Gulf War Syndrome, Chemical Sensitivity and Why Benefits of CPAP!

It has only been in the not-to-distant past that officials and medical experts have come out and admitted that Gulf War Syndrome is an actual disease and while many that have tried to find the cause the "true cause" is not yet known. In previous blogs, I have discussed how Gulf War Syndrome shares many of the same symptoms as other environmental conditions and are often co-morbid and include chronic fatigue syndrome, fibromyalgia and multiple chemical sensitivity and other environmental factors may contribute to fascilitate the condition that is commonly regarded as Gulf War Syndrome. One well-respected research blogger, Dr. Art Ayers, explains that CFS, MCS and fibromyalgia "can be induced by organophosphate pesticide exposure. In GWS, two insults seem to be needed: acetylcholine signal disruption and inflammation. He says that in the effected individuals the acetylcholine mimetics (pesticides, pyridostigmine) disrupted the nervous system and numerous immunological, infectious, chemical and emotional stresses generated a high level of chronic inflammation. The vaccine against anthrax and exposure to burning oil wells may have contributed to inflammation." Without a clear understanding of what causes GWS, physicians and health experts are mostly at a loss on how to treat it and clearly, most of the research is now focused on providing effective therapies until a cure is found for it.

In recent weeks, two interesting studies have been released that show CPAP (continuous positive airway pressure) may be beneficial in treating symptoms of Gulf War Syndrome with sleep disordered breathing. In the pilot study, findings demonstrated improvements in many symptoms including pain, fatigue, cognitive function, sleep quality, physical and mental health. The researchers' concluded from this experiment that CPAP can greatly improve overall health in GW patients with sleep disordered breathing which may be a distinguishing factor in veterans with GWI compared to veterans without Gulf War Illness. (Amin)  While this research is preliminary it provides interesting insight into GWS. Admittedly, there are reported side-effects associated with CPAP use and the pros and cons of it should be addressed fully with a qualified physician even if CPAP is taken out of the research lab and used as therapy for GWS.

To date, even with these published findings, the reader is left with the question why CPAP may be effective for treating some symptoms of GWS. The author only makes the comment that GWS experience a "frequency of arousals related to apneas, hypopneas, and mild inspiratory airflow limitation."  Taking a more holistic systematic approach to understanding the nature of GWS ; one can draw some conclusions that provide at least a reasonable explanation of what may be occurring in GW patients with sleep apneas and why CPAP may provide at least "some" relief. CPAP has been used for quite some time to  treat sleep apneas and more recently has been used for a variety of other medical respiratory conditions. Budhiraja explains that sleep disordered breathing is often associated with hypertension and that "sleep apnea, hypocapneas and hypoxemia contribute to alterations in sympathetic activity, changes in the renin-angiotensin pathway, impede xanthine oxireductase production, cause endothelial dysfunction and lower levels of eNOS."  If you are a consistent reader of my feeds, chronic low-level inflammation contributes to endothelial dysfunction and higher risk for cardiovascular disease in many environmentally-induced health conditions.

Recently, it has been suggested that sickness syndrome contributes to symptoms in GWS and may explain  fatigue, pain and other behavioral changes as well. Sickness syndrome is in associated with elevated levels of cytokines including Il-1b and Il-6 and these inflammatory cytokines may also be associated with PTSD and CFS and are activated during the general response to stress which can lead to changes in genetic expression. Two researchers, Burioka and Steiropoulis found significant changes in Il-6 and Tnf-a, uric acid and immune complexes after CPAP. These findings suggest intermittent hypoxia contibutes significantly to inflammation and noted positive changes in patients that use regularly CPAP .  We have suggested that insulin resistance may be a critical factor in environmental illness and obesity and dietary influences may influence the severity of many environmental diseases including sickness syndrome, PTSD, MCS, CFS and fibromyalgia. To some extent, this can be explained by the fact that inflammatory cytokines and adipokines such as leptin and adiponectin can produce systemic changes. Patients with OSA have a higher prevalence of insulin resistance both in the obese and non-obese. (Lam)

In severa studies, agents such as pesticides, particulates and compounds emitted from fires and other environmental conditions that GW veterans may have been exposed too, exert an inhibitory and/or negative influence on cell function. (Gulati) For example, the metabolites of many toxic chemicals consistent with these types of exposures bio-accumulate in adipose tissue and contribute to inflammation and insulin resistance. (Nov) More specifically, it is proposed immune-mediate macrophages in adipose tissue contribute to insulin resistance and Tregs dampen this response and their reduction may contribute to insulin resistance. (Winer) Also, smaller particulates that bind to metals and hydrocarbons and contain endotoxin may infiltrate deeply into body tissues and through a complex process, end up in vessels and contribute to inflammation that leads to vascular disease.  (Li) An August 2010 study of Gulf War patients demonstrate high prevalence of problems with hypercoagulation which are also common in sleep apnea patients and can potentially be reversed by use of CPAP in some individuals. (Guardiola, Nichols)

Sleep apnea often accompanies obesity and for years, it has been assumed that inflammation is an important consequence of obesity. However, many experts now believe endothelial inflammation probably precedes obesity. Whatever the case may be, CPAP has demonstrated therapeutic effects on inflammation in obesity and this inflammatory process is similar in other environmentally-induced diseases. This leads one to assume its benefits may be achieved in the same way for GWS patients. Budhiraja and others have shown,  "CPAP therapy improves endothelial function, decreases the abnormally increased levels of circulating apoptotic endothelial cells, attenuates free radical production from neutrophils and monocytes, reduces the levels of C-reactive protein (CRP), a marker of vascular inflammation, increases vasodilator levels and mediates a decline in vasoconstrictor levels  in patients with sleep apnea altering blood flow. In the future, more studies may demonstrate CPAP may be of benefit for other "somatic" environmental illnesses as well.  (Gold, El Soth) In CPAP studies in obese patients, CPAP therapy has shown to reduce oxidative stress as well as, raise levels of SOD and alter nitrate and nitrite levels. Other changes that are reflected during CPAP adjustments also may have positive influences on physiology in a so-far unknown way. (Calero)

I have agreed with a few health experts and proposed due to my own experiences with several environmental diseases, severe reactions of MCS may be caused by the "lack of tolerance" to environmental conditions. Reactions develops to conditions that were considered normal and therefore, is more like an autoimmune disease and inflammatory cytokines and epigenetic changes in gene expression are contributory to this disruption. This "loss of tolerance" could explain why MCS patients develop extreme sensitivity to very low levels of pollutants such as those found in perfumes and detergents. Chemical sensitivity is also common in Gulf War veterans but the research disagrees with the Treg theory at least in part. Interestingly, a recent study demonstrated that post-natal exposure to flame retardents in animals leads to inhibitory functions on the AhR and a reduction of Tregs (Wahl)  and supports that the AhR modulates Treg production (Mezrich) and they may  be a factor at least in some types of reactions to certain toxins.  It would be interesting to examine different Treg ratios and to compare them with patients with MCS that are not GW patients and also compare this to other factors. Specifically, one example would be extenuating circumstances that dramatically effect stress response regulation. From my own experience, I would suggest actual stress and anxiety levels may alter certain markers because my own reactions are significantly different in different environments.

As far as chemical sensitivity, the idea of "loss of tolerance" is relatively new and may involve a better understanding of a "bridge" that links the immune system and metabolic homeostasis.  Because glucose and metabolic dysregulation seems to be concurrent with many environmental illnesses, one must consider metabolic syndrome as a risk factor for any environmental illness and there is little doubt some may contribute to GWS.  Hersoug hypothesizes that diseases like atopy, asthma and autoimmune diseases which are more common with obesity are the result of changes in adipokines including leptin, adiponectin, Il-6 and tumor necrosis factor (Tnf-a) secreted by white adipose tissue.  He adds that body weight contributes to an increase of these inflammatory mediators which in turn down-regulate regulatory T cells which in turn results in a reduction of the anti-inflammatory Il-10. He proposes that this process forms the basis of the idea of "loss of tolerance" and this author believes the loss of "Tregs" contributes significantly to chemical and environmental pollutant sensitivity. Other factors such as endotoxin and loss by genetics or environmental depression of Nrf2 and aberrant AhR signalling may augment the inflammation and allergic and non-allergic reactions and responses and may explain some of the sensitivity to "oil fires".  This may partially be explained by the fact that crude oil and coal dust contain significant amounts of polyaromatic hydrocarbons (PAH) and are ligands for the AhR. (Neff)  They are present in high amounts in diesel exhaust and disruption of the Nrf2 raises allergic airway inflammatory reactions to oxidative stress at much lower levels of diesel exhaust exposure. This may be true and does not dismis some reactions may be a consequence of diesel hydrocarbon content. (Li) Quinatana concludes the AhR, depending on the ligand, is able to modulate both Tregs and Il-17 which is often upregulated in inflammatory autoimmune diseases. It is easy to gather from all of this, that there is probably no simple answer to resolution of environmental disease except to prevent and limit exposures to the "activating" agents.

Of course, one needs to consider the initial "trigger" and the resulting inflammatory immune response may be different through time and be altered through interaction with other other chronic environmental and behavioral factors such as exercise, diet and other noxious "agents" of exposure in one's environment.  The AhR may provide a clue or two because of its role in activation from dioxins and its aberrant signals could be enough to initiate inflammatory responses that may be important in GWS and chemical sensitivity. I have proposed that some of this is due to the communication channel between the Nrf2 and the AhR. Jensen explains that exposure to PAH AhR ligands suppress B cell production and suppress Il-6 and makes an important comment that any alteration in Il-6 can lead to assorted pathologies including autoimmune disease, vitiligo, lupus and multple sclerosis.  Under normal conditions, elevations in Il-6 increase significantly through time in response to endotoxin but when cells are exposed to dioxin or another AhR ligand, cells presented with much lower levels of Il-6. Jensen concludes, "Any environmental chemical capable of compromising this response has the potential to disrupt the regulation of many important stromal cell functions, including generation of inflammatory responses in general and the elaboration of several cytokines, including IL-6, to regulate blood cell development in particular."  In addition, Jensen's research shows that exposures of different AhR ligands including PAH which are prevalent both in indoor and outdoor environments may be different depending on the tissue and may lead to elevations in other inflammatory cytokines such as Tnf-a. Considering that these influences are common in the environment, they can serve to augment responses in GWS or any environmental disease for that matter. (Jensen) One potential consideration is that if alterations in cytokines contribute to blood abnormalities that contribute to hypoxic conditions,
improvements observed with CPAP may reflect improvements in blood parameters of one sort or another. (Incidentally, after my last chemical injury obvious symptoms could have been explained by blood abnormalities like these. Unfortunately, they were not diagnosed because of improper medical care by a licensed practitioner and brings up concerns about access to properly trained practioners for environmental disease which I have discussed at length in other blogs.)

Foster shows that impaired regulation to hypoxic condition in sleep apnea patients and CPAP increases blood flow to normal levels. Another study demonstrates "hypoxia and dioxin response pathways can compete for limiting cellular factor(s) and cross-talk that occur between the hypoxia and dioxin signal transduction pathways and identify Epo as an AHR-regulated gene." (Chan)  This suggests signal dysfunction may influence a battery of physiological and toxicological responses. Most recently in fish, there is evidence that hypoxia reduces the response of the AhR. (Matson) This brings to light two important concerns in light of the discussion here. One is that there is direct interaction between the AhR and the Nrf2 antioxidant system and two, the AhR is an activator of Tregs regulation. In this context, dysfunction could certainly lead to apneas and chronic inflammation. It also may lead to other impairments in the antioxidant system and possibly to chemical sensitivities with a lower Treg production and a "loss of tolerance". It is also worth pondering the extent of effects of blood cell production in relation to circadian rhythm and influence on the positive effects of CPAP (Burioka).

An alternative example of aberrant levels of Il-6 demonstrates the complexity of environmental disease in relation to inflammatory mediators. Curiously, a recent report shows how different factors may be instrumental and  suggest that stress and the effect of pyridostigmine bromide (PB) may be a plausible cause of GWS. Mauck says that his research shows that while stress normally upregulates muscarinic receptor density, the application of  pyridostigmine bromide or physostigmine reduces them. One of the muscarinic targets is the Nrf2 and may suggest a reduction in these receptors may also reduce or prevent the activation of Nrf2. In addition, GSK-3b inhibition also augments muscarinic signals and Treg expression. Thus, conditions where GSK-3b is upregulated may have a negative influence on both chemical sensitivity in GWS and also other types of chemical sensitivity.  The other part of the puzzle in these conditions may be explained and supported by evidence that shows pesticides may contribute to insulin resistance and diabetes and may negatively influence how the body reacts to infection. This could alter inflammatory mediator production and in turn, contribute to the neuroinflammatory process as shown through reductions of Il-6 by GSk-3b inhibition.(Beurel) Dioxins on the other hand, seem to contribute to insulin resistance independant of the AhR. (Hsu)

I have often said in other blogs that environmental illnesses seem more like a failure to adapt and the concept of down-regulation of Tregs provides a viable mechanism for "maladaptation" at least in multiple chemical sensitivity. It may end up that taking genetic expression and immune regulators into account could be what differentiates the forms of chemical sensitivity in autism and MCS from GWS. If Amin is correct and the presence of apneas can be a predictor of  GW syndrome, then one can presume dysregulation of glucose metabolism similar to that that would occur with obesity and the development of chronic inflammation even though GW patients may not be overweight may contribute to GWS. Obesity is a problem in all age groups and classes and is associated with Western diets and GSK-3b may also play its part. It is worth considering that Gulf War veterans that are overweight and eat a typical Western diet will be more at risk for more severe GWI symptoms and those with conditions that depress Nrf2 (which are often diet, exposure and epigenetic influences related) will be even more so!  One may suggest that a lifestyle that promotes healthy eating and low-inflammatory menu like a Mediterranean diet may provide some healthy benefits.





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Inflammation, Insulin Resistance and Decreased PPARs-- A Pathway to CFS?

I thought today I would review some points that I have made over the last several months about environmental illness specifically chronic fatigue syndrome. I do this today, because of recent research news that supports some of what I have been saying all along and that is that CFS is probably the result of stresses that alter cellular functioning and disrupt cellular metabolism. This is not a new thing but believe that many researchers  have failed to notice that many of the symptoms may be caused by alterations in glucose metabolism and insulin activity and include some influences like what occur in
sickness syndrome even though CFS and sickness syndrome are not the same thing. Sickness syndrome is a variety of changes that occur in the body as a response to sickness and provides a mechanism to fight whatever is causing the sickness. Personally, I can recognize it more in animals because humans have been taught that we "must" overcome --- and that goes for being ill too that usually leads to more sickness.

Michael Maes has probably been the leader in the idea of sickness syndrome in relation to CFS. In his last report, he definitely makes the distinction and I have to agree with him. CFS is not sickness syndrome and is more due to inflammation and oxidative and nitrosative stress and pathogenic conditions and permeability can be to blame. Again, I agree and am critical of some that try to base everything about CFS on oxidative stress because it does not really explain how one "gets there"! In my view, it all comes down to and the problem with labels and this always has been my issue..... IN this case, how can we understand where one illness like CFS starts and another one ends such as sickness syndrome if noone really has defined the former CFS well  in the first place?  It is my belief that sickness syndrome may be a prelude to CFS or maybe the beginning point of it, and different factors can inhibit or lead to a "full-blown" case of CFS and recognizing the biological factors that play a part may in fact, help to prevent CFS in its most severe form. As far as oxidative and nitrosative stress in CFS, I think if you just leave it at..then it is doing a disservice not only to the condition but to those who suffer from it. The reason I say this is because of the nature of oxidative/nitrosative stress --- it is a natural result of cellular processes. Just saying that CFS is caused from too much of these stresses does nothing to answer what is causing the overwhelming oxidative stress in the first place in CFS. Maes has implied that endotoxin may be a pathway to CFS and bacterial infection has potential for causing oxidative stress and changing environments and altered methylation. But the possibility that other environmental factors such as hyperglycemia and high-fat diets which promote bacterial translocation and consequently activate certain immune responses leadin to CFS also, can not be dismissed. I have suggested that the failure of the antioxidant system to adequately meet the needs of oxidative stress or maybe even at all to any real level may play a very important role.  In other blogs, we have noted that oxidative and nitrosative stress is needed to activate this system and nutritional and genetic factors may influence the speed and level of activation. So if we have overwhelming oxidative stress -- it makes sense that something like underactivation of the antioxidant system may be at fault or is just not working. So in essence, it should be a no-brainer to look at the Nrf2-Keap1 and other proteins it controls to get a better handle on what may be causing the failure of an adaptive immune response and elevations in inflammatory markers and oxidative stress that are obviously maladaptive.

Several new studies some evidence that a failure in the antioxidant system could contribute to CFS. It is not a direct road I admit, but considering I have been following these paths for 3 years now. They make sense to me, mainly because I look for the CFS from a more holistic and systems theory perspective. For someone that has been trained both in anthropology and biology, this perspective works better for me when I need to find out the answers to different questions that need to be investigated. In addition, one could ask what is a direct road or pathway in reference to disease anyway....to me, it is all relative and most always depends on personal interpretation.  Several months ago, I blogged that environmental pollutants may contribute to diabetes and insulin resistance. Since then several other reports conclude this may be the case and many studies have provided evidence how inflammation can lead to insulin resistance and diabetes through the down-regulation of genes and up-regulation of inflammatory cytokines. Several inflammatory markers, not just one, can contribute and can be produced as a consequence of the stress response including TNF-a, Il-1, Il-6. Some of these activate other responses that lead to neuroinflammation and also alteration of neurotransmitters and have other effects on brain chemistry which could be characteristic of the cognitive dysfunction associated with CFS.

It has been suspected that pollutants lead to the alteration of a class of class of genes. I refer to them most often as PARRs and may include PPAR-gamma, PARR-delta and PARR-alpha. I have discussed both PPAR-gamma and PPAR-alpha at length in different discussions and most notably, PPAR-gamma is an important anti-inflammatory which helps prevent the development of insulin resistance in addition to other functions and may help repress autoimmunity. (Klotz) Recently, a study of the combination of pioglitizone and caffeic acid, demonstrated significant improvement in a mouse model of chronic fatigue. In this study, the results showed improvements in running wheel activity, locomotor activity and anxiety. Other improvements included reductions in oxidative damage including  lipid peroxidation and nitrite concentration and increased glutatione and catalase levels in addition to altering mitochondrial function. When one digs a little deeper, interesting things appear related to the actions of these compounds. Caffeic acid is an antioxidant and anti-inflammatory that while having potential hazard qualities, also demonstrates the ability to " suppress MMP-9 enzyme activity and down-regulate NF-κB through inhibition of protein IKK and activation of Nrf2 (Lee) and other studies provide in vitro evidence it may effect DNA methylation.(Wipedia)" In contrast, pioglitizone is an anti-hyperglycemic medication and "stimulates the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) and to a lesser extent PPAR-α. Both of these compounds act through PARR-gamma directly or indirectly via Nrf which may explain why their benefits in the CFS model is synergistic compared to when they were used alone. (Kumar) Generally, PARRs modulates the transcription of the insulin-sensitive genes involved in the control of glucose and lipid metabolism in the muscle, adipose tissue, and the liver. (Wipedia)" What this says to me is that CFS very well could be considered a condition that is a consequence of significantly disrupted normal glucose uptake and cellular and energy metabolism and altered immune function in different tissues.

I have also postulated that the aryl hydrocarbon may play an important role in both CFS and MCS and there are several "conditions" that lead me to make this assumption and the hypothesis but unfortunately, how this interaction occurs is quite "muddy".  First,  it has been demonstrated that there is a close connection in the actions of the AhR and the Nrf2 in response to environmental pollutants and their "gene batteries".  Second, I have suggested that abnormal signalling from the AhR may influence the functioning of several proteins including the Nrf2 even though the specific mechanismin of how this is achieved is not entirely understood. Third, dioxin which persists in the environment, albeit at lower levels in the last decade in many locales but still present in food, has been associated with diabetes and activates the AhR. Four, for some time it has been believed the AhR may inhibit PPAR-gamma and therefore leads us to environmental conditions, at least physiologically, of elevated inflammation and an increased risk for diabetes. (Remillard)  Arguably, the role of the AhR on PPAR-gamma depends on the tissue. (Kitchner, Shin)  However, dioxins are bioaccumulative and activation of the AhR and its effects on PPAR-gamma may spill over to surrounding tissues.  Lastly, a new study has shown that Nrf2 drives PPAR-gamma in protecting against oxidant injury at least in the respiratory system. Taking all this into account, it is safe to at least suggest that CFS may be influenced by fluctuations in PPAR-gamma and the proteins that regulate it and factors that upregulate it may be beneficial or preventative against CFS. Because PPAR-gamma demonstrates inhibitory properties on autoimmune responses, its absence may play significantly in the "loss of tolerance" responses of chemical sensitivity and inflammatory bowel disease. Other studies show PPAR-gamma has as an important regulatory function with HO-1 and may be neuroprotective against Parkinson's (Lui, Schintu) and influences mitochondrial biogenesis through PGC-1a (Miglio). In other blogs, I discuss how certain nutritional compounds such as resveratrol and EGCG in different foods have shown some benefit and their modes of actions address some of the issues that are discussed in the paragraphs above.   IN addition, because these proteins can be effected by methylation this explains the inheritabilty factor that exists with CFS that is not explained just by the presence of oxidative stress.

Notes:

• Endotoxin is considered potential pathway to CFS and inhibits PPAR-gamma through Tnf-a (Zhou)
• It as been suggested that XMRV may play a role in CFS - I would suggest that while XMRV may be a piggy-back condition, any pathogen or infection or pollutant that inhibits PPARs and increase inflammatory mediators contribute to CFS.

Related Tags: Nrf2 , PPAR-gamma , PGC-1a,



Cho, H.-Y. Y., Gladwell, W., Wang, X., Chorley, B., Bell, D., Reddy, S. P., and Kleeberger, S. R. (2010). Nrf2-regulated ppargamma expression is critical to protection against acute lung injury in mice. American journal of respiratory and critical care medicine, 182(2):170-182. http://www.citeulike.org/user/HEIRS/article/6854883?show_msg=already_posted

Kumar, A., Vashist, A., and Kumar, P. (2010). Potential role of pioglitazone, caffeic acid and their combination against fatigue syndrome-induced behavioural, biochemical and mitochondrial alterations in mice. Inflammopharmacology. http://www.citeulike.org/user/HEIRS/article/7474822

Yang, J.-Y. Y., Della-Fera, M. A. A., Rayalam, S., Ambati, S., Hartzell, D. L., Park, H. J. J., and Baile, C. A. (2008). Enhanced inhibition of adipogenesis and induction of apoptosis in 3t3-l1 adipocytes with combinations of resveratrol and quercetin. Life sciences, 82(19-20):1032-1039. http://www.citeulike.org/user/HEIRS/article/7537205

Pioglitazone. Wipedia. Retrieved on July 24, 2010. http://en.wikipedia.org/wiki/Pioglitazone

Caffeic Acid. Wipedia. Retrieved on July 24, 2010. http://en.wikipedia.org/wiki/Caffeic_Acid

Zhou, M., Wu, R., Dong, W., Jacob, A., and Wang, P. (2008). Endotoxin downregulates peroxisome proliferator-activated receptor-gamma via the increase in tnf-alpha release. Am J Physiol Regul Integr Comp Physiol, 294(1):R84-92. http://www.citeulike.org/user/HEIRS/article/2439726

Remillard, R. B. and Bunce, N. J. (2002). Linking dioxins to diabetes: epidemiology and biologic plausibility. Environmental health perspectives, 110(9):853-858.  http://www.ncbi.nlm.nih.gov/pubmed/12204817

Kintscher, U. and Law, R. E. (2005). Ppargamma-mediated insulin sensitization: the importance of fat versus muscle. Am J Physiol Endocrinol Metab, 288(2):E287-291. http://www.citeulike.org/user/HEIRS/article/3824606

Shin, S., Wakabayashi, N., Misra, V., Biswal, S., Lee, G. H., Agoston, E. S., Yamamoto, M., and Kensler, T. W. (2007). Nrf2 modulates aryl hydrocarbon receptor signaling: Influence on adipogenesis. Mol. Cell. Biol., 27(20):7188-7197. http://www.citeulike.org/user/HEIRS/article/3787182

Klotz, L., Burgdorf, S., Dani, I., Saijo, K., Flossdorf, J., Hucke, S., Alferink, J., Novak, N., Beyer, M., Mayer, G., Langhans, B., Klockgether, T., Waisman, A., Eberl, G., Schultze, J., Famulok, M., Kolanus, W., Glass, C., Kurts, C., and Knolle, P. A. (2009). The nuclear receptor ppargamma selectively inhibits th17 differentiation in a t cell-intrinsic fashion and suppresses cns autoimmunity. J. Exp. Med., 206(10):2079-2089.  http://www.citeulike.org/user/HEIRS/article/5778777

Liu, S. H. H., Yang, C. N. N., Pan, H. C. C., Sung, Y. J. J., Liao, K. K. K., Chen, W. B. B., Lin, W. Z. Z., and Sheu, M. L. L. (2010). Il-13 downregulates ppar-gamma/heme oxygenase-1 via er stress-stimulated calpain activation: aggravation of activated microglia death. Cellular and molecular life sciences : CMLS. http://www.citeulike.org/user/HEIRS/article/6826740

Schintu, N., Frau, L., Ibba, M., Caboni, P., Garau, A., Carboni, E., and Carta, A. R. (2009). Ppar-gamma-mediated neuroprotection in a chronic mouse model of parkinson's disease. The European journal of neuroscience, 29(5):954-963. http://www.citeulike.org/user/HEIRS/article/4136907

Miglio, G., Rosa, A. C., Rattazzi, L., Collino, M., Lombardi, G., and Fantozzi, R. (2009). Ppargamma stimulation promotes mitochondrial biogenesis and prevents glucose deprivation-induced neuronal cell loss. Neurochemistry international, 55(7):496-504. http://www.citeulike.org/user/HEIRS/article/5345204

Lee, Y., Shin, D.-H. H., Kim, J.-H. H., Hong, S., Choi, D., Kim, Y.-J. J., Kwak, M.-K. K., and Jung, Y. (2010). Caffeic acid phenethyl ester-mediated nrf2 activation and ikappab kinase inhibition are involved in nfkappab inhibitory effect: Structural analysis for nfkappab inhibition. European journal of pharmacology, 643(1):21-28. http://www.citeulike.org/user/HEIRS/article/7394789

Hormone Modulates Immune Cell Activation after Cigarette Smoke Exposure in Mice.

Recent study says leptin may modulate the immune responses from cigarette smoke. Other studies demonstrate that leptin and Il-6 may be involved with sickness syndrome and may include modulation of hormones that regulate behavior such as orexins and may contribute to inflammation-induced insulin resistance.

Notes: Recent study also demonstrates that cigarette smoke induced epigenetic changes in epithelial cells in vitro that may contribute to cancer growth.

CiteULike: Leptin Modulates Innate and Adaptive Immune Cell Recruitment after Cigarette Smoke Exposure in Mice.: "Vernooy, J. H., Bracke, K. R., Drummen, N. E., Pauwels, N. S., Zabeau, L., van Suylen, R. J. J., Tavernier, J., Joos, G. F., Wouters, E. F., and Brusselle, G. G. (2010). Leptin modulates innate and adaptive immune cell recruitment after cigarette smoke exposure in mice. Journal of immunology (Baltimore, Md. : 1950)."


HEIRS H&H






Harden, L. M., du Plessis, I., Poole, S., and Laburn, H. P. (2006). Interleukin-6 and leptin mediate lipopolysaccharide-induced fever and sickness behavior. Physiology & behavior, 89(2):146-155.
http://www.citeulike.org/user/HEIRS/article/4745011
Liu, F., Killian, J. K., Yang, M., Walker, R. L., Hong, J. A., Zhang, M., Davis, S., Zhang, Y., Hussain, M., Xi, S., Rao, M., Meltzer, P. A., and Schrump, D. S. (2010). Epigenomic alterations and gene expression profiles in respiratory epithelia exposed to cigarette smoke condensate. Oncogene, aop(current).
http://www.citeulike.org/user/HEIRS/article/7154109

Il-6 Modulates CRF in the Hypothalamus in Response to Different Signals.

Module: 5/22/2010

Background: CRF can regulate signaling in response to different odors. In those cases, it can lead to an anxiolytic or elevation and other responses typical of the stress response including pain generation, immune regulation, itch, rash and other changes such as gastric function alterations. Of course, these are symptoms characteristic of chemical sensitivity and also some symptoms characteristic of other environmentally influenced conditions such as CFS and sickness syndrome.

A major regulator of sickness syndrome is Il-6 which can be functionally modulated through Il-10 and ultimately most probably HO-1 which has been shown in other studies to increase during exercise. Interestingly, one can identify similarities in cancer-related fatigue to some chronic symptoms of CFS and sickness syndrome including the exhausting fatigue and cachexia that is exhibited in the latter, in animals and humans. Preliminary studies suggest cytokine Il-6/Il-8 may modulate the severity of cancer-related fatigue and others show cancer-related fatigue is common with serotonin dysregulation. Coincidentally, in the trout corticotrophin activation by ammonia is associated with alterations in neurotransmitter levels including dopamine and serotonin. So here again, we see potential especially with periods of aberrant corticotrophin signalling, where symptoms of environmental illness such as anxiety, depression, weakeness and fatigue may present itself. These findings supports past studies that suggest that fatigue in CFS may be in part due to serotonin dysregulation and elevations in Il-6.(Ryan)

CiteULike: Transcriptional regulation of hypothalamic corticotropin-releasing factor gene.: "Glucocorticoid-dependent repression of cAMP-stimulated CRF promoter activity is mediated by both nGRE and SRE in hypothalamic cells. Interleukin (IL)-6 produced in the hypothalamus stimulates the CRF gene. Suppressor of cytokine signaling-3, which is induced by a cAMP stimulant and IL-6, is involved in the negative regulation of CRF gene expression in hypothalamic cells. Such complex mechanisms would contribute to stress responses and homeostasis in the hypothalamus."

Related: Hummel, M., Cummons, T., Lu, P., Mark, L., Harrison, J. E., Kennedy, J. D., and Whiteside, G. T. (2010). Pain is a salient ßtressor" that is mediated by corticotropin- releasing factor-1 receptors. Neuropharmacology.
http://www.citeulike.org/user/HEIRS/article/7177466
Coric, V., Feldman, H. H., Oren, D. A., Shekhar, A., Pultz, J., Dockens, R. C., Wu, X., Gentile, K. A., Huang, S.-P. P., Emison, E., Delmonte, T., D'Souza, B. B., Zimbroff, D. L., Grebb, J. A., Goddard, A. W., and Stock, E. G. (2010). Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder. Depression and anxiety, 27(5):417-425.
http://www.citeulike.org/user/HEIRS/article/7193107
Theoharides, T. C., Singh, Boucher, W., Pang, X., Letourneau, R., Webster, E., and Chrousos, G. (1998). Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its proinflammatory effects. Endocrinology, 139(1):403-413.
http://www.citeulike.org/user/HEIRS/article/7207688
Mustian, K. M., Fisher, S., Adams, J., Janelsins, M., Palesh, O., Darling, T., Peppone, L., Heckler, C., Williams, J., and Morrow, G. (2009). Cytokine-mediated changes associated with improvements in cancer-related fatigue induced by exercise: Results from a randomized pilot study of cancer patients receiving radiotherapy. Journal of Clinical Oncology, 27(15s).
http://www.citeulike.org/user/HEIRS/article/7207720
Ryan, J. L., Carroll, J. K., Ryan, E. P., Mustian, K. M., Fiscell, K., and Morrow, G. R. (2007). Mechanisms of cancer-related fatigue. The Oncologist, 12(1 supp):22-34.
http://www.citeulike.org/user/HEIRS/article/7207823

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:

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.

Alterations of BDNF, Behavior Hormones in PTSD, Fibromyalgia and Other Environmental Illnesses

Many experts believe that the functions of the hypothalamus are dysrupted in environmental illness. We recently blogged about how hypothalamus-stimulated signaling of  BDNF levels are altered in a number of environmental illnesses. In fibromyalgia they are increased while in other are they are lower. A more recent report has indeed supported the fact that BDNF levels are increased in fibromyalgia. Also, they have demonstrated that this hormone is elevated shortly after trauma in PTSD and evens out over time. Interestingly, these findings were independant of severity, psychiatric history and treatments with medication. Because BDNF has been implicated in learning and memory the higher levels of this protein may contribute to the pathology of PTSD and considering they are elevated in fibromyalgia, one may suspect they also contribute to the pathology of fibromyalgia also. Of course, further evidence is warranted but these findings are interesting none-the-less.

Note:

• Orexin is another signaling peptide of the hypothalamus and it has been demonstrated that altered levels are consistent with fibromyalgia, chronic fatigue syndrome, PTSD and panic attacks. We have discussed this hormone in other blogs and explained, it dictates a number of different animal behaviors and is sexually dimorphic and plays a role in sickness behavior.  In addition, there is an important connection between orexins and BDNF. Dopamine are regulators of orexins and low levels are also associated with Parkinson's disease.
• BDNF is mediated by GSk-3b which is implicated in a number of psychological disorders and can be activated by environmental exposures. (Mai)

For further Reading:

• Sleepiness in CFS and Fibromyalgia May Be a Form of Narcolepsy!

Reference Library Tags: orexin, narcolepsy, chronic fatigue syndrome, PTSD, BDNF
                HEIRS Blogs: orexins, BDNF, chronic fatigue syndrome, sickness syndrome, fibromyalgia,  PTSD,


Strawn, J. R., Pyne-Geithman, G. J., Ekhator, N. N., Horn, P. S., Uhde, T. W., Shutter, L. A., Baker, D. G., and Geracioti, T. D. (2010). Low cerebrospinal fluid and plasma orexin-a (hypocretin-1) concentrations in combat-related posttraumatic stress disorder. Psychoneuroendocrinology. http://www.citeulike.org/user/HEIRS/article/6644003
Thannickal, T. C., Lai, Y.-Y., and Siegel, J. M. (2007). Hypocretin (orexin) loss in parkinson's disease. Medscape Today.  http://www.citeulike.org/user/HEIRS/article/6640584
Bubser, M., Fadel, J. R., Jackson, L. L., Meador-Woodruff, J. H., Jing, D., and Deutch, A. Y. (2005). Dopaminergic regulation of orexin neurons. The European journal of neuroscience, 21(11):2993-3001. http://www.citeulike.org/user/HEIRS/article/6463668
Gaykema, R. P. and Goehler, L. E. (2009). Lipopolysaccharide challenge-induced suppression of fos in hypothalamic orexin neurons: their potential role in sickness behavior. Brain, behavior, and immunity, 23(7):926-930. http://www.citeulike.org/user/HEIRS/article/4967509
Stanley, S., Wynne, K., McGowan, B., and Bloom, S. (2005). Hormonal regulation of food intake. Physiol. Rev., 85(4):1131-1158. http://physrev.physiology.org/cgi/content/full/85/4/1131/F2
Mai, L., Jope, R. S., and Li, X. (2002). Bdnf-mediated signal transduction is modulated by gsk3β and mood stabilizing agents. Journal of Neurochemistry, 82(1):75-83. http://www.citeulike.org/user/HEIRS/article/6621876

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.




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