Particulate Matter in Pollution Exacerbates Environmental Illness via the Nrf2 Pathway!

In the past, I have made several post on particulate matter and how pollution may negatively influence the main environmental illnesses chronic fatigue syndrome, fibromyalgia and multiple chemical sensitivity. It is believe that what these conditions have in common is higher than normal oxidative stress and higher levels of inflammation. In addition, I believe that deficiencies in the Nrf2 pathway may exacerbate the conditions.

Through the discoveries from a study on dendritic cells, more has been learned about how Nrf2 and particulate matter interact to lessen or contribute to disease. Dendritic cells are an important part of the antigen-presenting immune system. The author writes that exposure to particulate matter in an Nrf2 deficient environment leads to 1) impairment of antigen endocytosis 2) significantly higher levels of oxidative stress probably due to lower levels of antioxidants like GCL and HO-1 3) higher levels of inflammatory cytokines including TNF-a and Il-6 4) lower levels of Il-18 4) less sensitivity to NAC and 5) Nrf2 deficiency may influence Th2 cytokine development leading to allergic diseases. (1)

This study provides clues to how particulate matter may influence the development of higher than normal levels of oxidative stress. People with conditions that already have conditions where these levels are higher should be aware that exposure to pollution indoors and outdoors may make their symptoms worse. In addition, we previously have written that many things can cause deficiency in the Nrf2 antioxidant pathway. This includes genetic factors, direct chemical exposure, changes to the microbiome and high fat diets.


1. Disruption of the transcription factor Nrf2 promotes pro-oxidative dendritic cells that stimulate Th2-like immunoresponsiveness upon activation by ambient particulate matter. Journal of immunology (Baltimore, Md. : 1950), Vol. 181, No. 7. (01 October 2008), pp. 4545-4559 by Marc A. Williams, Tirumalai Rangasamy, Stephen M. Bauer, et al.

Oxidative Stress, Nrf2 and Aging in Environmental Illness!

Next what I want to talk about is aging in environmental illness. I do not think anyone really talks about it but we know that aging is inevitable. Unfortunately, toxic environmental exposures make us age faster. Therefore, one can assume that people with environmental illnesses age faster. Like I said, it is not talked about much in the literature and probably most environmental illness patients do not want to admit.

So why would environmental exposures age us faster? Again, we can learn a lot about it through the study of the Nrf2. The inhibition of which causes oxidative stress. We now know that many diseases of aging are caused by oxidative stress. This includes diabetes and cardiovascular disease. Experts suspect that this is due to the decline in mitochondrial function and exposures to toxicants increase dysfunction. Alternatively, there is a natural decline of Nrf2 as we age. One study compared Nrf2 levels in young and older adults in bronchial cells.   It was determined that basal levels of Nrf2 are lower in the cells of older adults even though the expression of Nrf2-regulated genes, that are responsible for glutathione synthesis, was higher. In addition, the levels of Nrf2, activated by sulphoraphane (an activator of the Nrf2) was significantly lower in older participants. The researchers also noted that the suppressors of Nrf2, Bach1 and c-Myc, were higher in cells of older adults. (1)



1. Aging-related decline in the induction of Nrf2-regulated antioxidant genes in human bronchial epithelial cells. Redox biology, Vol. 14 (April 2018), pp. 35-40 by Lulu Zhou, Hongqiao Zhang, Kelvin J. A. Davies, Henry Jay J. Forman

Chronic Fatigue: The Nrf2 and Mitochondrial Connection

Chronic fatigue syndrome (CFS) is a condition where symptoms last more than 6 months. One identifying feature is that the overwhelming fatigue that comes with it is not resolved with rest. CFS is now recognized as a serious health condition that is known to effect the immune and neurological systems and have other physiological impacts. In my posts, I often classify CFS as an environmental illness for the sake of simplicity. I also consider multiple chemical sensitivity (MCS) and fibromyalgia (FM) as environmental illnesses. What is common in most patients with these illnesses, is that they have higher than normal levels of oxidative stress. Oxidative stress is produced by natural cellular processes or exposure to environmental toxicants. At high levels it leads to tissue damage and disease.  Currently, the true cause of these environmental illnesses are not known. 

While the cause of CFS might not be known, several theories have been proposed. One such theory is that mitochondrial dysfunction leads to the rampant increase of oxidative stress and overall, energy depletion. (1) This in turn leads to other inflammatory processes. Of course, the opposite could be true. In general, I believe that the inhibition of the Nrf2 pathway is at the root of environmental illness. The Nrf2 is a master gene regulater that regulates the natural antioxidant system in cells and neutralizes oxidative stress. It can be inhibited by many factors including TNF-a and abnormal methylation and xenobiotics. It is upregulated by natural phenols like EGCG, sulforaphane in broccoli, resveratrol and quercetin to name a few. Recent discoveries have also lead to a number of pharmaceuticals that increase expression of Nrf2. It is only in the past few years that researchers have identified a number of ways that the Nrf2 pathway promotes cellular respiration, ATP synthesis and provides other functions in the mitochondria. 

So how exactly does Nrf2 function in the mitochondria? It seems it does it in a number of ways including reducing oxidative stress by promoting the action of complex 1, regulating the expression of ATP synthase subunit α, allows for more efficient oxidative phosphorylation, increases the levels of ATP, there is better integration of fatty acid oxidation with the TCA cycle (a process that occurs through the action for example, of glucoraphanin which is the precursor of the classical Nrf2 activator sulforaphane ), it promotes biogenesis, increases PGC-1 and maintains mitochondrial integrity. (2)

While it is not known if mitochondrial dysfunction occurs in all environmental illnesses, it makes sense that it might be a possibility. In any case, there is a reason to believe that energy depletion from oxidative stress may be a factor in causing some symptoms. 

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

*Sexual Dimorphism in Mitochondrial Biogenesis! 
*Impairments in Muscle Function After Cigarette Exposure and Environmental Illness 
*Green Tea Catechins May Protect Cells From Particulate Matter!

1. Chronic fatigue syndrome and mitochondrial dysfunction International Journal of Clinical and Experimental Medicine, Vol. 2, No. 1. (2009), pp. 1-16 by Norman E. Sarah Myhill

2. The emerging role of Nrf2 in mitochondrial function. Free radical biology & medicine, Vol. 88, No. Pt B. (11 November 2015), pp. 179-188 by Albena T. Dinkova-Kostova, Andrey Y. Abramov.

The Evolution of Nrf2 and the Depletion of It in Chronic Fatigue Syndrome!

It has been a while since I have actually sat down and written a new blog. In fact, it has been several months. Things change but in no way, has the focus of my research changed. I still believe that many environmental illnesses are the consequence of depletion of Nrf2. In addition, I wonder if polymorphisms in the Nrf2 pathway can account for the development of diseases such as chronic fatigue syndrome and MCS. In the last several years, new studies point to the Nrf2 playing a role in at least chronic fatigue syndrome. Also, new studies on Prostandim, a supplement has had at least anecdotal benefits in fibromyalgia. Prostandim is a Nrf2 activator that has also demonstrated recovery benefits after exercise and in arthritis.

What is common in CFS, fibromyalgia and probably MCS is that patients have high levels of reactive species and oxidative stress. This is of course is what makes me think that the NRF2 antioxidant system is deficient. Oxidative stress can be caused by exogenous substances like chemicals and other pollutants or formed through normal and abnormal cellular metabolism. At high levels, it has the potential to damage tissue and if it goes unchecked, it can lead to disease. Scientists believe that aging causes higher levels of oxidative stress in the body. Many diseases of aging have been found to be caused by oxidative stress such as cardiovascular disease. Other diseases like diabetes also present with oxidative stress levels that can be considered abnormal.

Scientists believe that the Nrf2 system developed in eukaryotes to combat the rising levels of oxygen during what is known as the Global Oxygenation Event (GOE).   This is when organisms progressed from anaerobic to aerobic metabolism. As one author writes, the problem with the development of aerobic metabolism is that it becomes necessary to  "overcome the metabolic toxicity that results from use of highly reactive molecular oxygen. In aerobic respiration, enzyme catalysed four-electron reduction of oxygen is considered to be a relatively safe process producing water at the terminal end of the mitochondrial electron transport chain. The reductive environment of cells, however, provides ample opportunities for oxygen to undergo successive non-enzymatic univalent reduction, these processes being exacerbated by electrophilic xenobiotics and abiotic agents such as solar ultra-violet radiation. Oxidative stress is the net outcome of oxidative damage to biologically important molecules such as proteins, lipids, carbohydrates and nucleic acids caused by the generation of these reactive oxygen species (ROS). To survive in such a reactive oxygen environment, living organisms produce or sequester a variety of water- and lipid-soluble antioxidant compounds such as vitamins C and E. Oxygen metabolising organisms additionally produce an arsenal of antioxidant enzymes that inactivate ROS. Animal genomes often express over 200 antioxidant and xenobiotic detoxifying enzymes. <sup>" (1)

So what causes depletion of Nrf2? I expect that there are several pollutants that deplete Nrf2. Recent studies have shown that overexpression of TNF-a and methylation can also deplete it. I have already mentioned that polymorphisms in the Nrf2 can make it less readily available. One such instance is in inflammatory bowel disease, (2) where a polymorphism in Nrf2 contributes to the onset of the condition. One older study demonstrated that exposure in pigs to ochratoxin, a mold toxin, depleted Nrf2 in kidney cells.(3) It is important to note here that in another study, patients with chronic fatigue syndrome were found to have mold metabolites in their urine. (5) So we see here, the connection to Nrf2 depletion and CFS may be possible in humans from mold exposure.</sup>

In other blogs I have mentioned how a chemical found in broccoli activates Nrf2. Other chemicals in food that been demonstrated to active NRF2 is EGCG found in green tea, coffee, and resveratrol found in wine. The pharmacological industry is also engaged in numerous tests for agents that show Nrf2 activation. Incidentally, a new study has shown positive results of an edible fungus Sarcodon imbricatus, used in ancient Chinese medicine, in a mice model of Chronic fatigue syndrome to reduce fatigue by normalizing oxidative stress. (6)


1.Rising levels of atmospheric oxygen and evolution of Nrf2. Scientific reports, Vol. 6 (14 June 2016) by Ranko Gacesa, Walter C. Dunlap, David J. Barlow, Roman A. Laskowski, Paul F. Long. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906274/


2. Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach. Pharmacological reviews, Vol. 70, No. 2. (April 2018), pp. 348-383 by Antonio Cuadrado, Gina Manda, Ahmed Hassan, et al.http://pharmrev.aspetjournals.org/content/70/2/348.long

3. Nrf2 deficiency exacerbates ochratoxin A-induced toxicity in vitro and in vivo. Toxicology, Vol. 389 (15 August 2017), pp. 42-52 by Agnieszka Loboda, Anna Stachurska, Mateusz Sobczak, et al.

4. Ochratoxin A impairs Nrf2-dependent gene expression in porcine kidney tubulus cells. Journal of animal physiology and animal nutrition, Vol. 93, No. 5. (10 October 2009), pp. 547-554, doi:10.1111/j.1439-0396.2008.00838.x by C. Boesch-Saadatmandi, A. E. Wagner, A. C. Graeser, et al.

5. Detection of mycotoxins in patients with chronic fatigue syndrome. Toxins, Vol. 5, No. 4. (11 April 2013), pp. 605-617 by Joseph H. Brewer, Jack D. Thrasher, David C. Straus, Roberta A. Madison, Dennis Hooper. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3705282/

6. Antifatigue Potential Activity of Sarcodon imbricatus  in Acute Excise-Treated and Chronic Fatigue Syndrome in Mice via Regulation of Nrf2-Mediated Oxidative Stress. Oxidative medicine and cellular longevity, Vol. 2018 (2018) by Xue Wang, Yidi Qu, Yongfeng Zhang, et al. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046126/

Depression in Environmental Illness May Be Relieved by Eating Broccoli!

"Depressive symptoms in environmental illnesses are more likely due to activation of TNF-a which presents as "sickness behavior". It would account for the fatigue and the depression. Because sulforaphane enhances expression of Nrf2, depressive symptoms may be relieved by prophylactic ingestion of broccoli. While some think that the depression is caused by activation of the corticosteroid system, I do not agree." If nothing else, it is worth the try!

 Prophylactic effects of sulforaphane on depression-like behavior and dendritic changes in mice after inflammation. The Journal of nutritional biochemistry, Vol. 39 (January 2017), pp. 134-144 by Ji-Chun C. Zhang, Wei Yao, Chao Dong, et al. http://www.citeulike.org/user/kimberlykramer2015/article/14619968

Bipolar and Depression Could Be Caused by Dysregulation in the Body's Antioxidant System

"Although bipolar disorder and depression are not found at this time in the NRF2 diseasome, it is becoming evident that they exhibit neuroinflammatory and degenerative pathophenotypes that at least in mouse models imply deregulation of NRF2". 

         Systems Medicine Approach to NRF2 in Chronic Diseases 375. NRF2 (Martin-de-Saavedra et al., 2013; Freitas et              al., 2016; Yao et al., 2016).

A Component Found in Broccoli May Protect the Stomach from a Common Bacteria!

H. Pylori, a bacteria that lives in the intestinal tract, has been found to contribute to ulcers and stomach cancers. Common symptoms of general infection include abdominal pain, nausea and vomiting. In a recent study, a component in broccoli and broccoli sprouts called sulforaphane has been shown it can kill H. pylori when cells were exposed to it. This study shows that it may be possible for a diet high in broccoli to be preventative against infection and subsequent ulcers and cancer.

Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors. Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, No. 11. (28 May 2002), pp. 7610-7615 by Jed W. Fahey, Xavier Haristoy, Patrick M. Dolan, et al. http://www.citeulike.org/user/kimberlykramer2015/article/14619248

Exposure to Mold Toxins May Contribute to Autism Spectrum Disorder!

A recent study has shown that mold and mycotoxin may contribute to neurodevelopmental diseases including autism spectrum disorders.

Effects of Mycotoxins on Neuropsychiatric Symptoms and Immune Processes. Clinical therapeutics, Vol. 40, No. 6. (June 2018), pp. 903-917 by Aarane M. Ratnaseelan, Irene Tsilioni, Theoharis C. Theoharides

Protein Signalling From POPs: A Case for Environmental Illness!

Over the past several years, I have proposed that aberrant signalling from the AhR and the NRF2 may influence the development and chronicity of an environmental illness. Mant experts believe there is also chronic low-level inflammation that coincide with their development and continues through the course of conditions like MCS, CFS and fibromyalgia. In addition, I have made the case for the fact, that low-level inflammation from these conditions contributes to obesity which I also believe should be included under the umbrella of environmental illnesses. Mainly, because of the way low-level inflammation affects the adipocytes and because many environmental factors contributes to the development of obesity and as obesity progresses to the development of diabetes. I also point out several times, how the Western diet may contribute to environmental illnesses, especially as they become chronic and proceeds to last many months or years. Numerous studies in recent years have shed some light on adipocytes function and physiology. Many experts now consider the presence of healthy adipocytes as a necessary part of being healthy. The problems begin when low-level inflammation infiltrates the adipose tissue and leads to disease.
       As Greenburg and Obin point out, in 2001 the number of obese adults reached almost 21%. That statistic has grown to 34.9% of adults are obese adults in the U.S. alone. As the numbers of obese grow, obesity becomes more a more a public health issue. "Numerous diseases are considered to be either caused by obesity as the sole cause or in part caused by it. Just a few these include type-2 diabetes, cardiovascular disease, hypertension and stroke, hypercholesterolemia, arthritis, and certain cancers. Within the past few decades, more understanding of adipocytes has taken place. It is now known they are important metabolically. Their function is also dictated by a number of factors which include diet, exercise, hormones and genetics. Adipocytes play a role in controlling how much fat is deposited in important organs such as the liver and muscle, improving insulin sensitivity and decreasing triglycerides. They also regulate two important hormones, adiponectin and leptin.   Adiponectin is a hormone that regulates glucose tolerance and sensitivity. In addition, its levels are associated with type-2 diabetes and metabolic syndrome. On the other hand, leptin influences food uptake. In mice, missing the gene for leptin, exhibit extreme obesity and are diabetic. It also regulates fat mass.
     In individuals that are becoming obese, changes occur in adipocytes. Compared to their leaner counterparts, the obese have an inflammatory phenotype. In addition to TNF-a, they also produce higher levels of Il-6 and MCP-1. Macrophages increase with obesity and their presence is responsible for the production of TNF-a and a lot of IL-6. There is also a large increase in insulin. All of which decrease upon application of a diabetes drug. The inflammation also contributes to the downregulation of adiponectin which naturally  inhibits TNF-a." (Greenberg and Obin)
    In other blogs, I have explained that for those who suffer from environmental illnesses, it is important to clean up the gut. Recent studies show that there is a direct connection from the gut to the brain. I believe that many people that suffer from these conditions must be vigilant in how they eat and what they drink because the health of the gut depends on it. Again, let me mention that I also believe that aberrant signalling from the AhR and Nrf2 may contribute to environmental illness. At least in terms of  the AhR, Zhang et al states that the AhR plays an influential role in the gut and that role plays an important part in metabolism in obesity from persistent organic pollutants.  In a new study, Zhang and his colleague hypothesized that gut homeostasis is disturbed by exposure to persistent organic pollutants (POPS) through the diet and those exposures can lead to obesity. I must comment here that whether exposure to POPS or a Western diet leads to obesity, the process and the physiology is much the same as I described above. "During this study, 6 weeks old wild-type and mice that were AhR -/- were fed 2,3,7,8-tetrachlorodibenzofuran (TCDF), a persistent environmental contaminant for 5 days. Several studies were done to assess how this contaminant affected the gut microbiome and what other effects presented themselves from exposure to the TCDF. At the end of the study, the researchers determined there was a change in the populations from more Firmicutes to Bacteriodetes. Both of which have metabolic responsibilities.  Also, TDCF-treated mice were enriched with Butyrivibrio but depleted in Oscillobacter and the change was associated with altered bile metabolism. Also, there was a significant increase in inflammation as a result of bacterial fermentation  and altering hepatic lipogenesis, gluconeogenesis and glycogenolysis, in an AHR-dependent manner. It is concluded that POPs alter signalling the AhR to affect changes in metabolism. Changes also occur simultaneously in the gut species that increase inflammation. " The author states that past studies have demonstrated that the AhR-Il22 impacts mucosa in the gut. In addition, dietary components and environmental contaminants alter gut homeostasis and leads to disease including obesity, diabetes, and inflammatory bowel disease. (Zhang)


For further reading: (there are more than those listed here)
Inflammation Can Cause Depression!
Health Consequences Can Be More Severe When Multiple Environmental Toxicant Exposures Occur at the Same Time! 


TLR4 Activity in the Gut Contributes to Symptoms in Chronic Fatigue Syndrome!

What is the NRF2 and Why is Food Better than Supplements?

Adult Obesity Facts. Centers for Disease Control and Prevention. http://www.cdc.gov/obesity/data/adult.html

Obesity and the role of adipose tissue in inflammation and metabolism American Journal of Clinical Nutrition, Vol. 83, No. 2. (February 2006), pp. 4615-4655 by Andrew S. Greenberg, Martin S. Obin. http://www.citeulike.org/user/kimberlykramer2015/article/13568522

Persistent Organic Pollutants Modify Gut Microbiota-Host Metabolic Homeostasis in Mice Through Aryl Hydrocarbon Receptor Activation. Environmental health perspectives (13 March 2015) by Limin Zhang, Robert G. Nichols, Jared Correll, et al. http://www.citeulike.org/user/kimberlykramer2015/13565027