View Full Version : Maternal exposure to stress during pregnancy is associated with significant....


mildadhd
03-13-13, 09:29 PM
I understand this research involves expereiments with rats, and is not written specifically about ADD, but I am posting it for learning and discussion purposes.



Abstract

Maternal exposure to stress during pregnancy is associated with significant alterations in offspring neurodevelopment and elevated maternal glucocorticoids likely play a central role in mediating these effects. Placental 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) buffers the impact of maternal glucocorticoid exposure by converting cortisol/corticosterone into inactive metabolites. However, previous studies indicate that maternal adversity during the prenatal period can lead to a down-regulation of this enzyme. In the current study, we examined the impact of prenatal stress (chronic restraint stress during gestational days 14–20) in Long Evans rats on HSD11B2 mRNA in the placenta and fetal brain (E20) and assessed the role of epigenetic mechanisms in these stress-induced effects. In the placenta, prenatal stress was associated with a significant decrease in HSD11B2 mRNA, increased mRNA levels of the DNA methyltransferase DNMT3a, and increased DNA methylation at specific CpG sites within the HSD11B2 gene promoter. Within the fetal hypothalamus, though we find no stress-induced effects on HSD11B2 mRNA levels, prenatal stress induced decreased CpG methylation within the HSD11B2 promoter and increased methylation at sites within exon 1. Within the fetal cortex, HSD11B2 mRNA and DNA methylation levels were not altered by prenatal stress, though we did find stress-induced elevations in DNMT1 mRNA in this brain region. Within individuals, we identified CpG sites within the HSD11B2 gene promoter and exon 1 at which DNA methylation levels were highly correlated between the placenta and fetal cortex. Overall, our findings implicate DNA methylation as a mechanism by which prenatal stress alters HSD11B2 gene expression. These findings highlight the tissue specificity of epigenetic effects, but also raise the intriguing possibility of using the epigenetic status of placenta to predict corresponding changes in the brain.



http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039791

Tyler Durden
03-13-13, 10:01 PM
Hsd11b2:

Function: Catalyzes the conversion of cortisol to the inactive metabolite cortisone. Modulates intracellularglucocorticoid levels, thus protecting the nonselective mineralocorticoid receptor from occupation by glucocorticoids.

Stress sensitivity?

Tyler Durden
03-13-13, 11:09 PM
Just scanned the link looks interesting, i'll hopefully give it a proper read through tomorrow...

SB_UK
03-14-13, 04:00 AM
I think this paper provides a mechanism by which stress can, through, epigenetic mechanism - can alter the genome - in such a way - that the organism's survival is favoured.

The only real way of doing that 'd be to reduce the organism's calorific requirement.

And we're back to the principle underlying the 'Thrifty gene hypothesis' - and the basis of Syndrome X / ADHD.

-*-

Excellent find.

Thing is - though - that we can prevent disease without understanding how it arises - though if understanding is required - then you've nailed the mechanism.

The epidemiological approach teaches us that eliminating cigarettes will prevent the majority of cases of lung cancer - we don't actually need to know why - and i'd argue that why is a far distant secondary concern to actually eliminating suffering.

Stress-based Epigenetic modelling of the human genome towards increased likelihood of survival ... ... through reducing calorific requirement - the principle underlying the 'Thrifty gene hypothesis'.

The consequence (the basis to the 'Thrifty gene Hypothesis') of stress (noting the emergence of all of these diseases during the exponential phase of growth of the human population) ie stress through 'overpopulation' ... ... in the presence of excess food - results in diabesity.

So - is the stress which is driving ADHD emergence related more fundamentally to the human population growth curve or money ... ...

to which (as usual) - the point 'd be that the more fundamental effect of human population numbers are responsible for the stress (good stress) which drives selection of attention deficit/surfeit ... ... though where the disorder occurs when the attention surfeit epigenetically selected condition - is placed within an environment of unmanageable stress.

So - classical epigenetics is useful in understanding why ? ADHD is occurring (what's driving the emergence of attention deficit/surfeit as an attribute) - and this relates to a 'good' (necessary) stress in the evolutionary method ... ..
but the disorder is caused by context within a 'crowded' planet - where the societal infrastructure which we have in place (of money) isn't up to it.

The newstory on the Radio currently - is of the terrible consequences which we're due to experience (in Britain and globally) because of the ageing population.

Britain's BBSRC have a major thrust on 'Healthy ageing'.

We need to know how to age without disease.

We need - and desperately - to work out how to generate a planet in which people do not age with disease.

And of course - Mount Athos is filled with monks with an average very aged population - with no disease.

So we know how.

Back to epidemiology.

Now - do we need to understand why monks age without disease - or simply introduce a societal infrastructure which they use - to eliminate disease.

Well - we can do both - but neither requires a single further wet lab experiment to be performed.

All that's required is to think about it - with a genuine desire to get the right answer.

Epidemiology Epidemiology Epidemiology.

SB_UK
03-14-13, 04:26 AM
http://www.ncbi.nlm.nih.gov/pubmed/11756646
Reanalysis of 15 of 30 IUGR newborns in whom we previously reported an inverse relationship between cord blood cortisol levels and first trimester length gain (r = -0.54, p < 0.005) showed that the relative amount of the IGFBP-3 18-kD fragment was related inversely to cortisol (r = -0.67, p < 0.01) and directly to early postnatal growth (r = 0.65, p < 0.05). Connection directly between cortisol and growth - there needs to be a mechanism - that mechanism, as Peripheral describes - is epigenetic in nature -

what'd be more sensible than driving selection for a smaller baby which'll go on to be a smaller adult - with lower calorific requirements under maternal stress - with baby in utero.

Presumably - throughout the evolution of life - lack of food availability has been the single most significant stressor - and so it makes sense that gestating foetus in the presence of maternal stress - would react (epigenetically) - the way that it has reacted previously throughout history - and generate an individual with increased likelihood of survival under the conditions (which the stress misleads the epigenetic system into believing)- is of reduced food availability in the world outside.

It's just a very sensible mechanism to ensure survival.

There's no way of evolution putting in some discrimination between maternal stress from food availability versus eg fear of money availability ... ... however - one can see how fear of money availability - through meaning that one has no means of buying food - actually results in stress - which selection for low calorie requiring children - 'd help to overcome.

So - the key message here - is that stress arises from fear of survival - and fear of survival selects for 'types' which require less (food) to survive.

And there we arrive at Syndrome X/ADHD.

SB_UK
03-14-13, 04:34 AM
And of course - stressed mother gives birth to ADDer 1 and then the same stressed mother gives birth to ADDer 2 - and the conclusion 'll be that this is a genetic disorder.

However - it isn't a classical genetic disorder (in the same way as monogenic disorder) - exactly as Peripheral has just described - it's an epigenetically inherited disorder.

Now - twin studies pre-date the knowledge of epigenetics ... ... and so we're left - with the current state of knowledge of genetics/epigenetics - with a colossal flaw in the deductive trail from heritability estimates derived from *all* twin studies.

Familial nature of Attention deficit is accounted for by epigenetic mechanism.

As just described by Peripheral - actual modification to genomic regulatory sequences which occurs without any change in the A,G,C,T code of the genome ... ... occurring through fatty acid These modifications include acetylation, methylation, ubiquitylation, phosphorylation and sumoylation addition to regulatory elements - outside of the protein coding frame.

-*-

What are these epigenetic changes doing ?

Just one thing - forcing glycolysis/citric acid cycle and the mitochondrial electron transport chain into 1 pathway - making us fixed aerobic organisms - with a biochemical, metabolic optimal affinity for the ketogenic (low energy requiring) state.

That's the clearest way of evolution favoring survival of gestating infant in stressed mother.

So - 'good' stress evolutionarily selecting low calorific requirement ... ... 'bad' stress (everything to do with money) resulting in disorder - as the ADDer fails to be able to maintain the ketogenic metabolic profile.

SB_UK
03-14-13, 06:25 AM
Trying to simplify all the way down.

I think that stress simply epigenetically remodels the genome at every point from day 1 conception to death - and that this epigenetic remodelling scheme - simply results in the body reducing its dependence on calories from high to low - and that we witness this underlying biochemical transition to stress as the reduced need for calories - or as the increased rate of fat deposition if we maintain the exact same lifestyle with exact same calorific intake.

So - stress from day 1 conception up to physical death yielding epigenetic changes which try to alleviate the stress by reducing calories required ... ... however little realising that these changes are of no consequence in reducing the actual stress (actually increase levels of stress we're under) we're feeling - because the stress is not due to lack of food availability - but a criminally vicious societal infrastructure (one with money and law) in the presence of excess amounts of far overly high-calorific food..

So - we eat and eat (the stress sensitive) and to a metabolism which requires less food, no carbs, ketogenic metabolism - we (ADDers - particularly) break.

-*-

So - this is tricky - the stress drives emergence of ADDers - the stress leads to an exponential increase in disease which all people (particularly ADDers feel)
- explaining away the exponential increase in the common disorders reported globally.

The transition is now well underway - the emergence of ADDers (Syndrome X) as a new species - and so we're about ready to make life easier for them/us - by switching to a societal infrastructure which allows us to maintain our blood glucose levels at unswervingly low - ketogenic friendly levels
- in a societal infrastructure which doesn't cause us stress and reaching for the processed starch.

ADDers are born out of material world attachment - the reactive reaching for material world attachment (cakes,meat) is caused by sensitivity to stress.

We're not taking stimulants as 'uppers' but as stress relief - explaining the paradoxical effect - of them calming us down (in a lovely lovely way when they work)
- when we take them.

-*-

So - in conclusion -
we've stress (cortisol) operating epigenetically to change the genome/epigenome into a form which will instantiate an organism which is capable of surviving stress (it's all about survival)
- Syndrome X/ADDers result as a triumph of selection - resulting in a novel type which is able to survive on next to no food

- but in order to realise this new 'quality' - stress sensitivity (sensitivity to blood glucose variability) is gained.

SB_UK
03-14-13, 06:41 AM
So - when does the chronic application of stress end ?

When blood glucose ups and downs (pleasure and pain) are overcome and the individual can only exist in the ketogenic state (unswerving blood glucose levels).

Which is about the state I'm in now.

Is this state bliss.

No - not in a world in which the fundamentally corrupt construct of money rules human interaction.

Upon reaching a state in which material world attachment is lost (the individual no longer seeks blood glucose elevation) ... ... that is - the individual becomes self-contained without the need for anything
- in a society where it is demanded that you need to go and do something immoral for an immoral construct -
the 'bliss' state (loss of material world attachment) turns into your worst nightmare - because a mind of enforced moral consistency is not able to turn itself to issues of a fundamentally immoral nature (molecular medicine, money etc) ... ...

Enforced moral consistency wins - trying to force the mind into doing stuff like that which is below us - leads to a PTSD wiping of the individual themself

- it's literally as though it's impossible to make oneself do it - the mind won't go in that direction - the muscles can't be made to walk in that direction.

It's quite impressive that the higher mind (conscience) when it seizes control (at state wisdom) can exert such powerful control over behaviour - to the extent that one finds oneself unable to meet the immoral lowest requirement for survival -

- to earn money - because it's immoral.

SB_UK
03-14-13, 06:52 AM
So what's the hardest part to accept in this story ?

That stress changes the organism's genome/epigenome in a way which increases likelihood of survival by reducing caloric needs ie in a specific way - through driving a specific transition of the organism from anaerobic capable to fixed aerobic.

It should be noted that it's to be expected (from everything we know about lower organisms) - that stress 'd drive the mutation process into overdrive (to ensure survival).

We see this in eg HIV - where anti-retroviral results in mutation and then mutation selection for 'immunity' to retroviral drug challenge.

It's relatively impressive that stress operates to take the organism from one state to another (ADDer metabolism)
... ... however it's more than scientifically credible as an idea - it's a genetic/epigenetic mechanism which could exist - is compatible with the data we've accrued - and more importantly - on the epidemiological data (low birth weight etc) of Syndrome X/ADDers.

Just a simple biochemical shift from a model of reward which involves blood glucose ups and downs (pleasure and pain) to a model of reward which requires blood glucose levels to be unswervignly steady - supporting whole body ketogenic metabolism.

Now ... ... upon shifting away from the primitive reward mechanism - we end up with a sensitive internal neurochemistry (in dopaminergic and opiate systems) - ie we don't blunt these systems with the foods we eat - which activate these systems

... ... a sensitive dual pleasure (D and O) axis - which - as Peripheral/Panksepp describe
- results in, when in the sensitive state - the ability for pair-bonding from partner, child and upwards throughout the species - to fuel reward.

And that'd mean that ADDers are (given a societal infrastructure free from money) - a defined social organism.

Only money and law (the systems which prevent equality) make it not so - as the stressed ADDer blunts their neurochemical systems with stress-relief ... ... meaning that we're unable to reach out for 'social' reward and are stuck getting our kicks from exogenous (cakes, drugs, money, power) factors -
- none of which are internally regulated - all of which are administered (like the illicit drug) - without care to dosing ... ... resulting in addiction to insensitivity in the body's key neuro- endocrine systems affected adversely (in this way) by negative feeddback.

SB_UK
03-14-13, 06:58 AM
More simply - the primitive reward system is:
blood glucose levels up - happy fast
blood gluose levels down - sad (need to eat) slow

And the work of stress takes us from this pattern of metabolism (where anaerobic metabolism is happily performed) into the ketogenic lair -
where aerobic metabolism is strongly guarded.

Here -
blood glucose levels - stable (moving neither up nor down)

A fixed ketogenic state - which is selected for - because it's compatible with far lower (so I'm finding) caloric consumption.

Literally just the occasional bit of olive oil and seeds.

That'd be the end-point to this experiment.

AD(H)D - stress* sensitivity in an unnecessarily stress-ful world
- as a pre-condition to generating a properly (both internally and externally) social (stress*-less) (global) societal structure.
*good & *badStress sensitivity good - because of our new metabolic profile.
Stress sensitivty bad - because we're more at risk of adverse (immorality) environmental contexts.

We're a highly efficient new breed of engine which is being forced to consume the same amount of petrol as a standard engine - and are breaking under the stress of having to consume to the level of a less efficient mechanism.

-*-

The trick with the model of connecting glycolysis through CAC to ETC is that the connection of 3 (eg 3 fermions to 1 boson) is a model which evolution has at its disposal for structures formed in phenomenological (what we call reality) reality.

Male archetype (glycolysis) Female archetype (ETC) and child aechetype (connection = CAC) ... ... at balance - fusing to generate just 1 fixed aerobic/ketogenic pathway.

Stress epigenetically sculpting this pathway into existence.

SB_UK
03-14-13, 07:13 AM
That's all of the dots connected - as far as I can see.

What I'm finding is that olive oil / pumpkin|sunflower seed diet appears to work <- but even this diet has to be brought down and can't be eaten in unlimited levels.

The trick to all of this - and nobody'll get this intuitively - is to eat less and of food which doesn't satisfy - when your body/brain/mind screams for more, under weight of seemingly unmanageable stress.

That is to see that the body's reacting to psych. stress as if it's physiol. stress by demanding comfort food.
But psych stress (like physiol stress) is epigenetically slimming down your metabolic needs - to require less food.
Meaning that upon stress - one absolutely must not reach out for stress relief (food) - because the body is - under force of psych. stress making you less in need of food as its only defence to stress.

This is a very significant problem - you won't get anybody who'll even acknowledge this idea - it's far too unappealing.

Not reaching out for stress-relief when stressed is very difficult indeed; it appears that proper mind is our only get-out clause ... ... in that with mind - there's no need for blood glucose elevation/eduction - meaning that the attraction to those comfort foods wane.
Such that when under stress - we're able to avoid reaching for comfort food ... ... however - that doesn't mean that stress (unmanageable) does not cause disorientation.

With arrival at mind/happy ketogenic metabolism quality - the mind wants to settle into a dissociated state (happy place)** ... ... which is prevented by stress.

Literally - it's like you're trying to fall asleep - and some guy is firing off a klaxon just as you're about to fall asleep - where - it's well known that this can lead to death - that is failure to be able to fall asleep eventually leads to death.

** This is - unsurprisingly -a low EEG state - meaning - a low energy requiring state - the lower the EEG the less the firing - compatible with this whole general process as towards reduced energy use/efficient energy handling/fixed aerobic existence.

-*-

So that's all there is to the story of ADHD - dead simple.

Experiment over.

SB_UK
03-14-13, 09:05 AM
ADHD disorder - as anybody with any objectivity can see is just a stress reaction.
The stress reaction occurs more easily than in nonADDers because we're stress hormone sensitive.
We're stress hormone sensitive because we're blood glucose sensitive - because wildly fluctuating levels of blood glucose prevent us from remaining within ketosis.
Wildly fluctuating blood glucose levels occur to stress and eating a certain type of food which the stressed recognize as comfort foods.
Our stress sensitivity means that we're more sensitive to immunological dysfunction also - the immune system is controlled/reined back by cortisol.
Chronic exposure to hormones results in resistance to the mechanism of negative feedback.
Immunological dysfunction manifests itself in driving allergic/autoimmune diseases into being.

We can prevent all disease by shifting to a societal infrastructure which enforces equality by preventing hierarchy through eradication of money / legal system (ownership).

We don't need to worry about food shortages on a global level - because without stress and eating to the mount athos pattern - there's enough food to go around - especially as their diet requires no animal products which're much more inefficient to generate - relatively speaking.

So -what's left ?
To acknowledge how stress results in epigenomic sculpting - that is - how we're not finished at birth - though through stress (good stress = desperately trying to work out how we came into existence from point of big bang) can result - in building our mind - into a state which transcends the pleasure/pain paradigm - and is able to activate reward autonomously (eg see exp validation in monk in gamma EEG on compassion meditation) or via social bond (exactly as exp verified in vole, parent-child).

Thing is that when you're in paradise - the undirectional rule of evolution prevents you from engaging in the behaviours of Hell eg molecular medicine, law and money.

Why molecular medicine ?
Because the alleviation of human suffering is the highest human ideal - and molecular medicine gets in the way of the good guy - epidemiology from introducing changes to societal structure by offering the hope (pure fantasy) - of a magical potion or cure which'll allow people to have their cakes and eat them too.

You can't have your cake and eat it.

That's not how human physiology works.

You eat it and your body doesn't need any of the energy and you get fat and then a whole raft of diseases including cancer.

And the thing is - that as long as you're trapped in a stressful environment, with access to stress-relief (cakes,meat) - there's nothing you can do to stop yourself killing yourself.

Sole solution - change societal structure away from money-based whilst understanding (from a natural scoence and moral perspective) your context.

The dual effect of which 'll be to eradicate the chance of you falling victim to disease.

Kill off the desire for those comfort foods - and kill off the stressor whcih sends you reaching for them.

Eat properly - don't get diabesity and assocaited conditions - don't get cancer and associated conditions.

All confirmed by epidemiological studies on Mount Athos over 1000 years.

SB_UK
03-14-13, 10:18 AM
It's the same old story across the entire workplace and the reason why we need to get rid of money.

If you're rich and powerful because you're paid to 'fix' a problem - then you'll resist prevention of the problem occurring in the first place - and will want as much of the problem to occur as possible.

There's a dentist advertising on JassFM as I write - the idea of healthcare advertising flies in the face of prevention of disease - these guys want as many people as possible to be diseased - and handing over their money to be fixed.

The lawyer doesn't want a land without chaos - for they'd get no money.
The medical doctor doesn't want a land without disease - for they'd get no money.
A medical scientist doesn't want a land without disease - for there'd be no molecular mechanisms to study - and they'd get no money.
A banker doesn't want a land of equality - for that'd require and end to money - which'd mean that they'd surprise surprise! get none also.

-*-

So - and concluding once again - we're in the midst of emergence of a metabolically more efficient type which can activate its reward mechanism without need for material world attachment factors; we need an environmental context in which we build our minds and are allowed to be moral - in the generation of ourselves within a societal structure (with wife, with children, with others) which then (through social functioning) activates our reward mechanism.
This is not possible in a world of separation/division/hierarchy of money and law.

It is sufficiently rewarding for us to exist to perform a social function - but not unless we're allowed to.
We're prevented from doing so in a world of immoral workplace roles being performed for the immoral construct of money.

I can repeat this point over and over - but why do I need to ?

There were only ever 2 solutions to disease - at the micro (molecular) or macro (social) level
- where the molecular level is truly rejected based on, amongst other things, an understanding of the unidirectional process of evolution.

It's looking ahead - not behind at places it's been and moved on from.