View Full Version : Early life adversity, including adverse gestational and postpartum maternal enviro...


mildadhd
02-25-13, 06:53 PM
I am posting this information for discussion.


Differential gene body methylation and reduced expression of cell adhesion and neurotransmitter receptor genes in adverse maternal environment.

by Oh JE, Chambwe N, Klein S, Gal J, Andrews S, Gleason G, Shaknovich R, Melnick A, Campagne F, Toth M

Transl Psychiatry. 2013;3:e218
Authors: Oh JE, Chambwe N, Klein S, Gal J, Andrews S, Gleason G, Shaknovich R, Melnick A, Campagne F, Toth M
Abstract
Early life adversity, including adverse gestational and postpartum maternal environment, is a contributing factor in the development of autism, attention deficit hyperactivity disorder (ADHD), anxiety and depression but little is known about the underlying molecular mechanism. In a model of gestational maternal adversity that leads to innate anxiety, increased stress reactivity and impaired vocal communication in the offspring, we asked if a specific DNA methylation signature is associated with the emergence of the behavioral phenotype. Genome-wide DNA methylation analyses identified 2.3% of CpGs as differentially methylated (that is, differentially methylated sites, DMSs) by the adverse environment in ventral-hippocampal granule cells, neurons that can be linked to the anxiety phenotype. DMSs were typically clustered and these clusters were preferentially located at gene bodies. Although CpGs are typically either highly methylated or unmethylated, DMSs had an intermediate (20-80%) methylation level that may contribute to their sensitivity to environmental adversity. The adverse maternal environment resulted in either hyper or hypomethylation at DMSs. Clusters of DMSs were enriched in genes that encode cell adhesion molecules and neurotransmitter receptors; some of which were also downregulated, indicating multiple functional deficits at the synapse in adversity. Pharmacological and genetic evidence links many of these genes to anxiety.

PMID: 23340501 [PubMed - in process]

http://www.ncbi.nlm.nih.gov/pubmed/23340501?dopt=Abstract

ConcertaParent
02-25-13, 08:04 PM
Genome-wide DNA methylation analyses identified 2.3% of CpGs as differentially methylated IMHO, they should have explained WTH CpGs are, KWIM? ;)
I just learned a new acronym today - CpGs are sites where something called cytosine (C) lies next to something called guanine (G) in the DNA sequence. (The p indicates that C and G are connected by something called a phosphodiester bond.) Methylation of DNA occurs at any CpG site.

What little I am understanding so far is that adverse maternal environment can produce permanent epigenetic changes in neurons. Among the various epigenetic modifications, CpG methylation is probably the longest lasting. The study's final statement is:

Overall, our finding of differential methylation/expression at a large number of cell adhesion and neurotransmitter receptor genes suggests that some forms of anxiety following maternal adversity could be associated with epigenetic perturbations in multiple synaptic genes, each contributing only a small effect to the overall phenotype.

So aside from genetics, my DD's multiple challenges may be caused by early life adversity, such as maternal stress, maternal infection (e.g., immune activation during pregnancy) and maternal separation during early postnatal life.

Amtram
02-25-13, 09:31 PM
While it's an interesting study, it uses rats that have these particular genes bred into them, and the stressors are very limited and specific and acutely timed. The information may or may not translate perfectly to humans. I did note that the transplanted embryos exhibited the traits as well, but that they were also measuring a number of different changes, some of which were not statistically significant.

I'm not literate enough to be able to understand every piece of this paper, but I did read through it several times (free full text is available, and includes all the charts) and it appears to be expanding on previous research and setting the stage for more narrowly defined experiments. It demonstrates a sound hypothesis, not a conclusion, so we need to keep that in mind when considering what it says.

mildadhd
02-25-13, 09:37 PM
While it's an interesting study, it uses rats that have these particular genes bred into them, and the stressors are very limited and specific and acutely timed. The information may or may not translate perfectly to humans. I did note that the transplanted embryos exhibited the traits as well, but that they were also measuring a number of different changes, some of which were not statistically significant.

I'm not literate enough to be able to understand every piece of this paper, but I did read through it several times (free full text is available, and includes all the charts) and it appears to be expanding on previous research and setting the stage for more narrowly defined experiments. It demonstrates a sound hypothesis, not a conclusion, so we need to keep that in mind when considering what it says.

I agree. No conclusions should be drawn either way. Not limiting either genetic or environmental factors. (BOTH or more) A important 50:50 rule when discussing causation. May or may not. Depends.

mildadhd
02-25-13, 09:52 PM
(quote from Abstract found in OP research)

Early life adversity, including adverse gestational and postpartum maternal environment, is a contributing factor in the development of autism, attention deficit hyperactivity disorder (ADHD), anxiety and depression but little is known about the underlying molecular mechanism.



The "underlying molecular mechanisms" of the 7 primary emotional systems introduced to the world by Prof Jaak Panksepp.(Affective Neuroscience) I am 100% sure will help explain the 3 most common ADD commorbidities, anxiety, depression and addiction, such better on a molecular level.

(http://www.addforums.com/forums/showpost.php?p=1446769&postcount=3)




.

SB_UK
02-26-13, 06:28 AM
Early life adversity, including adverse gestational and postpartum maternal environment, is a contributing factor in the development of autism, attention deficit hyperactivity disorder (ADHD), anxiety and depression ...

The only question I'd ask/am asking is that under the assumption that this idea is true (and it certainly rings true) ... ... would elimination of maternal stress before, during, after pregnancy (I'm only pointing at the stresses related to money) result in and by itself in a normalization of optimal environment for development.

I think it would - and particularly so - if the need for the stress-free state in mother was appreciated; this'd help father to pull his weight in alleviating maternal stress.

It's not enough for father to simply to bring mother breakfast in bed, do the washing and ironing ... ... the elimination of maternal stress required complete redefinition of societal infrastructure on a global level - so mother need not fear for her child's fall into a life of pain ... ... as is occurring nowadays as the stress of debt cuts most noticeably into the younger generations (60% youth unemployment in Spain and Greece ... for instance).

SB_UK
02-26-13, 06:39 AM
A more general point - and as raised by epidemiologist Valerie Beral ... ... is if establish an irrefutable connection eg cigarette smoking -> leads to -> lung cancer, or adversity in childhood -> leads to psychological problems ... ... then aren't we wasting time by trying to define the precise molecular mechanisms by which the association is borne.

It takes time ... ... when the simple solution to lung cancer is to stop cigarettes being sold on every street corner, and to proper childhood development - is for men (and women) to create a stress-free world for women (and men) ... ... but mostly children to enjoy.

This type of world is not possible in a materialism-centred people who cling to money as if it's their reason for living - when in actaul fact, it's the direct cause of their premature death to chronic disease, beginning (in some of us and sadly) ... ... from (using Peripheral's idea) - as early as gestation ... that is ... even before we've breathed our first breath in polluted world.

One of today's news stories:
http://www.guardian.co.uk/world/2013/feb/26/chinese-pollution-study-blocked"major soil pollution study as public fears grow over environment and health"

Does knowing how a poison kills us, prevent a poison from killing us ?

As Valerie Beral states - as long as we've nailed causation - there really is no need to define mechanism; defining mechanism prevents change by offering hope that science 'll find a cure.

Never does though.

stef
02-26-13, 06:41 AM
Do you know more about what they mean by "adverse gestational and postpartum maternal environment"? in the first place ?

I was under quite a lot of stress (financially/trying to finish school) yet I remember feeling strangely calm, like I was in a kind of a bubble. my son does not have ADHD or anxiety disorders.

SB_UK
02-26-13, 06:45 AM
Do you know more about what they mean by "adverse gestational and postpartum maternal environment"? in the first place ?

I was under quite a lot of stress (financially/trying to finish school) yet I remember feeling strangely calm, like I was in a kind of a bubble. my son does not have ADHD or anxiety disorders.

Is it possible that any underlying stress is masked from consciousness by pregnancy's "happy" hormones ?

SB_UK
02-26-13, 06:47 AM
I think Valerie Beral's research is into the negative effects on woman of hormone replacement therapy ... ... that is - what is lost (cancer predisposition) from opting for the mood elevation from artificially (HRT) elevating hormone levels.

SB_UK
02-26-13, 06:50 AM
http://www.ncbi.nlm.nih.gov/pubmed/17512855
Women who use HRT are at an increased risk of both incident and fatal ovarian cancer. Since 1991, use of HRT has resulted in some 1300 additional ovarian cancers and 1000 additional deaths from the malignancy in the UK.

**** --- What on earth is the medical discipline doing to people ???

SB_UK
02-26-13, 06:55 AM
The plot thickens ... ... endorphins (pregnancy's 'happy' hormones) and ACTH (precursor to cortisol - stress hormone) come from the same gene (POMC).

http://www.schizophrenia.com/prevention/Stress.child.html
We found two possible mechanisms by which maternal stress during pregnancy could affect the development of the baby. One is if the mother is very anxious or stressed while she's pregnant, there's reduced blood flow to the baby through the uterine arteries, the main source of blood and nutrition for the baby, and this could explain why the baby doesn't grow as well and also set up a secondary stress response in the fetus. Second, we have shown that if the mother has high levels of cortisol, the main stress hormone, so does the fetus. It seems that enough cortisol crosses the placenta from the mother to the fetus to actually affect fetal levels. So if the mother is stressed, her cortisol goes up, so does the cortisol level in the fetus. This in turn could well affect the development of the brain and the future stress responses of the baby.So ... ... (I don't know if this is true) ... ... but if stress manifests itself as increased endorphin levels (as Stef suggests a happy feeling despite being under stress) ... ... then mother is automatically deflected (her mind) from seeing the damage being done ... ... because the stress (and increasing stress) manifests itself as increasing levels of endorphins (happy hormones).

Haven't had this idea before - not sure if it's correct ... ... it certainly would make sense though - there needs to be a biological mechanism for a pregnant mother under great stress - not to collapse under it.

stef
02-26-13, 07:10 AM
Is it possible that any underlying stress is masked from consciousness by pregnancy's "happy" hormones ?

That's exactly what I meant. looking back, it was more difficult than I thought at the time.

SB_UK
02-26-13, 08:01 AM
This idea really helps - just returning to the idea of a basal (honed) balance between the SNS and PNS -
eg 1 unit SNS -> <- 1 unit PNS
we've the idea that chronic stress lifts SNS output

2 units SNS
... ... and then physiological homeostasis attempts to restore balance
2 units SNS -> <- 2 units PNS
... ... whereby, chronic stress systematically takes the physiological set-point further and further from the desired level (1 unit SNS -> <- 1 unit PNS).

This idea then fuses in with the connection between increased vagal tone (PNS) and asthma.

The point being - that (and exactly as seen in the idea of maternal stress leading to opiate production (narcotic)) ... ... ie stimulant (stress) leading to narcotic (endorphin) to balance ... ... that stress leads to a decreasing sensitivity (whole bodily resistance symptoms) as homeostasis restores balance at non-physiological ideal set-points ... ...

... ... or in simple English - imagine that you've an electical device which trickle charges at 1 amp - imagine then forcing 10 amps down the circuit - the delicate circuit is overloaded (ie increased parasympathetic vagal tone because individual is required to balance the chronically elevated stress (SNS activation) the individual is under) ... ... leading to resistance syndromes (electronic device failure as the increased current cannot be supported).

-*-

SB_UK
02-26-13, 08:16 AM
For some reason - a little voice in the back of my head is whispering 'Le Chatelier's principle' ... ... which sounds like classical chemistry's version of neuroendocrine homeostatic balance/set-point definition.

SB_UK
02-26-13, 01:04 PM
Ultimately, though, if the idea of the generation of an actual structure incorporating all individuals within the species via pair-bonds is too freaky ... ... the simple idea that what's best for the species is best for the individual should be universally greeted as common sense ... ... meaning - that simply accepting this idea ... ... and thereby and therefore ... individuals working towards species wellbeing 'd be sufficient (all we require).

A thoroughly uncontentious idea, as long as the individual happens to stumble upon it.

Drewbacca
02-26-13, 02:44 PM
Moderator Note: Posts containing a religious reference have been removed as they violate forum guidelines (http://www.addforums.com/forums/showthread.php?t=15842). Discussion of materialism, as it applies to a moral position, will not be permitted.

Please remain on topic, which is, the effect of stress on an organism. It is OK to consider what types of things may contribute to what we call "stress." It is off topic to focus on any one of these, in detail, when such a suggestion begins to drive the discussion in a completely different direction.

Lunacie
02-26-13, 03:04 PM
http://www.ncbi.nlm.nih.gov/pubmed/17512855


**** --- What on earth is the medical discipline doing to people ???

That's an older study. More recent studies have NOT indicated that hormone replacement therapy increases the risk of any cancer, and seems to help reduce the risk of heart attack. Here's one:

http://www.telegraph.co.uk/health/healthnews/9595745/HRT-is-safe-and-cuts-heart-deaths-significant-study-finds.html

SB_UK
02-26-13, 03:07 PM
That's an older study. More recent studies have NOT indicated that hormone replacement therapy increases the risk of any cancer, and seems to help reduce the risk of heart attack. Here's one:

http://www.telegraph.co.uk/health/healthnews/9595745/HRT-is-safe-and-cuts-heart-deaths-significant-study-finds.html

Valerie Beral was on the radio last week in Radio 4's 'The life scientific' pretty much stating that the body of evidence against HRT is now overwhelming.
Didn't pay as much attention as I should have done - but that was definitely her stance.

SB_UK
02-26-13, 03:12 PM
http://www.bbc.co.uk/iplayer/episode/b01qdw1k/The_Life_Scientific_Valerie_Beral/

2:07 Adverse effects of HRT
9.35-10.24 HRT -> breast cancer

SB_UK
02-26-13, 03:25 PM
I think last week's interview was referring to this study (http://www.ncbi.nlm.nih.gov/pubmed/12927427):
Breast cancer and hormone-replacement therapy in the Million Women Study.

It's older than the ovarian cancer study though.

SB_UK
02-26-13, 03:31 PM
Without delving deeper into Lunacie's study - cohort sample = 1000 women ... ... where Valerie Beral's study features 1000000 women.

From my own experience - I've observed much more significant results from studying smaller cohorts ... ... ... spurious associations though !! I'd suggest that Beral's study be considered 1000 times better than a study 1000 times smaller.

mildadhd
02-26-13, 08:05 PM
The only question I'd ask/am asking is that under the assumption that this idea is true (and it certainly rings true) ... ... would elimination of maternal stress before, during, after pregnancy (I'm only pointing at the stresses related to money) result in and by itself in a normalization of optimal environment for development.

I think it would - and particularly so - if the need for the stress-free state in mother was appreciated; this'd help father to pull his weight in alleviating maternal stress.

It's not enough for father to simply to bring mother breakfast in bed, do the washing and ironing ... ... the elimination of maternal stress required complete redefinition of societal infrastructure on a global level - so mother need not fear for her child's fall into a life of pain ... ... as is occurring nowadays as the stress of debt cuts most noticeably into the younger generations (60% youth unemployment in Spain and Greece ... for instance).

I do agree that prevention should be priority. That being said, the reason why I am interesting learning more about the molecular science involved in the primary emotional systems,

is because some substances found in the environment that people get addicted to, have very similar molecules, that mimic, the molecules found naturally in the brain,

of some of the primary emotional systems, that may be imbalanced by abnormal stresses. When people have suffered from to much emotional pain, these substances that

mimic molecules actually make people feel better in the short term. (along with terrible side effects) When someone has suffered to much abnormal stresses (emotional pain).

It is very hard to stop using substances that have molecules that help the person in the short term stop the emotional pain. No matter how terrible the long term side effects

may be. I don't recommend people use substances, just trying to explain why some people get addicted. And find it very hard to stop. And how understanding the molecular

sciences, can help us understand addicition. Some people have suffered to much emotional pain. I am glad you bring up the subjects. I hope to learn how to explain this

information better in the future. Understanding the primary emotional systems can help in so many ways.

Amtram
02-26-13, 08:12 PM
Peripheral, keep in mind also that this study was using rats that had been bred to have high anxiety levels - a correlation had already been established between the presence of the genes and anxious behavior - and were placed in a maze that had been shown to produce higher levels of anxiety in rats in general. Even if you don't go all the way down to a molecular level, a rat with an anxiety disorder (!) who is put into an anxiety-provoking situation is going to have a lot of adrenaline pumping in her blood - which is going to go into the pups she's carrying.

As a chemical process, it's conceivable that high levels of adrenaline alone in maternal blood are going to have some sort of effect. This research appears to be trying to narrow down the genetic factors that increase vulnerability. I'd imagine that beyond that, an epigenetic study would involve analyzing the chemical component and finding out whether the timing of that chemical exposure is critical, and when it has the strongest effect.

mildadhd
02-26-13, 08:36 PM
Peripheral, keep in mind also that this study was using rats that had been bred to have high anxiety levels - a correlation had already been established between the presence of the genes and anxious behavior - and were placed in a maze that had been shown to produce higher levels of anxiety in rats in general. Even if you don't go all the way down to a molecular level, a rat with an anxiety disorder (!) who is put into an anxiety-provoking situation is going to have a lot of adrenaline pumping in her blood - which is going to go into the pups she's carrying.

As a chemical process, it's conceivable that high levels of adrenaline alone in maternal blood are going to have some sort of effect. This research appears to be trying to narrow down the genetic factors that increase vulnerability. I'd imagine that beyond that, an epigenetic study would involve analyzing the chemical component and finding out whether the timing of that chemical exposure is critical, and when it has the strongest effect.

All mammals that Prof. Jaak Panksepp has researched, including rats and humans, all have the same primary emotional systems. Different mammals may have different rates of growth

and size. But the primary emotional systems that are found in all mammals all work the same way. I will present more information in the future about the similarities. I don't mind

you or others questioning the information. I plan to present the material better in the future. And hope we can explore/discuss the information more in the future. I need to

learn to express the material better. All I ask is that people consider the information with both genetics and environmental factors in mind. (and more) I actually think that

understanding the primary emotional systems may point to the genetic predisposition that may contribution to ADD, that may result in extra sensitive people. (will explain more in the future).

Amtram
02-26-13, 09:04 PM
Similar, though, doesn't mean identical. There are too many examples to count of research that worked just fine with animal subjects but didn't translate well to humans. Many of the medications that went to clinical trials but were never released fell victim to the difference between animal models and humans.

Even in the case of genes that have the same responsibility in more than one species, the complex interconnection with other genes and the differences in anatomy can make for different gene expressions when they're in different creatures.

mildadhd
02-26-13, 09:16 PM
Similar, though, doesn't mean identical. There are too many examples to count of research that worked just fine with animal subjects but didn't translate well to humans. Many of the medications that went to clinical trials but were never released fell victim to the difference between animal models and humans.

Even in the case of genes that have the same responsibility in more than one species, the complex interconnection with other genes and the differences in anatomy can make for different gene expressions when they're in different creatures.

(Maternal) CARE is one of the primary systems, all mammals require maternal care to survive. There is differences but there is also similarities.

mildadhd
02-26-13, 09:28 PM
Similar, though, doesn't mean identical. There are too many examples to count of research that worked just fine with animal subjects but didn't translate well to humans. Many of the medications that went to clinical trials but were never released fell victim to the difference between animal models and humans.

Even in the case of genes that have the same responsibility in more than one species, the complex interconnection with other genes and the differences in anatomy can make for different gene expressions when they're in different creatures.

Amtram,

Are you familiar with Prof. Jaak Panksepp and Affective Neuroscience?

SB_UK
02-28-13, 04:37 AM
Do you know more about what they mean by "adverse gestational and postpartum maternal environment"? in the first place ?

I was under quite a lot of stress (financially/trying to finish school) yet I remember feeling strangely calm, like I was in a kind of a bubble. my son does not have ADHD or anxiety disorders.

Idea taken from Radio 4 currently.

Post-natal depression is where the heightened levels of stress mother was under in pregnancy (protected by endorphins during pregnancy) manifests itself.

Reduce stress in pregnancy - reduce post-natal depression ... ...

- makes sense, I think.

Stress level under (undue) isn't manifest until after the event - making it impossible (too late when depression strikes) - to do anything about it.

SB_UK
02-28-13, 05:32 AM
This idea then fuses in with the connection between increased vagal tone (PNS) and asthma.


Stress ups SNS tone.
Homeostasis ups PNS tone to balance SNS tone.

General pattern that SNS tone dominates during waking hours/when sun's up.
PNS tone then dominates eg at the interface between wake and sleep.

I've noticed that my asthma becomes most severe at the interface between wake and sleep.

So ... ... it's elevated PNS tone which predisposes to asthma - and it's chronic SNS elevation from stress which accounts for PNS tone elevation.

Also - definitely.

Amtram
02-28-13, 11:05 AM
Amtram,

Are you familiar with Prof. Jaak Panksepp and Affective Neuroscience?

I saw that you had posted a video, but I haven't had the time or attention for those lately (or I would have posted some of the cool new things that have come up in my youtube subscriptions from UC Davis. . .) but I opened up a tab with a search on A.N. to remind me to look at it later.

SquarePeg
02-28-13, 12:15 PM
Idea taken from Radio 4 currently.

Post-natal depression is where the heightened levels of stress mother was under in pregnancy (protected by endorphins during pregnancy) manifests itself.

Reduce stress in pregnancy - reduce post-natal depression ... ...

- makes sense, I think.

Stress level under (undue) isn't manifest until after the event - making it impossible (too late when depression strikes) - to do anything about it.
I donīt think itīs that simple. I know women who have suffered Post natal depression and they were all high achievers, these women expected to cope better with birth and motherhood. They expected not to feel irritated, exhausted, knackered, angry etc. They were used to being more able to control and function at a high level.

I mentioned this to my midwife who said that she had met hundreds of women who had suffered Post natal depression and she agreed that this was the case. She said stress during pregnancy didnīt appear to be a factor.