Infant Jaundice Linked To Higher Risk Of Autism And Psychological Development Disorders In General

"A baby with neonatal jaundice, meaning jaundice within a few days or weeks of being born, has a higher risk of being diagnosed with autism or some other psychological development disorder later on in life compared to infants who did not have neonatal jaundice,"


Read more: Infant Jaundice Linked To Higher Risk Of Autism And Psychological Development Disorders In General:

Prenatal Polycyclic Aromatic Hydrocarbon Exposure Leads to Behavioral Deficits and Downregulation of Receptor Tyrosine Kinase, MET — Toxicol Sci

"common pollutants, such as the polycyclic aromatic hydrocarbon benzo(a)pyrene, can have a direct, negative impact on the regulated developmental expression of an autism risk gene with associated negative behavioral learning and memory outcomes."

Read more: Prenatal Polycyclic Aromatic Hydrocarbon Exposure Leads to Behavioral Deficits and Downregulation of Receptor Tyrosine Kinase, MET — Toxicol Sci:

Central tetrahydrobiopterin concentration in neurodevelopmental disorders.

Hmmm, I would say considering that Nrf2 helps to maintain coupling of NO via tetrahydrobiopterin....the resources of methionine, proper functionings of the pathway and methylation status of the pathways involved may throw a really big wrench into things....and could account for a number of conditions including those in autism and other environmental illnesses including multiple chemical sensitivity or idiopathic intolerance.

"citrulline-to-methionine was found to correlate with the cerebrospinal fluid BH(4) concentration (r = -0.67, p < 0.05). Both citrulline and methionine are substrates in inflammation and oxidative stress pathways - two pathways that utilize BH(4) and are abnormally activated in autism. These data suggests that central BH(4) concentration may be related to systemic inflammation and oxidative stress pathways."

Read more: CiteULike: Central tetrahydrobiopterin concentration in neurodevelopmental disorders.:

Further Reading:

• Dysfunction of Methylation and Nrf2 in Environmental Illness-  
  Is This A Better Explanation than NO/ONOO- ?
  
  

Additional Citation:

• Frye, R. E., Huffman, L. C., and Elliott, G. R. (2010). Tetrahydrobiopterin as a novel therapeutic intervention for autism. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 7(3):241-249.
  http://www.citeulike.org/user/HEIRS/article/7557630

Chronic metals ingestion by prairie voles produces sex-specific deficits in social behavior: an animal model of autism.

"chronic metals exposure may contribute to the development of autism, possibly by interacting with central dopamine function, and support the use of prairie voles as a model organism in which to study autism."


CiteULike: Chronic metals ingestion by prairie voles produces sex-specific deficits in social behavior: an animal model of autism.:

HO/CO and NO Regulate Oxytocin - Anxiety and Autism Implications?

Considering the relationship of oxytocin to behaviors such as fear, aggression and attachment, this study may have significant implications for PTSD as well as social problems such as violence and neglect. Also, it presents a question of whether a decline in the antioxidant system may also positively or negatively have an influence because it regulates HO-1.

Blockade of HO inhibited both basal and osmotically stimulated OT release, and induced a marked increase in NOS activity. These results indicate the involvement of CO in the regulation of NOS activity. The present data demonstrate that hypothalamic OT release induced by osmotic stimuli is modulated, at least in part, by interactions between NO and CO.

CiteULike: Carbon monoxide and nitric oxide modulate hyperosmolality-induced oxytocin secretion by the hypothalamus in vitro.: "Gomes, D. A. A., Giusti-Paiva, A., Ventura, R. R. R., Elias, L. L. K. L., Cunha, F. Q. Q., and Antunes-Rodrigues, J. (2010). Carbon monoxide and nitric oxide modulate hyperosmolality-induced oxytocin secretion by the hypothalamus in vitro. Bioscience reports, 30(5):351-357."

SNP in Gene Associated W/ Autism Present in CFS, Study Says!

DISC1 Ser704Cys might be a functional variant that affects one of the mechanisms implicated in the biology of CFS.

"Fukuda, S., Hashimoto, R., Ohi, K., Yamaguti, K., Nakatomi, Y., Yasuda, Y., Kamino, K., Takeda, M., Tajima, S., Kuratsune, H., Nishizawa, Y., and Watanabe, Y. (2010). A functional polymorphism in the disrupted-in schizophrenia 1 gene is associated with chronic fatigue syndrome. Life sciences."

CiteULike: A functional polymorphism in the Disrupted-in schizophrenia 1 gene is associated with chronic fatigue syndrome.:

The Ammonia Hypothesis - A Science and Protocal of Spiritual Alchemy

The following ties together much of what I have written on the possible physiology of kundalini so far and is the most speculative piece in this book. I am pretty sure that convulsive/seizure/kindling can actually produce ammonia, as well as be caused by ammonia. If so this could be one of the main causes of people running into extended periods of difficulty with kundalini.

CiteULike: The Ammonia Hypothesis - A Science and Protocal of Spiritual Alchemy: "The ammonia hypothesis - a science and protocal of spiritual alchemy."

Thought for the Day: Hyperammonemia and Environmental Illness...

Does anyone see these as being familiar symptoms? To me, they seem like some common symptoms in CFS or exposures????

The symptoms and blood ammonia values of mild to moderate chronic hyperammemia (CH) are similar to those observed during physical exhaustion with ‘exercise-induced hyperammonemia’ (EIH). These include confusion, hyperventilation, and muscular dysfunction.....Treatments for lowering CH and EIH are similar, and include: 1) restriction of dietary
protein, 2) increasing carbohydrate (%) intake, 3) administration of amino acids (AA’s)that enhance ammonia clearance into (the less toxic) urea, and 4) correction of the underlying metabolic etiology

HEIRS Library Tags: Hyperammonemia
Blog Tags: Hyperammonemia, ammonia

Edwards, W. ARM CRANK POWER AND HYPERAMMONEMIA IN RESPONSE TO L-ASPARTIC ACID SUPPLEMENTATION. PhD thesis, Louisiana State University.
http://www.citeulike.org/user/HEIRS/article/7111333

Environmental factors maybe key in autism boom since 1988 says EPA

Environmental factors maybe key in autism boom since 1988 says EPA: "Environmental factors maybe key in autism boom since 1988 says EPA"

Dysfunction of Methylation and Nrf2 in Environmental Illness - Is This A Better Explanation than NO/ONOO- ?

One of the most important themes of my research is that accumulation of ammonia may play a causal role in including in conditions such MCS and autism through alterations in the methionine and glutamine synthetase pathway and elevations of ammonia in general which may change the expression of a variety of genes that regulate cell function. Of course, this has been suggested by a number of experts. Further, I also have proposed that the dysfunction in Nrf2 and related genes contribute to the severity and elicits autoimmune-type responses and chemicals such as PFOS may influence it or "trigger" it in addition to other chemicals that are more commonly considered as more toxic. In support, in support it has been suggested that hyperammonemia may alter that nitric-oxide-cGMP pathway (Hermenegildo) and as a result this could alter NO funtioning and contribute to conditions such as fibrosis in some tissuesand endothelial dysfunction. Alterations in the ornithine pathway may contribute to this but it is worth mentioning that NO may alter this pathway on it own. (Bauer) Interestingly, recently it has been reported that one of the benefits of fish oil may be mediated through the eNOS-cGMP pathway. (Lopez)  Nrf2 also has an important role in regulating NO and CO through its interaction with the antioxidant HO-1 and plays a substantial neuroprotective role against diseases such as Parkinson's disease. The deficiency or lack of Nrf2 expression offers one explanation of why individuals with MCS are so sensitive to carbon monoxide, nitrous oxide and other greenhouse gases. Mainly, because of the dysregulation of their regulator HO-1 by Nrf2. Tinnitus is common with MCS and can be associated with over-exposure to nitrous oxide which may also indicate problems associated with vitamin B and methylation. (Wipedia) Genetic polymorphisms in HO-1 and metal toxicity may also contribute to this problem. (You can see how lead, mercury and aluminum alter function in different steps in the cycle....here but you have to look closely.) Other Nrf2 interactions include modulation of Il-6 which is elevated in neuroinflammatory responses in the brain and Il-10 which is an anti-inflammatory that modulates sickness syndrome. According to a new report, sickness syndrome may be implicated in causing some of the symptoms of Gulf War Syndrome.


In addition, conditions such as elevations of ammonia activate the CRF pathway in animals that display hyperanxious behavior and recently this pathway has been shown to regulate both anxiety and depression as a consequence of stress. (Biomedicine) Interestingly, the glutamine pathway is also altered during depression and as a result, one may suggest this pathway may be dysregulated from exposure to chemicals such as PFOS and cause mood changes such as depression and anxiety and endogenous elevations of ammonia may induce mood changes even more. In addition, dysfunction of Nrf2 may lead to neurotoxicity and other consequences including augmenting ammonia accumulation. Chemical sensitivity has been implied as important in autism and ammonia may contribute to this which is produced endogenously and exogenously and many therapies used for MCS have also been used to reduce ammonia levels in autism. An interesting suggestion is that in some form through the dysfunction of Nrf2, deficits in the ornithine pathway contribute to the cellular toxicity experienced in MCS and autism. Of course, there are a number of other genetic defects that may alter the urea-cycle, including minor ones that may not appear until adulthood or later because of compensation from other pathways lost with ageing. Ammonia production is higher correlated with inflammatory markers in liver injury and has a profound effect on the permeability of the blood-brain-barrier, providing access of more toxic agents to brain tissue. (Jalan)

Alterations in the methionine pathway have also been suggested to play an important role in autism and we suggest here, MCS and relies on the notion of abherrant methylation "tagging" that potentiate the problems or vice versa. Q10 and vitamin B12 has been used as a therapy for MCS but is also used to assist mitochondrial function and support the methionine cycle and reduce ammonia, respectively. In methyl cycle disfunction, BH4 is drained in ammonia detoxification (Yasko ?) in addition in contrast to its role for NOS production and peroxynitrite which is part of the NO/ONOO- hypothesis. (Pall) Here we see the dichotomy between the Methyl Pathway and the NO/ONOO- hypothesis where BH4 is concerned. In one BH4-dependant process, NOS is converted to nitric oxide and on the other hand it assists in ammonia detoxification in the methylation cycle. If you put alterations in Nrf2 function, which is activated by ONOO- into the mix it can alter expression of genes important for these processes. ONOO- is not the only pro-oxidant that activates the Nrf2, it has been suggested that H2O2 is a much stronger activator and numerous other conditions normally upregulate Nrf2 in normal circumstances. Marzec recently demonstrated that SNPs that exist in the Nrf2 may make on more or less susceptible to oxidative stress and therefore cellular injury and disfunction. The inheritability hypothesis of epigenetics also relies on methylation and helps to explain why environmental illnesses largely run in families and the relationships between gene expression help to explain why gender plays an important role too! Unfortunately, alterations in methylation and consequently, alteration of function has been demonstrated in Nrf2 and several other genes implicated in environmental illness including autism. (To get an idea of how complicated genetics in environmental illness is --click here. ) In addition, alterations in Nrf2 and PGC-1a may contribute to diabetes and insulin resistance and are associated with POP exposures. In addition, GSK-3b involvement from reduced expression of PGC-1a, elevations in dopamine and exposures to bacteria (endotoxin) are a few additional factors that may hamper Nrf2 detoxification system which can lead to more elevations of neuroinflammatory processes, mood changes and significantly increase the likelihood of more neurodegeneration; all associated with environmental illness. GSK-3b signalling also may involve alterations in dopamine-regulated behaviors such as twitching (Tourette's) and ADHD that are often co-morbid with environmental illnesses after exposure injury. Incidentally, a number of behavioral responses to drugs (ie cocaine) can be reduced by GSK-3b inhibitors.

Currently, the NO/ONOO- cycle hypothesis which implicates elevation in ONOO as an important cause for responses in the conditions and proposed by Martin Pall, PhD is one of the most commonly accepted hypothesis to explain many of the symptoms in many environmental illnesses including MCS, chronic fatigue syndrome, fibromyalgia and PTSD. While this hypothesis is an important one, I can not say that it accurately describes the multi-inflammatory processes that occur in all of these illnesses and fails to adequately describe the metabolic processes that lead to these conditions. For one, obesity and insulin resistance and diabetes are important in environmental disease and the complications of ageing augment most of these and others as well. Recent evidence is highly suggestive these conditions may influence the development of the more commonly accept EI conditions and for this reason, I have to include them under that umbrella as well. In addition, there is no mention of methylation or how dysregulation of the antioxidant system Nrf2 negatively impacts the expression of NO, CO, HO-1, Il-10 as well as, modulates inflammatory cytokine expression. HO-1 (again with interaction from Nrf2) and vitamin D are involved in the suppressive function of regulatory Tcells. Their absence has been implicated in autoimmune disease that provides an explanation for why environmental illnesses like CFS and GWS and others including diabetes have autoimmune-type behavior. A recent study has presented the hypothesis that exposure to environmental pollutants and high ammonia levels directly alters Treg behavior. In would suggest the inability of oxidants including peroxynitrite and H2O2 to activate Nrf2 is one explanation for failure of the Nrf2 antioxidant system in addition to impairments in activation and regulation of Keap1 and genetic expression of the many genes that regulate the system in different ways. Not only does Nrf2 regulate NO but so does SIRT1 through AMPK, all of which are indirectly or directly involved in activating PGC-1a upregulated by exercise which prevents activation of GSK-3b that turns off the antioxidant system which provide upregulation of nuclear factors including NRF1. In further support, pharmaceutical therapies such as those that elevate PGC-1a and reduce ammonia levels, electroacupuncture, food therapies that elevate Nrf2 through sauna or Waon therapy and nutrition and antioxidant support to reduce mitochondrial dysfunction may be a valuable "tool kit" for the treatment of MCS, autism, provide some relief in CFS and PTSD and help prevent endothelial damage that may be instrumental in causing a number of conditions in many of them.

HEIRS Tags: ammonia, hyperammonemia, homocitrulline, diabetes, insulin resistance, GSK-3b, HO-1, Nrf2, PGC-1a, SIRT1, AMPK, NO/ONOO-, H2O2, dopamine, DAR, cocaine, encephelopathy, Il-6, neuropathy, B12, methionine


HEIRS Tags: ammonia, hyperammonemia, homocitrulline, diabetes, insulin resistance, GSK-3b, HO-1, Nrf2, PGC-1a, SIRT1, AMPK, NO/ONOO-, H2O2,

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Original Article and Citations:

Preliminary Study Shows Polymorphism in Different Loci of Autism/Aspberger's Gene in Chronic Fatigue Syndrome.

Preliminary Study Shows Polymorphism in Different Loci of Autism/Aspberger's Gene in Chronic Fatigue Syndrome.

A preliminary study suggests that a polymorphism in the DISC1 gene is associated with chronic fatigue syndrome. These findings, if found to be true, have important implications for the conditon, as well as, may have an influence on research findings of other environmental illnesses. DISC1 is also known as Disrupted in Schizophrenia and has been associated with a number of mental health conditions including schizophrenia, bipolar disorder and major depression. Just recently the gene has also been implicated in playing a role, in addition to other genes, in autism. We have noted before that some experts believe that conditions such as ADHD and certain types of MCS are in fact, autism spectrum disorders. As one author points out, DISC1 is responsible for a number of physiological activities including the production of new neurons during brain development and adult neurogenesis. A defective DISC1 gene which has been demonstrated in schizophrenia could lead to a reduction in dendritic spines and also influence nerve cells to maintain weaker connections with neighboring neurons and for the purpose of simplification, reduce the "cross-talk" between neurons by influencing dopamine production. If similar disruptions through mutation in DISC1 were to occur, it does make sense it may be involved in the development of autism because of its effect on the central nervous system. (Tsai)


Of course, the idea that it plays a role in chronic fatigue syndrome is a novel finding. From my standpoint, the idea that DISC1 may play a role in CFS makes a lot of sense. As I have described in other blogs, a protein called GSK-3b is an on/off switch for Nrf2 which provides a protective role against endogenous threats that may negatively influence neurotransmission  in autism. Recently, it was demonstrated that the Wnt pathway is a pathway involved in ammonia and urea excretion that also involves the activities of GSK-3b. Biochemically, one researcher writes that DISC1 inhibits GSK-3b and therefore, this pathway has been suggested to play the important role in a number of mood disorders which we noted earlier. Like most anything in cell biology, too much activity or too little can have dramatic effects on function. In the case of GSK-3b, blocking its abherrant signaling has been associated with symptomatic benefits in MS, colitis, sepsis and arthritis and conditions involving inflammation. The latter implicates an inhibitory role of GSK-3b signaling on Nrf2. Elevations of GSK-3b activity are also present in patients with Parkinson's disease and Alzheimer's. A recent report from MIT demostrates that DISC1 knock-out present with behaviors including hyperactivity, a characteristic of schizophrenia and GSK-3b inhibitors reversed these behaviors. The author suggests that the scewed balance of neural cell development and alterations in signaling may lead to compromised cognition and behavior alterations. (Halber) A polymorphism in DISC1 that has been suggested in CFS could very well lead to abherrant signaling from GSK-3b, elevations in oxidative stress and uncontrolled expression of inflammatory proteins and changes in redox because of subsequent loss of Nrf2 signaling. Of course, other factors such as genetic SNPs in Nrf2 and suppression of gene expression should also be considered.

Citations and Original Document

Autism, Ammonia, Irritable Bowel Syndrome, Inflammatory Bowel Disease and Environmental Odorants

It is often asked whether or not intestinal problems such as irritable bowel syndrome and inflammatory bowel disease are associated with environmental illnesses such as chemical sensitivity. As a researcher, I would say undoubtedly so and to explain some of the reasons for this and present some interesting hypotheses and studies as well. First, it is true there is still no general consensus on what causes irritable bowel syndrome. However, in the last few years inroads have been made on settling the debate. In a preliminary report out of Heidelberg, the author states they have found mutations possibly associated with IBS, that "appear to cause changes in the composition or number of receptors on the cell surface. "The signal transduction in the digestive tract may be disturbed and this may lead to over stimulation of the intestine. Resulting disturbances in fluid balance could explain the occurrence of diarrhea," says Johannes Kapeller, a PhD student in the team.  Other studies and researchers have found similar findings and other possible causative agents for the development of both conditions.

I recently discussed at length the potential relationship of high ammonia levels in autism, in addition to the fact it may be implicated as a causal factor in a number of environmental illnesses including multiple chemical sensitivity and irritable bowel syndrome. Chemical sensitivity in autism has been noted for many years and I find it curious that a writer from 2003 notes several things about autism including autism therapies (Deth, Cully) that are similar to therapies for treatment of MCS in Pall's book "Unexplained Illness" and the NO/ONOO cycle. While the true cause of autism is still unknown, for the last several years, a number of health experts have proposed that symptoms of autism may be associated with small bacterial overgrowth (SIBO) and excess ammonia in the intestinal tract. Recent reports also suggest a role of bacteria and high ammonia in the inflammatory and pain and anxiety conditions, inflammatory bowel disease and irritable bowel syndrome, respectively. Enterochromaffin cells are secretory cells in the digestive tract and regulates intestinal responses depending on the immunological profile of the inflammatory response (TH1/Th2). In post-infectious IBS (PI-IBS) the enterocromaffin cells which are associated with serotonin secretion are implicated in some of the "mood" issues including anxiety and depression as well as, responding to the chemical composition of gut contents and pathophysiological contractions. (Nozawa) Of MCS significance, Tack has recently identified that "odorants present in the luminal environment of the gut may stimulate serotonin release via olfactory receptors present in human enterochromaffin cells" that may influence gut motility, nausea, vomiting and IBS. (Braun) Also, TRPV1 nociception which has been implicated in MCS also may alter motility through EC cells. (Nozawa, Pall)  Kim explains that the normal mucosal layers of the intestinal tract may play a role in the chronic inflammatory process in inflammatory bowel disease. Further he says,  "the enteric microbiota may drive the development of the gut immune system and can induce immune homeostasis as well as contribute to the development of IBD although the precise etiology is still unknown. However, the interactions with microbiota with T cells, intestinal epithelial cells, dendritic cells have all been implicated as contributors to the condition. (Kim) It might be wise to consider that environmental triggers might influence the constituents of the microbiota to act differently that lead to more pathogenic behavior. In colitis, a recent report suggests that a higher level of serotonin is the result of an increase in enterochromaffin cells (EC), and/or more serotonin in them and a decrease in the serotonin exporter RNA. (Bertrand)  Other reports show the involvement of GSK-3b protein which interacts with something called the Wnt/Catenin pathway and may increase ammonia levels as well as, shut of the astrocyte protective and antioxidant system Nrf2 which increases the likelihood of tissue injury and potential nerve damage from intestinal inflammation. Inhibitors of GSK-3b have been protective of endotoxic shock and also show significant benefits in treating mood disorders, prevent weight loss and activations of the inflammatory cascade by a protein called NF-kappaB. (Whittle) These mechanisms also support a recent discovery of a significant communication pathway of regulation between the gut and the brain, and even more strongly supports why inflammation in the gut may lead to changes in neurotransmission and upregulate or downregulate a number different genes and therefore, play a part in sickness syndrome.

Two decades ago, a study determined that H pylori, a bacteria in the gut, causes elevations of gastric juice ammonia (which can also bind transition metals) and subsequent findings include alterations in other gastric juices and enterochromaffin cells, changes in stomach mucosa and general injury and inflammation. (Lichtenberger) As far as the role of bacterial overgrowth goes as an important factor in IBS, this is still somewhat controversial, however, the idea is gaining in popularity. Spiller explains that recovery from post infectious-IBS can take 5 years or more and that time-table does not include potential for reinfection. The most recent studies on some strains of probiotics show promise for treatment and these findings are interesting because they support ammonia involvement in intestinal issues. Hyperammonemia is a common complication of acute and chronic liver disease and therapy may consist of antibiotics and lactulose that slows down the production and absorption of ammonia. In treating, hepatic encephalopathy lactulose works by reducing absorption from the gut to prevent the toxin from getting to the brain. Under pathological conditions, ammonia can pass through the blood brain barrier and may impair brain function, cause confusion and in the most severe cases, coma. (NetDoctor) Elevated levels can be consistent with chronic conditions and as we noted before, have been implicated in causing symptomatic issues in autism. Nicaise et al demonstrates that in his study probiotics decrease blood and fecal levels of ammonia and were better at it than lactulose. He found the study probiotics strains were able to convert ammonia to alanine to reduce ammonia levels. Astrocyte swelling is reduced with probiotic use and expression of Nrf2 has been shown to protect astrocytes from damage in hyperammonemia. Also, the probiotics decreased hyperammonemia by acting on the ammonia transporter and genetically-altered-probiotic-consuming NH3 strains reduced ammonia levels even farther. Recently, other studies show probiotics may be used effectively in IBS, colitis and Crohns and are able to modulate IL-10 an anti-inflammatory cytokine. This same cytokine is implicated in modulating sickness syndrome and is regulated by HO-1 which is modulated by Nrf2.

Alterations in cortico-releasing factors (CRF), a key regulator of cortisol in the brain have been associated with IBS, depression and anxiety. I recently wrote how hyperammonemia is associated with negative effects of cortico-releasing hormone(CRF) on mood and how high ammonia levels cause a number physiological effects in trout that are comparable to symptoms in sickness syndrome. These changes may include changes in dopamine and serotonin and the latter, may influence ammonia-mediated appetite suppression. While I hesitate to compare health conditions in humans to those in animals such as fish, these finding are interesting never-the-less. (Ortega) In mice, CRF effects similar behaviors including feeding, anxiety and activation of the sympathetic nervous system. Hyperammonemia alters the circadian rhythym of corticosteroids and motor activity in rats while not producing anxiety (Ahabrach) while flavanoids such as quercetin, can reduce CRF's activation of the HPA axis. (Kawabata)

Therer are any number of genes and polymorphisms that can effect metabolism that may lead to diseases of the intestinal tract or any organ for that matter and ammonia is just one of many. At present, scientists have only just begun to discover with the use of genetic studies to discover how these polymorphisms may differently effect the health of individuals and populations. There are many yet to be discovered. Genetic counselors can be a tremendous help in this respect, sometimes just by noting and being familiar with "patterns".  Dr. Yasko supplies a pretty good break-down of genetic conditions that may alter and contribute to high ammonia levels in one posted article but it is not all inclusive.  A genetic counselor I am not going to discuss each of the genes SNPs because the article is long and detailed but quite informative. She does note that ammonia regimines need to be monitored and sometimes changed and therefore, any therapeutic program that addresses genetic influences needs to be done in consultation with a physician. I have explained how different genetic conditions can impair proper ammonia excretion and much of that is explained in this paper. I am not a doctor and therefore will not comment on her treatments but have read about her practice in the literature. She points out a few things I found interesting including hazards associated with some "alternative" therapeutics including epsom salts, MSM and the consequence they can be metabolically be converted to ammonia and may effect the function of another enzyme. I have researched this enzyme and indeed, there may be some concerns with this enzyme in some people with environmental illnesses. This article in this respect and as a whole provides an interesting read and more importantly possibly warrants a discussion with your doctor. (Yasko) Because ammonia levels may influence autism and other conditions as mentioned above, I believe this discussion may be an important priority.

It is difficult to predict how endogenous and exogenous chemicals are going to react to produce health effects including increasing the tendency for chronic conditions like IBS and autoimmune-type inflammatory disease. A recent study demonstrated different mouse strains have different before and after levels of antioxidant genes including glutathione, Nrf2 and HO-1 and also have higher levels of oxidative stress upon exposure to cigarette smoke. It also demonstrates variations exist between individual organisms (mice) which may be comparable to differences in the immune response that might occur in individuals in different populations. From a population health standpoint, different populations may be more or less susceptible to exposures and consequently certain diseases. This potentially becomes more of a concern when there is a poor quality of health care system and disparities already exist in those populations. To support this idea, a study was released in 2007 that identified population differences exist in the Nrf2 gene and concluded they may make them more or less resistent to oxidative stress and lead to an increased prevalence of disease and lower quality of life. (Marzec) Conditions of mixed and chronic environmental stress where there is a reduction in the ability to activate and control the adaptive response has important and broad implications for the health status and adaptive ability of a population as a whole. Several years ago, one researcher found hydrazine, an agricultural product, had a negative effect on the B12-dependant methionine synthase pathway and as a consequence from homocysteine elevations impaired the urea cycle and sulphur amino acid detoxification. (Kenyon) Exposure to nitrous oxide (laughing gas) can deactivate B12 and potentiate impairments in the cyles that eliminate ammonia and in recent weeks, it was reported that exposure to the greenhouse gas nitrous oxide from home maintainance of lawns can be as significant as the amount produced by agriculture and therefore ubiquitous in the environment. With this in mind and in a mixed environment, the study on cigarette smoke mentioned earlier becomes more significant because in the past cigarettes have added ammonia to make themmaking them more addictive. In addition to the hundreds of contaminants in cigarette smoke, it also contains bacteria that may have the potential to cause infectious disease and contains endotoxin that elicits inflammatory responses. Interestingly, the absence of GSK-3b, the on and off switch for Nrf2, eliminates Tnf-a and NF-kappaB signaling from both endotoxin and cigarette smoke. (Takada) This suggests ammonia in cigarette smoke has the potential to down-regulate the Nrf2 system and may help explain the variety of health effects from these exposures and increased sensitivity to them in some individuals. In support the research by Hubner reported that Nrf2 plays "important roles in cellular defenses against smoking in the epithelium and there is variability within populations of oxidant burden. (Hubner) All of this, can lead one to assume that variants in the exposures to agricultural products, alterations in nutritional status and genetic variants may increase the likelihood of any number of diseases including irritable bowel syndrome and inflammatory bowel disease.

Finally, it is important to review some important general health consequences of high ammonia levels. As we have noted, hyperammonemia can be caused by enzyme deficiencies or liver disease and because liver damage and impairment of antioxidant systems are concerns upon exposures, high ammonia levels should be considered as a factor in patients with environmental illnesses. "Hyperammonemia does cause astrocyte swelling (acute hyperammonemia) to astrocytosis (chronic hyperammonemia) and when the urea cycle is impaired, changes to allow for the excretion of ammonia occur in the brain. Some of these changes include changes in glutamate regulation and drug receptors (benzodiazipine) in the mitochondria. Acute changes include activation of NMDA receptors (although some may argue this) and chronic hyperammonemia may cause increases in tryptophan metabolites including serotonin. As one author stresses, current therapies for hyperammonemia are mediated through reduction of ammonia levels through the gastrointestinal tract and increased ammomia in the muscle." (Butterworth) Further studies show that IDO, an enzyme involved in the catabolism of tryptophan, has protective qualities against certain immune reactions and this is achieved through T cell suppression. These findings may lead to more supportive evidence of a loss of T cell suppression and an increase in autoimmune responses in MCS reactions. Other studies show oxidative stress plays a role in the neuropathology of ammonia toxicity and cause derangements in the cerebellum and cerebral cortex that lead to both increasing or decreasing antioxidant levels in both of these areas in acute and chronic ammonia toxicity.(Singh)

For further emphasis:

• Iron Leads to Memory Impairment that is Associated with a Decrease in Acetylcholinesterase Pathways.

For Clinical Professionals:

Citations located here.

Nrf2, Ornithine Transferase, Autism and Maternal Age -- A Possible Link?

Recently a report was published of a link between autism and maternal age. While some may criticize that such admissions are worthless, I beg to differ. The Nrf2 antioxidant system which controls a battery of protective genes also controls an enzyme called ornithine aminotransferase which protects against ammonia. High ammonia levels have been implicated as a possible cause for some types of autism. There are behavioral conditions that may improve levels of Nrf2 expression including diet and exercise. While this may be premature, it should be worth more study from autism experts.

Past HEIRS Environmental Illness Research Blogs of Interest:

• Chronic hyperammonemia impairs the glutamate-nitric oxide-cyclic GMP pathway in cerebellar neurons in culture and in the rat in vivo.
• Mitochondrial MAO Enzyme May Contribute to Oxidative Stress in Hyperammonemia!
• Chronic hyperammonemia alters the circadian rhythms of corticosteroid hormone levels and of motor activity in rats.
• Episodic hyperammonemia in adult siblings with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome.
• Hyperammonemia, Subordination, Hypoxia Influence Stress Hormone CRF Production in Fish
• Neutrophic Factors Protect Against High Ammonia Levels
• Ammonia, Methamphetamine, Cigarette Smoke and Parkinson's Disease
• Nrf2 and Cigarette Smoke ---A Possible Link to B12 Deficiency.......?
• Altered Metabolism, Toxicity, Glutamate Dehydrogenase and NRF-1 and Its Activator PGC-1
• Taurine rescues hippocampal long-term potentiation from ammonia-induced impairment.
• Effect of Acute Exposure to Ammonia on Glutamate Transport in Glial Cells Isolated From the Salamander Retina -- Mort et al. 86 (2): 836 -- Journal of Neurophysiology
• Endotoxin Inactivates Glutamine Synthetase and Impairs Ammonia Elimination in Rats
• Ammonia, ASIC Channels and Mental Health
• Ammonia and Its Relationship To Environmental Illness
• Appetite-suppressing effects of ammonia exposure in rainbow trout associated with regional and temporal activation of brain monoaminergic and CRF systems
• Effects of ammonia and allopurinol on rat hippocampal NMDA receptors.
• Elevated Ammonia and Endotoxin: Implications for Synergistic Toxicity in Environmental Illness
• ImmunoGenetics in Autism, MCS and Cancer -- What Has Food Got To Do With It!

HEIRS Library Tags: PGC-1a, Nrf2,
    Other Blog Tags: PGC-1a, Nrf2,

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Thimmulappa, R. K., Mai, K. H., Srisuma, S., Kensler, T. W., Yamamoto, M., and Biswal, S. (2002). Identification of nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res, 62(18):5196-5203. http://www.citeulike.org/user/HEIRS/article/3728059?show_msg=already_posted
University of California - Davis - Health System (2010, February 8). Link between advanced maternal age and autism confirmed. ScienceDaily. Retrieved February 9, 2010, from http://www.sciencedaily.com/releases/2010/02/100208102411.htm
Holmes, Amy, MD. Heavy Metal Detoxification and Metallothionein Promotion. Autism Treatments. The Healing Center Online. Retrieved on February 10, 2010.

Ammonia, ASIC Channels and Mental Health

We recently have been discussing how the biological accumulation of ammonia may be an important condition related to a number of environmental illnesses. In fact, several studies suggest that accumulation of ammonia may contribute to autism and others note it plays a very important role in hepatic failure. As we noted, elevated levels of homocysteinemia may impair the urea cycle - which helps the body get rid of excess ammonia and glutamine synthetase genes of the Wnt/Catenin pathway, also regulate  ammonia concentrations in the body. Interestingly, several "so-called therapies" for MCS also have the capacity to reduce ammonia. Also, it is well-known that psychological disturbances are co-morbid with a number of environmental conditions, in addition to those mental effects associated with autism and liver disease.

In light of the potential for elevated ammonia levels to influence the psychological and physical effects of environmental disease, I thought I would point out two interesting studies. The first is a study that suggests that ASIC channels contribute to the health consequences where hyperammonemia becomes an issue. As the author points out, this may include hepatic encephalopathy, cirrhosis and neuronal disorders. This study discusses how these types of channels have been implicated in neuronal death after their activation. Incidentally, nociceptive behavior is associated with acidic environments that develop from injury and inflammation and therefore could play a role in the pain generation in environmental illnesses including  MCS (Pall) and chronic fatigue syndrome (Light).  Pidoplichko provides evidence the involvement of these channels may contribute to the loss of dopamine neurons in Parkinson's disease because these channels are associated with those neurons and "ammonium sensitivity is a widely distributed ASIC characteristic in the CNS, including the hippocampus." The second study seems to suggest that these same channels have an important role in the development of depression-related behavior by demonstrating genetically altered -/- mice presented with anti-depressant-like behaviors even while put under experiemental stress. In addition, the dysruption of these channels interfered with an important "biomarker of depression" which is a decrease of levels of BDNF in the hippocampus. In past blogs, we have explained how BDNF is important for "olfactory neurogenesis" and may be important consideration in the development of MCS.  Coryell concludes by saying that his "findings of ASIC1 signaling in the amydala in mood regulation support others and that pharmaceutical approaches that target ASIC1 signaling may be therapeutic for this kind of depression. We might propose that investigating therapies that reduce ASIC signaling may be beneficial for a number of environmentally-related conditions may be of value.

Notes:

• A recent study shows that HO-1 activates bilirubin and CO to modulate BDNF/GDNF in neurons and astrocytes. This provides a protective effect on dopaminergic neurons.

Coryell, M. W., Wunsch, A. M., Haenfler, J. M., Allen, J. E., Schnizler, M., Ziemann, A. E., Cook, M. N., Dunning, J. P., Price, M. P., Rainier, J. D., Liu, Z., Light, A. R., Langbehn, D. R., and Wemmie, J. A. (2009). Acid-sensing ion channel-1a in the amygdala, a novel therapeutic target in depression-related behavior. J. Neurosci., 29(17):5381-5388. http://www.citeulike.org/user/HEIRS/article/6607146
Pidoplichko, V. I. and Dani, J. A. (2006). Acid-sensitive ionic channels in midbrain dopamine neurons are sensitive to ammonium, which may contribute to hyperammonemia damage. Proceedings of the National Academy of Sciences of the United States of America, 103(30):11376-11380. http://www.citeulike.org/user/HEIRS/article/6607127
Light, A. R., White, A. T., Hughen, R. W., and Light, K. C. (2009). Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects. The journal of pain : official journal of the American Pain Society. http://www.citeulike.org/user/HEIRS/article/5370052
Ugawa, S., Ueda, T., Ishida, Y., Nishigaki, M., Shibata, Y., and Shimada, S. (2002). Amiloride-blockable acid-sensing ion channels are leading acid sensors expressed in human nociceptors. The Journal of clinical investigation, 110(8):1185-1190. http://www.citeulike.org/user/HEIRS/article/2942104
Pall, Martin (2007). Explaining Ünexplained Illnesses": disease paradigm for chronic fatigue syndrome, multiple chemical sensitivity, fibromyalgia, post-traumatic syndrome, Gulf War syndrome, and others. Harrington Park Press:Hawthorne Press, 10 Alice Street Binghampton NY 13904. http://www.citeulike.org/user/HEIRS/article/3042479
Hung, S.-Y. Y., Liou, H.-C. C., and Fu, W.-M. M. (2010). The mechanism of heme oxygenase-1 action involved in the enhancement of neurotrophic factor expression. Neuropharmacology, 58(2):321-329. http://www.citeulike.org/user/HEIRS/article/6196852

Ammonia and Its Relationship To Environmental Illness

Background: The build-up of excess ammonia has been implicated in environmental conditions such as autism and may contribute to physiological effects of others as well. In recent days, we have discussed how homocysteinemia may impair the urea cycle which may lead to excess ammonia levels and that some common treatments used for environmental illness also are used as treatments to reduce physiological ammonia levels. Exogenous environmental factors may also lead to elevations in ammonia. Interestingly, in fish, exposure to ammonia leads to symptoms one may conclude typical of sickness syndrome which includes loss of appetite. While it is difficult to extrapolate behavior in these animals to similar behaviors in humans, we have mentioned previously that sickness syndrome is not exclusive to the human organism and has been observed in other animals (ie domesticated dogs). In the recent study of fish, ammonia activates the stress regulator corticotropin releasing factor and other stress systems including the one that controls dopamine and leads to elevations in this stress hormone also. The activation of this system has also been implicated in psychological effects associated with PTSD in humans and addictive behaviors such as alcohol abuse.

Taken these studies into account, one would suggest that ammonia which also contributes to mitochondrial dysfunction may contribute to a number of environmental illnesses by activating different systems during the stress response and may exacerbate the complications associated with injury or down-regulation in function from toxic exposures to the liver.  In addition, there are several negative psychological and physical effects in environmental illnesses that can be attributed to abherrant signaling by GSK-3b which is modulated through the Wnt pathway.   As Burke writes, "The liver contains two systems for the removal of ammonia - the urea cycle and the enzyme glutamine synthetase. These systems are expressed in a complementary fashion in two distinct populations of hepatocytes, referred to as periportal and perivenous cells. One of the unresolved problems in hepatology has been to elucidate the molecular mechanisms responsible for induction and maintenance of the cellular heterogeneity for ammonia detoxification. There is now a potential molecular explanation for the zonation of the urea cycle and glutamine synthetase based on the Wnt/-c:atenin pathway[]." Experts admit there is a lot to learn about this relatively unexplored molecular pathway. However, the most recent evidence suggests it is an important pathway that interacts with other pathways in inflammation and acts as a crucial regulator of functions of different biological systems. Recent studies associate Wnt signaling in inflammation in adipocytes which is the major site for bioaccumulation of toxicants in the body.  This fact elevates the significance of this pathway in environmental health studies. Of course, further research is needed to identify the level of the role it plays on the physical and mental effects of exposures from environmental contaminants.

The Wnt/β-catenin pathway: master regulator of liver zonation?. Zoë D. Burke. 2006; BioEssays - Wiley InterScience

Ortega, V. A., Renner, K. J., and Bernier, N. J. (2005). Appetite-suppressing effects of ammonia exposure in rainbow trout associated with regional and temporal activation of brain monoaminergic and crf systems. J Exp Biol, 208(10):1855-1866. http://www.citeulike.org/user/HEIRS/article/6594636
Castelo-Branco, G., Rawal, N., and Arenas, E. (2004). Gsk-3beta inhibition/beta-catenin stabilization in ventral midbrain precursors increases differentiation into dopamine neurons. J Cell Sci, 117(24):5731-5737. http://www.citeulike.org/user/HEIRS/article/6582306

Neuroinflammation,Diabetes and GSK-3b in Environmental Illnesses

Background: In other blogs, we have described how different proteins interact in molecular pathways to achieve specific metabolic processes. Most often we focus on the Nrf2-PGC-1a-SIRT1 pathway because activation or non-activation will effect cell survival. Recently, we spent quite a bit of time discussing the importance of PGC-1a for metabolic homeostasis and energy metabolism. Friedrich's ataxia is a neurodegenerative conditions that strikes early in life and have used FA as an example for comparison of complications of diseases that arise from Nrf2 dysfunction. Newer studies show that some of the complications in FA arise from dysregulation of PPAR-gamma and PGC-1a and symptoms associated with this dysfunction includes insulin resistance, cardiomyopathy and diabetes. Generally, dysregulation of the PPAR-gamma pathway which is anti-inflammatory leads to abherrant signaling from NF-kappaB. NF-kappaB increases mediation of inflammatory cytokines and in addition to inflammation and other health-related consequences, overexpression of NF-kappaB may alter drug metabolism including CYP3A4 which is responsible for the detoxification of over 50% of the drugs currently marketed.


Some of the most severe complications of environmental illnesses occur from neuroinflammation from inflammatory signals initiated through TLR and NF-kappaB. Under normal conditions, a number of different proteins interact to provide protective mechanisms to prevent inhibition of cellular function. It has been shown that GSK-3b overactivation is a major contributor to neuroinflammation through its role in the disruption of the blood brain barrier (Ramirez) and is at least in part, responsible for complications of a number of neurodegenerative diseases including PD. The activation of GSK-3 increases the production of a number of cytokines including IL-6 and inhibits IL-10. Both PPAR-gamma and another anti-inflammatory Il-10 that modulates sickness syndrome cytokines can inhibit GSK-3b. The over expression of the latter using a kind of "feedback mechanism". In addition to preventing neuroinflammation, GSK-3b inhibition also stabilizes PGC-1a and important regulator of normal mitochondrial biogenesis and energy metabolism. Other studies have showed that GSK-3b also inhibits glycogen synthase that regulates long term energy storage and may account for some of the weight problems reported in those with EI. This hormone is also inhibited by epinephrine and therefore, one may suggest that stress and overactive expression of GSK-3b may potentiate the effects of each other and further exacerbate complications of energy metabolism. In addition, this protein has been implicated as a factor contributing to a number of what are suspected to be neural inflammation-induced mental health conditions including autism, bipolar disorder, other mood disorders, Alzheimer's disease and others.  Incidentally, studies have demonstrated that both endotoxin may influence the activation of GSK-3b. Endotoxin has been implicated as a factor in environmental illness including chronic fatigue syndrome and it has been shown that endotoxin infection-induced GSK-3b by Tnf-a leads to a "synergistic effect" of increasing nitric oxide and reduction of IL-10 while promoting IL-6. GSK-3b, although a necessary protein, has potential for being a therapeutic target for a number of health conditions, including several that are under the "umbrella" of environmental illness. Several months ago we blogged about the evolutionary development of IGF-1 and its relationship to the olfactory system as well as DAF-16 and SKN-1 in lower organisms. Heavy metals may inhibit IGF-1 during the methionine cycle and is a common constituent of air pollution and particulate matter. Bondy explains how IGF-1 has an inhibitory effect on GSK-3b and has direct effects on neural growth and survival during brain development. She further explains how GSK-3b contributes to the loss of olfactory and dentate neurons when IGF-1 is underexpressed which may be important considering that environmental illnesses often present with loss of olfactory function and /or dysregulation.(Bondy) On the other hand , reductions in IGF-1 expression promote longer lifespans and reduce effects of endotoxemia while abherrant IGF-1 signaling may contribute to neuropathic pain, especially in diabetes. (Pabbidi) During nerve injury {ie lead (Williams), low-level toluene(Fujimata)}, NGF (Nicols) can activate both GSK-3b and nociceptors generating inflammatory pain.(Gould) Nociceptive behaviors have been implicated in MCS. (Pall)

Notes:

• EGCG, a compound in green tea, can suppress neurotoxicity by inhibiting GSK-3b.
• Exercise may positive influence the expression of glycogen synthase by inhibiting GSK-3b in skeletal muscle.
• Aging influences increased expression of GSK-3b. (Mercado-Gomez)

For Further Reading:

• GSK-3beta inhibition/beta-catenin stabilization in ventral midbrain precursors increases differentiation into dopamine neurons
• Promoters & Inhibitors of the Metabolic & Antioxidative Pathway of PGC-1a and Its Role in Environmental Illness

Original article and citations located here.

ImmunoGenetics in Autism, MCS and Cancer -- What Has Food Got To Do With It!

ImmunoGenetics in Autism, MCS and Cancer --
What Has Food Got To Do With It

Research scientists are gaining more understanding why certain physical changes occur and are passed on to successive generations without changes to DNA. The field of research that studies involving these kinds of changes is called epigenetics and ultimately examines how behaviors and their influence on biological systems, whether beneficial or detrimental, can be passed on to their descendants. This process is called methylation and simply put, is a where a methyl group attaches to an amino acid which permanently or temporarily silences gene expression. Interestingly, as understanding of methylation advances, its role as a cause of environmental illnesses becomes more and more ignored, at least in the media. Why this is true I can tell you but need to stress here that methylation may be the one or one of the most important factors that contributes to environmental illness including chemical sensitivity, autism, cancer and as you will read probably more....Methylation and its impact on genetic expression provides a mechanism that explains why environmental illnesses run in families and why environmental illnesses and exposures effect children, the elderly and males and females differently. It also provides an explanation for the wide range of reactions and "immunological footprints" present in EI patients.

B12 is considered an important part of most therapy protocals for chemical sensitivity. In addition, it has also been shown that it is beneficial as a cancer treatment because of its ability to cycle homocysteine to methionine which provides a "methyl" group for methylation. Research shows that a B12 deficiency can lead to hypomethylation of DNA which increases the risk for cancer. On the other hand, methylation is important for any number of processes in metabolism that occur billions of times in the body each second and therefore, it is an indespensable process for life. One physician, Dr. Schneider explains that silencing viral genes, methylating the dopamine receptor, changing brainwaves and increasing attention and focus are just a few biological processes that utilize methylation. In addition, she describes that "low methylators" will suffer from a variety of health conditions including eczema, asthma, arthritis, colitis and a host of other illnesses because methylation is necessary to make glutathione; the primary antioxidant used in the body to battle inflammation. S-adenosylmethionine (SAMe) is a "product of methionine metabolism" which modulates Il-10 and Il-6. Both Il-6 and Il-10 are involved in pathogies of environmental diseases including sickness syndrome, PTSD and inflammatory and autoimmune diseases. Il-10 provides a number of effects including protection against cytokine-induced insulin resistance, Il-6, fatigue and motor deficits after pathogenic exposure. It also plays a role in adaptive immunity and differentiation of T cells.

Chronic inflammation can lead to autoimmune diseases. Alterations in Nrf2 function are also implicated in driving TH2 that may present very much like autoimmune disease. If one looks a little closer at autism, one may see some similarities to symptoms common in multiple chemical sensitivity. Autistic children also suffer from a variety of maladies including chemical sensitivity. All in all, it leads one to suspect they may have common "roots" so to speak and the "root" of malfunction lies in the methylation pathway. Remember, autism spectrum disorders include by its definition a spectrum of disorders. It is noteworthy to mention several "methy donors" mentioned for treatments of autism and are also considered to be effective for the treatment of MCS. These include methylcobalamin which is a form of B12, the active form of folate which is a precursor to tetrahydrobiopterin (BH4) and Q10 which improves mitochondrial function.

To further understand the relationships between MCS, autism and other environmental illnesses, we propose and Dr. Scheider, MD suggests, it might be useful to look at several autism pathways which include catecholamine-o-methyltransferase (COMT), methionine synthase, crystathione beta synthase (CBS) and PON1. (Care) These are also pathways suggested in MCS, CFS and other environmentally-induced conditions. Just today, it was announced mutations in PON1 and the exposure to pesticides make one more susceptible to at least one type of Parkinson's disease. (Manthripragada) Methionine is protective against dopamine induced oxidative stress but may induce cellular damage of its own. A cellular enzyme called methionine sulfoxide reductase protects against methionine oxidation; a deficiency in Msra may increase DNA damage. Thus, Msra dysfunction must be considered as a factor in environmental illness. Several studies show that Nrf2 is protective against liver injury which is of course, what one has to consider after chronic or acute toxic injury and Nrf2 deficiency has been associated with autoimmune-type disease. (Li) Homocysteine has also been shown to contribute to liver disease and whether caused by genetic or diet, elevated homocysteine levels "alter the abundance of liver enzymes in methionine metabolism, the urea cycle and antioxidant defense. Homocysteine may impair the urea cycle.Normally this cycle is responsible for converting ammonia into urea for subsequent excretion by the kidneys. As we noted above, pesticides and other crop treatments may influence the development of environmental diseases including Parkinson's disease, autism and MCS. Studies have determined hydrazine, a chemical in fertilizer, causes a reduction in methionine reductase with no involvement from NO or NOS or reversal by arginine, increases homocysteine and impairs the sulphur amino acid pathway. In addition, several gene variants including cysteine b synthase, the less active MTHFR allele and weaker forms of nitric oxide synthase can predispose an individual to high ammonia levels that may also be produced by gut bacteria. Methytetrahydrofolate is often prescribed for high ammonia levels and its mode of action raises tetrahydrobiopterin (BH4). BH4 is an important component of the NO/ONOO cycle mechanism for causing environmental illness including multiple chemical sensitivity developed by Dr. Martin Pall, PhD. As he states, when "BH4 is limited, nitric oxide synthase produces superoxide instead of NO". To support Nrf2's role in chemical sensitivy, it is now understood that Nrf2 sustains the balance between eNOS and the production of NO. Also, gut dysbiota has been suggested as a factor in a number of environmental illnesses including chemical sensitivity, fibromyalgia and especially autism. (Care)

The methionine synthase pathway is dependant on B12 and as Deth explains this pathway is a link between folate and methionine. Recent discoveries have revealed methionine synthase is required for the normal metabolism of dopamine such as its neurotransmission and cognitive functioning of attention and focus and can be inhibited both by thimerasol and heavy metals. At the same time, dopamine activates Nrf2 to minimize the effects of the oxidative stress it produces. Some scientists believe abnormal levels of B12-dependant methionine synthase may contribute to ADHD which occurs much more often in boys and may be, as some experts believe, a mild form of autism. Other studies suggest the difference in prevalence of ADHD in boy and girls is less significant and more likely a consequence of failure to diagnose it accurately in girls. (Consentino) In any case and in keeping with this train of thought, caffeine, a methyl donor, is given to remedy some of the symptoms of ADHD but is more addictive to boys than girls. (MedPage Today) From this, one must ask is there a metabolic difference in the methylation cycle and dopamine cycling or another gene such as COMT that effects males and females differently which increases a male's risk for ADHD? Or could there be a sexual dimorphism in Nrf2 expression that can account for this difference. There is no reason why this could not be true, considering caffeine mediates some of its effects through the Nrf2 antioxidant system? (Cavin) Health studies of Nrf2's role in autoimmune disease shows sexual dimorphism with an increased risk for females. It may be the methionine synthase pathway and Nrf2 together account for the sexual dimorphism of ADHD, in caffeine addiction and possibly overall fitness. It could be these two systems have different influences both positive and negative in both boys and girls.(One study demonstrates methionine deficiency complicates Nrf2 deficiency and Nrf2 regulates the MAO system which can control the expression of neurotransmitters and as a result, influence behavior.) Also, why are male flies more resistant to Paraquat and live longer than females flies that are heterozygous for Keap1. (Keap 1 is an an important regulating protein of Nrf2 and sensor for oxidative stress environments.) These are interesting questions and future research may provide answers to these and other questions such as why do more females suffer from environmental diseases like CFS and fibromyalgia but males suffer more from ADHD! (Sykiotis) An Adaptive Biologist and Medical Anthropologist might suggest these dimorphisms exist as trade-offs in behavior control and provide a protective and limiting mechanism for fertility and child-bearing in females but increase lifespan and elevate the drive for sexual foraging in males. At this point, I do not think anyone really knows!

Deficiencies in Nrf2 null animals of methionine and choline, both methyl donors, make them more susceptible to inflammation and fatty liver. This demonstrates Nrf2 deficiency adds to medical pathologies of "poor methylation". In addition, reduced expression of other proteins that coordinate activities with Nrf2 such as the AhR may also influence susceptibility to symptoms of environmental disease including autism and chemical sensitivity. For instance, both the AhR and Nrf2 are required for the induction of UGT transferases which aid in the excretion of toxic compounds such as drugs, bilirubin, hormones and steroids. In the literature, the alteration of UGT function has been implicated in multiple chemical sensitivity and different cancers. Also, the increase of IGF and dopamine increases methionine synthase activity which also requires an increase in B12 and other biological resources. Studies have shown that blocking the methionine synthase pathways inhibits nerve growth factor's (NGF) induction of differentiation and another researcher reports elevation in NGF in B12 deficiency increases neurogenic inflammation resulting in chronic cough and chronic airway discomfort which are symptoms attributed to MCS. (Battaglia-Hsu) The result of B12 deficiency includes "a peripheral sensory neuropathy, causing symptoms such as numbness, tingling, burning, and complete lack of sensation". (Jockers) These are also commonly reported symptoms in MCS. Mercury and lead have been demonstrated to block this pathway, in addition to, an agent called wortmannin which blocks the pathway PI3K. PI3K inhibitors are used experimentally against inflammation and eventually may be used in cancer therapy. (Crane, Science) In a type of liver cancer, the loss of methyltransferases results in uncontrolled epigenetic methylation of DNA. By looking at some of these other pathways that influence methionine metabolism, one must consider a relationship to MCS and autism spectrum disorders.

An important study was released last year by a Canadian research team that demonstrated inflammation in peripheral organs may cause neuroinflammation in the brain. Specifically, the study explains that diseases such as inflammatory bowel disease, hepatitis, and others can lead to inflammatory processes in the brain that can change neurotransmission, alter gene regulation, etc. One of these cytokines is Tnf-a which activates MCP-1. Currently, neuroimmune inflammation is considered one of "the best" hypotheses of what causes autism spectrum disorders and as Dr. Bratt explains, autism is a complex medical condition involving dysfunction in the brain and nervous system, as well as gastrointestinal, immune, emdocrine and detoxification systems." Specifically, "dysregulated immune responses either directly or indirectly adversely affect the course of neurodevelopment in the brain, leading to the development of autism. Immune abnormalities include increased inflammatory cytokines in the plasma and CNS, specifically neuroinflammatory cytokine interleukin-6 (IL-6), proinflammatory cytokine tumor necrosis factor alpha (TNF-a) and chemoattractant cytokine macrophage chemotactic protein-1 (MCP-1). (Enstrom)In addition to the inflammatory mediators above, altered levels of Il23 are found in patients with autism.

Interestingly, these inflammatory processes have been implicated in most environmental illnesses including MCS. IL-23 is a cytokine that initiates T cells to differentiate into IL17 cells which are different from Th1 or Th2. The difference, is a very recent distinction which adds to confusion in the literature of whether inflammatory and autoimmune diseases such as rheumatoid athritis, lupus and MS are Th2 or Il17. Nonetheless, IL17 can stimulate the battery of inflammatory cytokines mentioned above which is capable of neuroimmune dysregulation in the brain and body systems. Last week, we suggested that the absence of Tregs may influence a Nrf2 positive or negative phenotype into an autoimmune-type disorder and demonstrated how environmental pollutants can change the "immune footprint" depending on the type of pollutant and accordingly drive a Th2 driven phenotype characteristic of environmental illnesses such as MCS because they have inflammatory and autoimmune-like presentations. In addition, a study set of CFS patients have been identified with a lower freguency of a protective variant against an anti-inflammatory phenotype of Il-17 giving credibility to the idea that IL-17 may also play an important role in CFS. This also gives support to the idea that CFS and other environmental illnesses including autism are closely linked to one another, are autoimmune and inflammation driven and Nrf2 and cytokine profiles may significantly influence disease presentation and inflammation severity. In addition, individual genetics can influence the exact nature of disease development and the level of methylation may be key to more differences in genetic expression.

Nutrition is an important mechanism for controlling environmental illnesses. Recent nutritional studies show Western Diets promote inflammation. One reason for this, is because saturated fat alters TLR signals that can lead to potentially harmful "immunological footprints". Personally, in addition to the impact of the influences of environment and genetics on environmental illness, another research focus I have is animal health and human nutrition and how different aspects of both can be effect environmental illness. Domesticated pets suffer from many of the same diseases people do and many experts believe these disease may be attributed to imbalances from eating extruded kibble. Poor diet adaptation is common in both animals and humans. Numerous studies have shown that as humans culturally adapt to a more modern diet the prevalence of several diseases increases. As we have demonstrated a number of dietary factors influence environmental illnesses such as autism, CFS and MCS and the modern diet may not only be lacking in B12, vitamin D and fatty acids (ie omega 3) but may lack other macro and micronutrients. Specifically for the diseases I mention here, including autism and chemical sensitivity one must consider methionine (too much or too little) and the pathway that regulates it as a contributing factor.

New studies suggest that dietary restriction and subsequent restrictions of methionine reduces the amount of oxidative stress on mitochondrial DNA and there are studies have shown that patients with environmental illness have higher levels of oxidative stress. (Caro) From these results, the subject of limiting dietary sources of methionine and supplementation of methionine could be an important conversation to have with a physician. Anthropolically, it is true different people can tolerate different foods and the nutritional resources they provide better than others and this is all due to genetics. It becomes a problem when an individual's genetics do not "mesh" well - so to speak or as I have often said "do not get along" or specific influences (like a lack of biological resources, ie. B12) are altering genetic expression at "that point in time". This, unfortunately, adds to the complexity for diagnosis and treatment of environmental diseases and may contribute to the "fluctuating presentation" of these conditions. Interestingly, elk and fish contain higher levels of methionine and are eaten more by indigenous people. Compare that to a higher consumption of beef (also high in fat) which is part of a more "Western and Modern Diet" and contains less methionine. (eHow) Unfortunately, the prevalence of environmental diseases like cardiovascular disease and diabetes in indigenous people is increasing at an astounding rate and experts believe that eating more foods from "modern" diets in contrast to foods from a traditional diet may be partly to blame. Ethnically-derived genetic mutations in Nrf2 may increase liver injury (and increase environmental disease) exaggerating the effects of inhibiting factors on the methionine synthase pathway. Conditions like these may increase the prevalence of autoimmune and inflammatory disease in some more than others (like indigenous people and their descendants).

In other blogs we discuss how other dietary factors influence environmental illness. Several studies show polyphenols can effect methylation. As we noted above, DNA methylation has been associated with the silencing of genes and the most current research shows there is a relationship of methylation to different kinds of cancer such as bladder and prostate cancer. Fang points out both hypermethylation and hypomethylation are associated with carcinogenesis. Currently, prostate cancer is the second leading cause of cancer in men and a common cause is the silencing of GSTP1. This is a process that occurs through the methylation of "CG islands" by DNA methyltransferase (DMNT) early on in the cancer process. Polyphenols inhibit DMNT and in theory, can reverse hypermethylation of suppressed genes. (Fang) Other studies show abherrant methylation and suppression of Nrf2 expression in prostate tumorigenesis and as Arisawa demonstrates the polymorphisms in Nrf2 greatly effect abherrant methylation and for cancer, Nrf2 becomes a "very" significant factor. Over the years, studies with sulphoraphane (a chemical in broccoli) have shown health benefits at slowing prostate cancer growth and inhibiting colon cancer. Another study demonstrates isothiocyanate prevents glutathione depletion in Parkinson's disease. Also, EGCG, a compound in green tea, has demonstrated promising therapeutic benefits for prostate, breast, pancreatic cancer and most recently, lung cancer. Both sulphoraphane and EGCG activate the Nrf2 antioxidant system, in addition to other mode of therapeutic modes of action.

It has been reported that autism now effects 1 out of 150 children. Although some believe this figure is closer to 1 in 100. Yet there are no "specifics" on the major cause of the spectrum of these disorders. In 2006, over 11 million cases of cancer were reported and the combined cases of prostate, skin, breast and colon cancer cases made up almost 50% of them. While the study of epigenetics is in its infancy, there is substantial support, as we have discussed here, that methylation influences can and do lead to the development of environmental illness. In addition, new research seems to support that all of these conditions are very similar to one another but present with different "genetic footprints" and Nrf2 expression only adds to their complexity. Because of the complexity of environmental illnesses, the severity of their consequences including high morbidity and mortality and the tremendous toll they take on public health resources, there is a critical need for an increase in credible and verifiable environmental illness research which will undoubtedly reveal more about how to diagnose, treat and cure them. In addition, it is important for medical practioners to be trained in both allopathic and complementary and holistic care that emphasizes understanding the genetic, cultural and environmental influences that impact wellness and disease. Lastly, more informed communications should be disseminated to the media and the public at large about new insights and discoveries in environmental medicine and new, innovative and alternative therapies used to treat these diseases that work and to objectively clarify why there are some therapies out there that do not work.




Original document and citations

Mercury Levels In Children With Autism And Those Developing Typically Are The Same, Study Finds

Mercury Levels In Children With Autism And Those Developing Typically Are The Same, Study Finds

ScienceDaily (2009-10-20) -- In a large population-based study, researchers report that after adjusting for a number of factors, typically developing children and children with autism have similar levels of mercury in their blood streams. ... > read full article

No scientific link between childhood vaccines and autism

No scientific link between childhood vaccines and autism

Genome-wide study of autism published in Nature

Genome-wide study of autism published in Nature