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Fishing for Answers: Autism, Genes and Mercury.

Posted Sep 10 2010 12:00am


Teresa fishing By Teresa Conrick

I continue to "fish" the internet looking for answers about autism.  My recent analysis of research papers and data began when I was wondering about Redheads, Autism and a possible increased susceptibility.  That connected me to melanin, mercury and more neurodegenerative disorders like, ALS, Parkinson's, Alzheimer's, Schizophrenia,etc., (HERE) then to autism symptoms that were either hypo-melanic or hyper-melanic.  HERE

Investigating those brought me to neural crest cells, melanocytes, mast cells, and more mercury, which seemed to be common factors in many of these "autism-gene" disorders, like Tuberous Sclerosis, Neurofibromatosis, Hypomelanosis if Ito, Prader Willi, Mastocytosis etc., and to a surprising, possible relationship to Melanoma. HERE

It seemed very plausible that this could be a dot-to-dot connection that needed investigation to make it a complete picture.  Mercury seemed to be involved in each dot, in each illness or disorder, but more "bait and fishing" was needed. I am a fishing guide.  I don't know the answers but like fishing, there are patterns and areas that look promising and so off we go.

To recap that last part about Melanoma:" Link Between Human Birth Defect Syndrome, Cancer Metastasis Explored"  HERE

"Most cells lose developmental potential as they differentiate," said Joanna Wysocka, PhD, assistant professor of developmental biology and of chemical and systems biology. "But neural crest cells are a spectacular example of migratory cells that are capable of becoming over 100 different cell types, including neurons, the bone and cartilage of the face, jaw and teeth, pigment cells and certain heart structures....Wysocka, who studies how chromatin modification affects development, became interested in the cells when it became apparent that mutations in a protein called CHD7 were responsible for CHARGE syndrome  ( HERE )  .....

"It's apparent that CHD7 is required for the reprogramming and migration of the neural crest cells, which is when one would predict major changes in chromatin organizaiton would be taking place."

Quick definition of chromatin: Wiki - Chromatin is the combination of DNA and proteins that makes up chromosomes.  Chromatin contains genetic material-instructions to direct cell functions. 

Changes in chromatin structure are affected by chemical modifications of histone proteins such as methylation (of DNA and proteins) and acetylation (of proteins), and by non-histone, DNA-binding proteins.  We are looking at epigentics when we look into chromatin.  Wiki-"In biology, and specifically genetics, epigenetics is the study of inherited changes in phenotype (appearance) or gene expression caused by mechanisms other than changes in the underlying DNA sequence....Additionally, the chromatin proteins associated with DNA may be activated or silenced."

So interestingly, I came upon Rett's Disorder while reading about CHARGE syndrome and Melanoma, being linked to this issue of chromatin: "Chromatin Remodeling in Development and Disease: Focus on CHD7" HERE

"There are many human developmental disorders known to result from mutations in chromatin modifying proteins, including Rubinstein-Taybi (CBP and EP300), X-linked Alpha Thalassemia (ATRX), and Rett Syndrome (MECP2),......" and then Tuberous Sclerosis, another "gene-autism" disorder"Regulation of PCNA and CAF-1 expression by the two tuberous sclerosis gene products".  HERE

"We suggest that deregulation of the control of chromatin assembly might contribute to development of tumors in tuberous sclerosis patients and provide important new insights into the molecular development, especially since deregulation of chromatin assembly and DNA repair results in genomic instability, a hallmark of tumor development."

And in Melanoma:"Chromatin and cell surface receptors mediate melanoma cell growth response to nerve growth factor"  HERE
 
So what is up with chromatin and is there a connection with mercury?

"Long-lasting depression-like behavior and epigenetic changes of BDNF gene expression induced by perinatal exposure to methylmercury"
HERE

"We have found that early exposure to MeHg induces long-lasting repressive changes in the chromatin structure of the BDNF gene in the hippocampus, consisting of an increase in histone H3-K27 tri-methylation and decrease in H3 acetylation at the BDNF promoter IV.  Although the actual mechanisms underlying MeHg induced effects on plasticity and gene expression require further investigation, the results of the present study point to the importance that early environmental factors play in programming gene activity patterns via epigenetic changes. Toxic agents present in nature and recognized as environmental stressors are among the factors that can target epigenome causing long-lasting and even **transgenerational effects"

**Transgenerational - Acting across many generations.
 
Critical Periods of Vulnerability for the Developing Nervous System:Evidence from Humans and Animal Models   HERE

"In addition, a number of known developmental neurotoxicants like ethanol (42) and methyl mercury affect both proliferation (35-37) and migration (43,44) after gestational exposures.  Methyl mercury disrupts migration in both humans (43) and animal models (44)..........Alterations induced by xenobiotics can result in the progressive loss of neurons and may result in compromised neurological function later in life, as is the case in some neurodegenerative diseases (124-128)."

"Comparative Genotoxic Potential of Mercury and Cadmium in Soybean" HERE
"The purpose of the present investigation was to evaluate the influence of Cd and Hg concentrations on somatic as well as gametic cells of soybean .... the percentage of these abnormalities and the total abnormalities induced differed between the two treatments.  Hg is much more genotoxic than Cd since it induces greater abnormalities. The induction of cytological disturbances in the mitotic as well as meiotic cells is of great value, as it results in genetic damage that is handed over to the next generation."

It appears that mercury can effect chromatin by causing "transgenerational" effects, "later in life" effects and "next generation" effects.  No matter how it's said, the meaning is the same - damage to offspring and/or later, downstream effects on the victim.

Looking further took me to a paper by Dr. Eric London in June, 2000.  The title, "The Environment as an Etiologic Factor in Autism: A New Direction for Research" - HERE
It seemed pertinent and maybe ahead of its time.  As I started reading, I realized how off this study truly was.  Here it was just a year from this: "On July 7, 1999, the American Academy of Pediatrics (AAP) and the United States Public Health Service (PHS) issued a joint statement that because of the "neuro-developmental effects posed by exposure to thimerosal", "thimerosal-containing vaccines should be removed as soon as possible."......and Dr. London had not typed one word about thimerosal or mercury, yet he signifies "the environment" as an etiologic factor.  That is odd, strange and should be a red flag that this paper he presented was a possible decoy.  Here are the key words listed:  autism, autism epidemiology, autism etiology, children, developmental disorders, retinoids, gene-environment interaction, Hox genes. Kind of ridiculous but....the Hox genes caught my eye.  I had read somewhere in my "fishing trips" about Hox genes and chromatin, and looking more showed this:

"Colinear gene expression from these Hox gene clusters may involve an initial change in chromatin structure (histone modification and chromatin decondensation) of the entire loci"
HERE

and look what mercury can do:

"Results show that after mercury treatment at subtoxic levels (1microM): (a) chromatin changes were the earliest signs of cytotoxicity, (b) two major parts in nuclear material of K562 erythroleukemia cells could be distinguished, highly condensed supercoiled and decondensed veil-like chromatin," Apoptogenic and necrogenic effects of mercuric acetate on the chromatin structure of K562 human erythroleukemia cells -- HERE

I wondered if thimerosal was capable of also altering chromatin and it wasn't hard to find my answer:

"Therefore, thimerosal might induce phosphorylation of the Bcl-2 family or alter their intracellular localization without affecting the protein levels. It is also possible that other proapoptotic molecules like Bmf (Bcl-2-modifying factor), Bik, Bak, or Bim9,52,53,54 are upregulated by thimerosal. AIF once released from mitochondria, is transported into the nucleus, where it stimulates (ATP-independent and caspase-independent) large DNA fragmentation and condensation of chromatin.23 Since thimerosal also causes AIF release from the mitochondria, it is possible that, in addition to cytochrome c-mediated caspase-dependent apoptosis, thimerosal might also induce apoptosis by a caspase-independent manner."  "Biochemical and molecular basis of thimerosal-induced apoptosis in T cells: a major role of mitochondrial pathway"  HERE     (apoptosis inducing factor = (AIF))

or this
"Apoptotic morphology was detected in thimerosal-treated cells. Figure 5 demonstrates that, after 6 h of incubation, both fibroblasts and neurons showed morphological signs of apoptosis, which included chromatin condensation on the nuclear membrane"  "Thimerosal Induces DNA Breaks, Caspase-3 Activation, Membrane Damage, and Cell Death in Cultured Human Neurons and Fibroblasts  HERE

How is it possible that Dr. London and so many like him, representing multi-million dollar organizations, agencies and questionable foundations, don't investigate this area of research?

Here is more that they have NOT investigated:

"Autistic spectrum disorders (ASD) and epilepsies are heterogeneous disorders that have diverse etiologies and pathophysiologies. The high rate of co-occurrence of these disorders suggest potentially shared underlying mechanisms. A number of well-known genetic disorders share epilepsy and autism as prominent phenotypic features, including tuberous sclerosis, Rett syndrome, and fragile X. In addition, mutations of several genes involved in neurodevelopment, including ARX, DCX, neuroligins and neuropilin2 have been identified in children with epilepsy, ASD or often both.."  "Epilepsy and autism spectrum disorders: Are there common developmental mechanisms?"  HERE

Why are they not looking into the REASON for these "phenotypic features"?  Interestingly, here is a study that could give them an answer:

"Neuroligins are postsynaptic cell adhesion proteins that bind specifically to presynaptic membrane proteins called neurexins. Mutations in human neuroligin genes are associated with autism spectrum disorders in some families. ...... However, neuroligin mutants are defective in a subset of sensory behaviors and sensory processing, and are hypersensitive to oxidative stress and mercury compounds; the behavioral deficits are strikingly similar to traits frequently associated with autism spectrum disorders. Our results suggest a possible link between genetic defects in synapse formation or function, and sensitivity to environmental factors in the development of autism spectrum disorders."Neuroligin-deficient mutants of C. elegans have sensory processing deficits and are hypersensitive to oxidative stress and mercury toxicity."  HERE

And yet still more evidence that is denied:

"Binding of mercury by chromatin of rats exposed to mercuric chloride" HERE

"The extent of mercury binding by the chromatin of kidneys and liver of rats exposed to HgCl2 (20 mg Hg/kg body wt; single intravenous injection) was investigated. A considerable accumulation of this metal into cell nuclei of both the examined organs was observed (1.9 and 0.1 μg Hg/mg protein, respectively). Even higher mercury content was recorded in the chromatin preparations. The nonhistone chromatin proteins (NHP) were mainly responsible for deposition of mercury in the chromatin. One mg of these proteins contained 5.2 and 0.6 μg Hg for the kidneys and liver. Mercury bound to NHP constituted about 50% of the metal retained in the cell nuclei and 78–85% of mercury contained in the chromatin."

Warning Sign:  This from 1978 - "The effect of methyl mercury hydroxide on meiotic chromosomes of the grasshopper Stethophyma grossum"
HERE

"As the chromatin fibres contain the double helix of DNA, this assumption would imply that parts of the DNA molecule might be lost from the chromosomes in this way. The mercury compounds are known to block the sulfhydryl groups in proteins and therefore, they must be able to disturb many processes in a living cell. The observed effects on the chromosomes must be the result of an interaction with chromosomal proteins rather than DNA.

And more, back to even earlier days: "GENETIC EFFECTS OF ORGANIC MERCURY COMPOUNDS - CHROMOSOME SEGREGATION  IN DROSOPHILA MELANOGASTER - 1967"  HERE  "mercurials cause c-mitosis at exceedingly low concentrations....mercury compounds act as mitotic poisons, giving rise to c-mitosis and polyploidy."

"An increased effect of mercury induced exceptions was found in males carrying a heterochromatin deficient X chromosome."   Could this be a link to Fragile X?

 "....it should be mentioned that all the mercurials tested form c-mitotic tumors.." Is it possible that this could be a similar action with Tuberous Sclerosis, Neurofibromatosis, and even Melanoma?

"These observations are of interest from a practical point of view in relation to the mercury pollution of the environment, referred to earlier. This pollution includes some important human food stuff, like eggs and fresh water fishes, and therefore it obviously is of interest to establish what kind of human health risks may be involved. With reference to the experimental data, the genetic aspects of such a health problem primarily concerns the risk of an induction of cells with aberrant chromosome numbers. This might cause an increase for instance of trisomic defects like mongolism or Klinefelter's syndrome.  Although it of course is difficult to relate the data obtained on Drosophilia to the situation in humans, the present results do indicate the possibility of such a genetical risk."

And so a profound prediction of the dangers in the environment, the dangers that we see in a soybean, a grasshopper, a fruit fly yet the injected mercury, the thimerosal that was to increase horrifically twenty years after this paragraph, was to prove more than these predictions could ever envision. These mechanisms appear to be true, that mercury could give rise to genetically altered disorders, the trisomies, the mitotic tumors, the heterochromatin deficient X chromosome. Mercury is capable of cellular damage yet we have thousands of children who regressed into autism after mercury-containing vaccines and somehow that does not count? On Sept 14th, please read, share, discuss, and help end the denial - "The Age of Autism: Mercury, Medicine and a Man-Made Epidemic."

Teresa Conrick is Contributor Editor to Age of Autism.
 

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