative stress in PE
cells constantly generate reactive oxygen species (ROS) mostly as a biproduct of oxidative phosphorylation in the mitochondria. the cell has antioxidant systems to counteract/balance this ROS. these enzymes include superoxide dismutase, catalase, and molecules like vitamin C and E.
when ROS are high, they exceed the cell’s antioxidant systems, ROS are highly reactive and will damage membrane phospholipids, proteins, and DNA if not counteracted.
oxidative stress effect on PE fetus
oxidative stress causes the placenta to release unknown mediators that impact neuronal development of the fetus.
what does ROS regulate normally in fetal brain
neural progentior cell proliferation, differentiation, axonal guidance.
what is observed in animals with oxidative stress
suboptimal neurodevelopment
what are epigenetics?
heritable changes to gene expression, do not affect the actual gene expression, can include methylation of DNA and phosphorylation of histones
effect of prenatal stressors on fetal epigenetics
v little research but can affect the fetus neurodevelopment
what has been observed in the gut and vaginal microbiota of women with PE
Altered gut and vaginal gut microbiome
how does PE affect breast milk
decreased BDNF, increased nervonic acid and DHA
what mediates the effect of oxidative stress in PE on neurons
astrocytes and glutamate
