Contaminants in Air Pollution Including Endotoxin and Dioxin May Increase Insulin Resistance~!

Complications associated with insulin resistance may play a significant role in environmental diseases including obesity, sleep apneas and potentially Gulf War Syndrome and chemical sensitivity just for examples. Other studies show that sustained endotoxin, a potential consideration in CFS and other environmental illnesses, is a common component of particulate matter and environmental pollutants may alter insuling signalling in muscle especially under sustained stress such as malnutrition. These conditions may potentiate one another if they occur at the same time.....


"TCDD stimulates expression and secretion of TNF-alpha in adipocytes through activation of AhR, ERK1/2, and JNK, and the secreted TNF-alpha causes the downregulation of IRbeta, IRS1, and GLUT4 through TNFR1, resulting in insulin resistance."

Read more: CiteULike: 2,3,7,8-tetrachlorodibenzo-p-dioxin impairs an insulin signaling pathway through the induction of tumor necrosis factor-alpha in adipocytes.:


For further understanding: IRS-1

McCowen, K. C., Ling, P. R., Ciccarone, A., Mao, Y., Chow, J. C., Bistrian, B. R., and Smith, R. J. (2001). Sustained endotoxemia leads to marked down-regulation of early steps in the insulin-signaling cascade. Critical care medicine, 29(4):839-846. http://www.citeulike.org/user/HEIRS/article/7782376

PFOS Significantly Elevates Inflammatory Cytokines From LPS Stimulation.

CiteULike: Subchronic effects of perfluorooctanesulfonate exposure on inflammation in adult male C57BL/6 mice.: "Dong, G.-H. H., Zhang, Y.-H. H., Zheng, L., Liang, Z.-F. F., Jin, Y.-H. H., and He, Q.-C. C. (2010). Subchronic effects of perfluorooctanesulfonate exposure on inflammation in adult male c57bl/6 mice. Environmental toxicology."

Neuroprotective and Anti-inflammatory Activities of Ketogenic Diet on MPTP-induced Neurotoxicity.

Comments: I believe the results of this study are indicative of the fact that a keen understanding of the patients environmental illness and the factors that lead to it are crucial for the best holistic treatment and management of it. It is obvious that a one size fits treatment plan is probably not in the best interest of most patients.

"The change of dopamine was very similar to dopaminergic neurons in the SN. KD inhibited the activation of microglia induced by MPTP in the SN. The levels of proinflammatory cytokines (interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha) in the SN were also decreased and induced by MPTP. So, we concluded that KD was neuroprotective and anti-inflammatory against MPTP-neurotoxicity."

Read more: CiteULike: Neuroprotective and Anti-inflammatory Activities of Ketogenic Diet on MPTP-induced Neurotoxicity.:

Endotoxin-induced Enzyme Causes Depressive Symtoms Before Cytokine/NO Production~!

"IDO by direct application of LPS was preceded by synthesis and secretion of TNFalpha and IL-6 protein and activation of iNOS while IFNgamma expression was undetectable."

CiteULike: Central Administration of Lipopolysaccharide Induces Depressive-like Behavior in Vivo and Activates Brain Indoleamine 2,3 Dioxygenase In Murine Organotypic Hippocampal Slice Cultures

Tumor Necrosis Factor-Induced Neutrophil Adhesion Occurs Through SphK-1 Activation of Integrin

"TNFalpha activated endothelial cells being sphingosine kinase-1, alpha5beta1, and angiopoietin-2 dependent. Moreover, this work supports the notion that sphingosine kinase-1 may be the single target required for an effective broad spectrum approach to combat inflammation and immune disorders."

Tumor Necrosis Factor-Induced Neutrophil Adhesion ... [Am J Pathol. 2010] - PubMed result:

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

Suppression of Inflammatory Mediators by Cruciferous Vegetable-Derived Indole-3-Carbinol and Phenylethyl Isothiocyanate in Lipopolysaccharide-Activated Macrophages

I3C and PEITC both found in leafy green vegetables possess antiinflammatory effects by inhibiting the productions of NO, TNF-, and IL-10 in LPS-stimulated macrophages. NO’s inhibitory effect on I3C, in addition to decreasing the expression of iNOS, may at least partly be through interfering with iNOS enzyme activity as well as direct NO clearance activity, whereas PEITC may act through its direct NO clearance activity but not interfere with iNOS enzyme activity.

CiteULike: Suppression of Inflammatory Mediators by Cruciferous Vegetable-Derived Indole-3-Carbinol and Phenylethyl Isothiocyanate in Lipopolysaccharide-Activated Macrophages: "Tsai, J.-T., Liu, H.-C., and Chen, Y.-H. (2010). Suppression of inflammatory mediators by cruciferous vegetable-derived indole-3-carbinol and phenylethyl isothiocyanate in lipopolysaccharide-activated macrophages. Mediators of Inflammation."

Immune Differences Between Mice Strains Determine Susceptibility to Cigarettte Smoke

Snippet: Strain A and B showed differences in baseline production of ROS and H2O2 and also glutathione, Nrf2, heme oxygenase 1 and GPX2. This was associated with reduced HDAC2 expression, activation of NF-kappaB and higher basal levels of TNF-alpha and IL-6. CSE induced a decrease in HDAC2 protein levels strains, however, the level of HDAC2 was significantly lower in strain A than in strain B. (Names of mouse strains have been changed for purpose of simplicity.)
Comment: One can assume from this there is significant potential for different people (because of their genetic makeup that results in different expression of antioxidant and immune genes) to be more prone to the health consequences of cigarette smoke. This has important implication for health conditions including but not limited to conditions like COPD, asthma and also other conditions like MCS.

For further reading: Ammonia, Methamphetamine, Cigarette Smoke and Parkinson's Disease

Blog Tags: Nrf2 , HO-1 , Tnf-a, Il-6



CiteULike: Reactivity of Mouse Alveolar Macrophages to Cigarette Smoke is Strain Dependent.: "Vecchio, D., Arezzini, B., Pecorelli, A., Valacchi, G., Martorana, P. A. A., and Gardi, C. (2010). Reactivity of mouse alveolar macrophages to cigarette smoke is strain dependent. American journal of physiology. Lung cellular and molecular physiology."

Fat tissue as an endocrine organ.

Immune cells "macrophages are an important part of the secretory function of adipose tissue and the main source of inflammatory cyokines, such as TNFalpha and IL-6. An increase in circulating levels of these macrophage-derived factors in obesity leads to a chronic low-grade inflammatory state that has been linked to the development of insulin resistance and diabetes.

Adipose tissue as an endocrine organ.: "Galic, S., Oakhill, J. S., and Steinberg, G. R. (2010). Adipose tissue as an endocrine organ. Molecular and cellular endocrinology, 316(2):129-139."

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.

Impairments in Muscle Function After Cigarette Exposure and Environmental Illness

PGC-1a a protein factor necessary for mitochondrial function and may be reduced with exposure to LPS as well as, from impairments in Nrf2. This study demonstrates that TNF-a (already identified as a factor in CFS and Parkinson's) is generated from exposure to cigarette smoke (and lots of other environmental contaminants) and has been shown to down-regulate PGC-1a that may lead to vascular and myocyte dysfunction. PGC-1a also regulates a number of glucose transporters such as GLUT1 and GLUT4 which trasport glucose into cells.  When one looks at a condition related to glucose uptake from impairment of glucose transporters such as in GLUT1 deficiency, there are recognizable patterns of impairment one may recognize in other environmental illnesses including CFS and fibromyalgia and also described as Parkinsonism and ataxia-like symptoms.  Because Nrf2 contributes to PGC-1a expression, a deficiency in Nrf2 may also present with these types of symptoms impaired after cigarette exposure and particulate matter from diesel exhaust. Of course, other factors such as accumulation of ammonia and genetic SNP may also pose potential cellular threats. PGC-1a can be increased through exercise but this will be dependant on the availabity of NRF1 (another protein) regulated by Nrf2/HO-1. Sauna and Waon therapy have been shown to elevate PGC-1a and Nrf2. Deficiencies of PGC-1a may exacerbate the autoimmune-type presentation of environmental illness in Nrf2 deficiencies which produce less HO-1. Lack of PGC-1a and Nrf2 may contribute to the development of chronic diabetes in addition to other metabolic complications and numerous other conditions, such as cardiovascular disease.


For review:

• Chemical Sensitivity and Th2 Autoimmune Disease: The Loss of Treg Cells As Referee!
• Immunosuppression in Environmental Illness By High Fat and Cytokines: Ameliorated By Green Tea Compound!?
• Nrf2 Expression Is Regulated by Epigenetic Mechanisms in Prostate Cancer
• T Regulatory Cells and Vitamin D - Their Importance to Environmental Illness Including Chemical Sensitivity.

CiteULike: TNF-alpha-mediated reduction in PGC-1alpha may impair skeletal muscle function after cigarette smoke exposure.: "Tang, K., Wagner, P. D., and Breen, E. C. (2010). Tnf-alpha-mediated reduction in pgc-1alpha may impair skeletal muscle function after cigarette smoke exposure. Journal of cellular physiology, 222(2):320-327."





Lihua CHE, N. and Chiwai WON, G. Estrogen-related receptor a inverse agonist enhances basal glucose uptake in myotubes through reactive oxygen species. Biological Pharmacology Bulletin, 32(7):1199-1203. http://www.citeulike.org/user/HEIRS/article/6512026
Arany, Z., Foo, S.-Y. Y., Ma, Y., Ruas, J. L., Bommi-Reddy, A., Girnun, G., Cooper, M., Laznik, D., Chinsomboon, J., Rangwala, S. M., Baek, K. H. H., Rosenzweig, A., and Spiegelman, B. M. (2008). Hif-independent regulation of vegf and angiogenesis by the transcriptional coactivator pgc-1alpha. Nature, 451(7181):1008-1012. http://www.citeulike.org/user/HEIRS/article/2406298
Pons, R., Collins, A., Rotstein, M., Engelstad, K., and De Vivo, D. C. (2009). The spectrum of movement disorders in glut-1 deficiency. Movement Disorders, 9999(9999):NA+. http://www.citeulike.org/user/HEIRS/article/6512017
Piantadosi, C. A., Carraway, M. S., Babiker, A., and Suliman, H. B. (2008). Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via nrf2-mediated transcriptional control of nuclear respiratory factor-1. Circ Res, 103(11):1232-1240. http://www.citeulike.org/user/HEIRS/article/4617070?show_msg=already_posted
Glucose Transporter. Wipedia. Retrieved January 10, 2009.

Epstein Barr: Interesting Interactions With Inflammatory Mediators Implicated in Environmental Illness

Summary: This nuclear translocation of NF-kappaB may promote viral latency by negatively regulating BZLF1 transcriptional activity. In situations where p65 activity is limiting in comparison to BZLF1, the ability of BZLF1 to inhibit p65 transcriptional function may protect the virus from the host immune system during the lytic form of infection.


Morrison, T. E. and Kenney, S. C. (2004). Bzlf1, an epstein-barr virus immediate-early protein, induces p65 nuclear translocation while inhibiting p65 transcriptional function. Virology, 328(2):219-232. http://www.citeulike.org/user/HEIRS/article/6463038

Nitrite protects against morbidity and mortality associated with tnf- or lps-induced shock in a soluble guanylate cyclase-dependent manner

Cauwels, A., Buys, E. S., Thoonen, R., Geary, L., Delanghe, J., Shiva, S., and Brouckaert, P. (2009). Nitrite protects against morbidity and mortality associated with tnf- or lps-induced shock in a soluble guanylate cyclase-dependent manner. J. Exp. Med., 206(13):2915-2924. http://www.citeulike.org/user/HEIRS/article/6428693

Hypothalamic Actions of Tumor Necrosis Factor {alpha} Provide the Thermogenic Core for the Wastage Syndrome in Cachexia.

Hypothalamic Actions of Tumor Necrosis Factor {alpha} Provide the Thermogenic Core for the Wastage Syndrome in Cachexia.: "URL: Hypothalamic Actions of Tumor Necrosis Factor {alpha} Provide the Thermogenic Core for the Wastage Syndrome in Cachexia.

"

Hypothalamic actions of tumor necrosis factor alpha provide the thermogenic core for the wastage syndrome in cachexia.

Summary: However, by acting directly in the hypothalamus, TNFalpha can activate thermogenesis and modulate food intake. Here we show that high concentration TNFalpha in the hypothalamus leads to increased O2 consumption/CO2 production, increased body temperature, and reduced caloric intake, resulting in loss of body mass....In addition, the systemic inhibition of beta3-adrenergic signaling results in a reduced body mass loss and increased survival in septic rats. These data suggest hypothalamic TNFalpha action to be important mediator of the wastage syndrome in cachexia.




Arruda, A. P. P., Milanski, M., Romanatto, T., Solon, C., Coope, A., Alberici, L. C., Festuccia, W. T., Hirabara, S. M., Ropelle, E., Curi, R., Carvalheira, J. B., Vercesi, A. E., and Velloso, L. A. (2009). Hypothalamic actions of tumor necrosis factor alpha provide the thermogenic core for the wastage syndrome in cachexia. Endocrinology. http://www.citeulike.org/user/HEIRS/article/6368716?updated=1260645988

Doxorubicin acts through tumor necrosis factor receptor subtype 1 to cause dysfunction of murine skeletal muscle

Doxorubicin acts through tumor necrosis factor receptor subtype 1 to cause dysfunction of murine skeletal muscle: "URL: Doxorubicin acts through tumor necrosis factor receptor subtype 1 to cause dysfunction of murine skeletal muscle

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TNF-alpha-mediated reduction in PGC-1alpha may impair skeletal muscle function after cigarette smoke exposure

Summary: "this data suggest that in response to smoke exposure, TNF-alpha-mediated down-regulation of PGC-1alpha may be a key step leading to vascular and myocyte dysfunction, effects that are more evident in oxidative than glycolytic skeletal muscles."

Citation: Tang, K., Wagner, P. D., and Breen, E. C. (2009). Tnf-alpha-mediated reduction in pgc-1alpha may impair skeletal muscle function after cigarette smoke exposure. Journal of Cellular Physiology, 9999(9999):n/a+. http://www.citeulike.org/user/HEIRS/article/6018324

Microbial induction of IBD Through Protein Expression By TLR Signaling

HEIRS Environmental Illness Research Blog: Why Endotoxin Can Increase Pain,Chemical and Mold Sensitivity and Causes Sickness Behavior!


Summary: A number of gram negative, gram positive and other anaerobes stimulate protein that contributes to IBD. This process is dependant on TLR signaling and can be inhibited by blocking the P38 pathway. In an earlier study showed that the levels of TL1A and number of cells that expressed it correlated with the level of inflammation, especially in Crohn's disease.

Title:Microbial induction of inflammatory bowel disease associated gene tl1a (tnfsf15) in antigen presenting cells.
Shih, D. Q., Kwan, L. Y., Chavez, V., Cohavy, O., Gonsky, R., Chang, E. Y., Chang, C., Elson, C. O., and Targan, S. R. (2009). Microbial induction of inflammatory bowel disease associated gene tl1a (tnfsf15) in antigen presenting cells. European Journal of Immunology, 9999(9999):NA+. http://www.citeulike.org/user/HEIRS/article/6009014
Bamias, G., Martin, C., Marini, M., Hoang, S., Mishina, M., Ross, W. G., Sachedina, M. A., Friel, C. M., Mize, J., Bickston, S. J., Pizarro, T. T., Wei, P., and Cominelli, F. (2003). Expression, localization, and functional activity of tl1a, a novel th1-polarizing cytokine in inflammatory bowel disease. Journal of immunology (Baltimore, Md. : 1950), 171(9):4868-4874. http://www.citeulike.org/user/HEIRS/article/6009138

Inflammation and Alterations in Fat Cells By Pesticide Alterations of Anti-inflammatory Protein Genes!

Background: Some experts believe that changes in gene expression may be a consequence of certain chemical exposures. Researchers are now focusing a lot of attention on the effects of these exposures on adipocytes which can produce inflammatory chemokines which may generate inflammation.  It has been observed that some types of exposures are associated with obesity which is a risk factor for diabetes while, others can lead to weight reduction.   Arsenescu demonstrated toxic exposures can stimulate and increase expansion of adipose tissue and other studies show alterations in the process of differentiation of preadipoctyes into adipocytes. In 2008, a preliminary study suggested endothelial dysfunction contributes to fat cell development because adipose stromal cells are in close contact with endothelial cells of capillaries and small blood vessels. (ScienceDaily) Long-term high serum levels of dioxin has been shown to contribute to endothelial dysfunction which provides a possible mechanism for the association of certain exposures to endothelial dysfunction, obesity and a higher risk for diabetes. (Peclova)

In the past, obesity has been characterized by differentiation of preadipocytes to adipocytes and involves the coordinated responses of a number of proteins with fatty acids that leads to increases of the size of fat cells.(Uto-Kondo) However, a recent study suggests that in in the case of abdominal obesity which may have more severe long-term health effects, there is impairment of the ability for preadipocytes to differentiate into adipocytes. Irakson says that "inhibition of this type can lead to a proinflammatory state and macrophage-like phenotype and as Hou explains "elevated levels of TNF-a or Il-1b in inflammatory tissues prolongs the survival of these immune cells and lengthens the durations they remain in an inflammatory state." 

 In one study, eldrin causes inhibition of a binding protein and interfered with expression of the anti-inflammatory protein PPAR-gamma and altered the expression of NF-kappaB which usually decreases as adipocytes differentiate. (Moreno-Aliego) We have suggested that the aberrant signaling from the AhR, which normally is important for cellular homeostasis and contributes to detoxification of PAHs and HAHS, may be an important factor in MCS. Hanlon et el notes that activation of the AhR by dioxin blocks hormone-induced adipocyte differentiation through the suppression of PPAR-gamma. The presence of inflammatory mediators are also associated with insulin resistance which can further impair normal cell function and reductions in the expression of Nrf2 may further complicate it. Chronic inflammation have been suggested as a causal factor in environmental illnesses including obesity and diabetes. One study shows proteins associated with cell death are less efficient in diffentiated adipocytes than in undifferentiated cells when introduced to a reactive species stimulus. Kojima confirmed an increase in antioxidants including MnSOD, catalase, Cu/ZnSOD as well as, FOXO with the the progression of adipocyte differentiation.  From this study, it has been concluded that ROS-generated apoptosis is associated with the expression of FOXO3a in undifferentiated adipocytes and FOXO expression suppresses ROS-apoptosis through activation of scavenging enzymes in differentiated ones. With this study in mind and considering that uncontrolled production of ROS contribute to cellular processes that cause inflammation, preventing differentiation of adipocytes may have negative consequences in certain cases.

Kojima, T., Norose, T., Tsuchiya, K., and Sakamoto, K. Mouse 3t3-l1 cells acquire resistance against oxidative stress as the adipocytes differentiate via the transcription factor foxo. Apoptosis. http://www.citeulike.org/user/HEIRS/article/5998696
Isakson, P., Hammarstedt, A., Gustafson, B., and Smith, U. (2009). Impaired preadipocyte differentiation in human abdominal obesity. Diabetes, 58(7):1550-1557. http://www.citeulike.org/user/HEIRS/article/5017576
Hou, F. F., Boyce, J., Zhang, Y., and Owen, W. F. (2000). Phenotypic and functional characteristics of macrophage-like cells differentiated in pro-inflammatory cytokine-containing cultures. Immunology and cell biology, 78(3):205-213. http://www.citeulike.org/user/HEIRS/article/5998701
Hanlon, P. (2003). Ahr- and erk-dependent pathways function synergistically to mediate 2,3,7,8-tetrachlorodibenzo-p-dioxin suppression of peroxisome proliferator-activated receptor-γ1 expression and subsequent adipocyte differentiation. Toxicology and Applied Pharmacology, 189(1):11-27. http://www.citeulike.org/user/HEIRS/article/5778106
Moreno-Aliaga, M. J. and Matsumura, F. (1999). Endrin inhibits adipocyte differentiation by selectively altering expression pattern of ccaat/enhancer binding protein-alpha in 3t3-l1 cells. Mol Pharmacol, 56(1):91-101. http://www.citeulike.org/user/HEIRS/article/5998840
Uto-Kondo, H., Ohmori, R., Kiyose, C., Kishimoto, Y., Saito, H., Igarashi, O., and Kondo, K. (2009). Tocotrienol suppresses adipocyte differentiation and akt phosphorylation in 3t3-l1 preadipocytes. J. Nutr., 139(1):51-57. http://www.citeulike.org/user/HEIRS/article/5998926
Healthy Blood Vessels May Prevent Fat Growth. ScienceDaily. September 23, 2008.
Pelclová, D., Prázny, M., Skrha, J., Fenclová, Z., Kalousová, M., Urban, P., Navrátil, T., Senholdová, Z., and Smerhovsky, Z. (2007). 2,3,7,8-tcdd exposure, endothelial dysfunction and impaired microvascular reactivity. Human & experimental toxicology, 26(9):705-713. http://www.citeulike.org/group/7254/article/6000451

Tumor necrosis factor-alpha modulates effects of aryl hydrocarbon receptor ligands on cell proliferation and expression of cytochrome p450 enzymes in rat liver ßtem-like" cells

Title: Tumor necrosis factor-alpha modulates effects of aryl hydrocarbon receptor ligands on cell proliferation and expression of cytochrome p450 enzymes in rat liver ßtem-like" cells.

Summary: "This is the first evidence that capsaicin-sensitive afferents exert a protective role in endotoxin-induced airway inflammation, but contribute to increased bronchoconstriction."


Umannova, L., Zatloukalova, J., Machala, M., Krcmar, P., Majkova, Z., Hennig, B., Kozubik, A., and Vondracek, J. (2007). Tumor necrosis factor-alpha modulates effects of aryl hydrocarbon receptor ligands on cell proliferation and expression of cytochrome p450 enzymes in rat liver ßtem-like" cells. Toxicol. Sci., 99(1):79-89.