UA-45667900-1
Showing posts with label smoking. Show all posts
Showing posts with label smoking. Show all posts

Thursday 13 October 2016

Multigenerational Epigenetic Change Stimulating Inflammatory Disease



Multigenerational transmission of nicotine-induced effects. The diagram illustrates the experimental design and findings of Rehan et al. [4]. Pregnant dams (F0 generation) are injected with nicotine or nicotine + rosiglitazone. The lungs and gonads of both male and female offspring (F1 generation) of nicotine-treated dams exhibit epigenetic changes, and the lungs show an asthma-like functional phenotype (blue nicotine-induced changes). These nicotine effects are not seen in the offspring of animals treated with nicotine + rosiglitazone. Offspring of F1 mated pairs (F2 generation) exhibit the same nicotine-induced changes to lung function as their parents, even though they were not exposed to drug.


Today’s post is again filling in some gaps in this blog to date.

A big question in autism is whether the incidence is increasing or not.  According to the now best-selling autism author Silberman, incidence is not increasing at all; it is just that diagnosis is much better than it was half a century ago.  So it is not an “autism epidemic”, rather a “diagnosis epidemic”.

I did not buy Siberman’s book and while I would like to believe he has accurately assessed the facts, in this case he really has not.

Psychiatrists have done none of us any favours by constantly changing the definition of autism and clinicians have never adequately collated data on those who match those criteria.

It does actually matter whether or not incidence of autism is increasing, because this would then stimulate research as to why.  In time this better understanding would lead to therapeutic avenues.

Being neither a professional researcher, nor a best-selling author, my level of evidence can be a little lower.  In earlier posts we saw incidence of ASD (autism, Asperger’s and PDD-NOS) is around one percent of both the child and adult population.  Many adults with Asperger’s and milder dysfunctions were never diagnosed as children, because they did not have speech delay or great cognitive difficulties.

The autism figures are always of low quality, but there is an opinion that underlying them is a real increase in severe autism, as well as the increased diagnosis of milder autism due to lowering of the diagnostic threshold.

The data I would like to see is the incidence of severe autism over the last few decades, but it does not exist.  All we have is anecdotes.

I remember asking my retired doctor mother how many patients had autism in her medical practice of about 10,000, where she saw all the children.  They did not have any and apparently until the Wakefield autism-MMR business nobody even talked about autism.

Hidden away in a group of 10,000 there “should be” about 100 with some degree of autism.  About 30 might have quite severe autism, many with MR/ID and epilepsy. 30 sounds a lot, but it is only one or two births a year.  People with severe autism live half as long as typical people, so you would not see many past middle age. I suppose it was easy to just diagnose mental retardation and then put the child into “care” when the parents could not cope.  

When a friend of mine from graduate school asked our alumni group of 200 how many had a child with autism there were six responses.  None were Asperger’s, all were strictly defined autism (SDA).

Some disease surprisingly does correlate with educational level.  I recently read that IBS/IBD is much more common among more educated people.

So my take is that hidden in all those poor quality statistics is a rise in the incidence of strictly defined autism (SDA).  Just as it is known that there has been a rise in inflammatory disease like asthma.

Asthma and COPD are really well researched and we know at least some of the reason why they have become more common.  I think the same general mechanism is behind the increase in SDA.

By understanding this mechanism you can then try and reverse it.  This is already being done in COPD research and some of the single gene autisms like Pitt Hopkins.

The mechanism is epigenetics, where you can modify when genes turn on, or turn off.  COPD is a severe disease because an environmental factor (normally smoking) has caused the body's oxidative stress response genes to be turned off.  Pitt Hopkins is caused by an insufficient expression of the TCF4 gene.  This was unlikely to have been caused by epigenetic changes, but could potentially be treated by using epigenetics to turn on the TCF4 gene.

Today’s post highlights pretty convincing research that shows how an environmental factor, smoking in this case, can cause heritable epigenetic changes.  It shows how a Grandparent smoking increases asthma incidence in the grandchildren.

Other than sending the message that smoking can affect the health of your future grandchildren, it becomes clear that many other environmental insults could also be heritable.  The accumulation of these insults over generations affects the incidence of certain diseases, particularly those complex ones often caused by multiple hits (cancer, autism etc.).
  
This makes me recall how it is theorized that epilepsy can develop as an acquired channelopathy.  We saw how the threshold for a person’s first seizure is quite high, but after the first seizure the threshold falls.  The proposed mechanism is called an acquired channelopathy.  This means that one of the many ion channels whose dysfunction is known to lead to epilepsy has been permanently disturbed.  The ion channel can now behave aberrantly with little provocation,

Ion channel diseases are classified as ‘acquired’ or ‘genetic’. Genetic ion channel disorders of the brain generally manifest as epilepsy, migraine, paroxysmal dyskinesia or episodic ataxia.

Acquired channelopathies can be caused by antibodies which target specific ion channels or by toxins which block voltage-gated ion channels. Altered transcription of ion channels may contribute to many acquired neurological ion channel disorders.

Mutations in genes which encode subunits of CNS sodium, potassium, calcium channels, GABAA and nicotinic receptors have been reported in association with various epilepsy syndromes.

While genetic (inherited) ion channel disorders may be the cause of most people’s epilepsy, it is suggested that acquired channelopathies are also involved.  Perhaps both are present?



 the “acquired channelopathy” hypothesis suggests that proepileptic channel characteristics develop during epilepsy.

In summary, cell type-specific information on epilepsy-related ion channel modifications can explain and support AED strategies. Precisely those inhibitory ion channels which appear to be effective AED targets in preclinical tests are the ones upregulated in DG GCs during TLE. These data indicate that cell-endogenous ion channel homeostasis mechanisms could be used as “channelacoid” archetypes in the search of antiepileptic strategies. In particular, the enhancement of static shunt via combined K/Cl/cation leak channel support appears to be a promising strategy.


The science, though complex, is still in its infancy.  You do wonder if acquired channelopathy cannot be caused by epigenetic changes to the genes encoding the ion channel.



Nicotine, your genes and those of your heirs

Finally, the subject of today’s post, the research showing the epigenetic effects of nicotine. In place of nicotine you could likely substitute other environment damage such as intense air pollution in cities like Beijing.  Another example below is lead pollution. 

 First the easier to read article:-


"Our results therefore indicate that the increased disease risk associated with smoking is partly caused by epigenetic changes. A better understanding of the molecular mechanism behind diseases and reduced body function might lead to improved drugs and therapies in the future," 


Now the more interesting study that shows how the effect of nicotine is passed down the generations to non-smokers.






Multigenerational transmission of nicotine-induced effects. The diagram illustrates the experimental design and findings of Rehan et al. [4]. Pregnant dams (F0 generation) are injected with nicotine or nicotine + rosiglitazone. The lungs and gonads of both male and female offspring (F1 generation) of nicotine-treated dams exhibit epigenetic changes, and the lungs show an asthma-like functional phenotype (blue nicotine-induced changes). These nicotine effects are not seen in the offspring of animals treated with nicotine + rosiglitazone. Offspring of F1 mated pairs (F2 generation) exhibit the same nicotine-induced changes to lung function as their parents, even though they were not exposed to drug.

A recent preclinical study has shown that not only maternal smoking but also grandmaternal smoking is associated with elevated pediatric asthma risk. Using a well-established rat model of in utero nicotine exposure, Rehan et al. have now demonstrated multigenerational effects of nicotine that could explain this 'grandmother effect'. F1 offspring of nicotine-treated pregnant rats exhibited asthma-like changes to lung function and associated epigenetic changes to DNA and histones in both lungs and gonads. These alterations were blocked by co-administration of the peroxisome proliferator-activated receptor-γ agonist, rosiglitazone, implicating downregulation of this receptor in the nicotine effects. F2 offspring of F1 mated animals exhibited similar changes in lung function to that of their parents, even though they had never been exposed to nicotine. Thus epigenetic mechanisms appear to underlie the multigenerational transmission of a nicotine-induced asthma-like phenotype. These findings emphasize the need for more effective smoking cessation strategies during pregnancy, and cast further doubt on the safety of using nicotine replacement therapy to reduce tobacco use in pregnant women.


More on epigenetic changes related to heart disease.





Finally the effect down the generations of lead, a known neurotoxin.



We report that the DNA methylation profile of a child’s neonatal whole blood can be significantly influenced by his or her mother’s neonatal blood lead levels (BLL). We recruited 35 mother-infant pairs in Detroit and measured the whole blood lead (Pb) levels and DNA methylation levels at over 450,000 loci from current blood and neonatal blood from both the mother and the child. We found that mothers with high neonatal BLL correlate with altered DNA methylation at 564 loci in their children’s neonatal blood. Our results suggest that Pb exposure during pregnancy affects the DNA methylation status of the fetal germ cells, which leads to altered DNA methylation in grandchildren’s neonatal dried blood spots. This is the first demonstration that an environmental exposure in pregnant mothers can have an epigenetic effect on the DNA methylation pattern in the grandchildren.



Conclusion

As regards autism, heritable epigenetic changes could well explain the increase in strictly defined autism (SDA) that cannot be explained away in terms of widening diagnostic criteria and awareness.

With respect to many diseases it is hardly surprising that they are becoming more prevalent if we accumulate the environmental insults experienced by our ancestors, via heritable epigenetic changes.  Where this will lead in future generations?

There are further studies looking at the role of PPAR gamma agonists (the rosiglitazone given to protect the mouse from epigenetic change) and HDAC inhibitors, which together can do very clever things regarding epigenetics.

You may recall the broccoli sprout extract being given by John Hopkins researchers to protect Beijing residents from the effects of severe air pollution.  The sulforaphane produced is an HDAC inhibitor.  

The mouse studies showed how to protect a mouse from epigenetic change occurring, what would be more interesting would be studies looking at reversing that change, once it has already occurred.

The only bad thing in the Mediterranean diet/lifestyle is smoking; just imagine how healthy the Greeks would be without smoking 2,000 cigarettes per adult per year, compared to 1,000 in the US.