Multiple Chemical Sensitivity Etiology
Airway Genetics and Ambient Combustion Aerosol
D. Neural Pathways: Central Sensitization (a)
...Introverted intuition apprehends the images arising from the a priori inherited foundations...
...introverted intuition, through its perception of these inner processes, can supply certain data which may be of the utmost importance for what is going on in the world. It can even foresee new possibilities in more or less clear outline, as well as events which later actually do happen...
...an extraordinary dependence on sense-impressions. This compensates the rarified air of the intuitive's conscious attitude, giving it a certain weight, so that complete "sublimation" is prevented...hypersensitivity of the sense organs..."
V. MCS 3ad: MCS Genetics - Likely a Neural Portrait
Outline
A. Genetics in Detox Enzymes Not Majority Etiology
B. Inflammatory Cause of Detox Enzyme Dysfunction
C. A Genetic Neuroinflammatory Portrait
D. Neural Pathways: Central Sensitization
A. Genetics in Detox Enzymes Not Majority Etiology
Several studies have been widely misreported by the MCS Community: Haley 1999 concerned gulf war veterans and PON 1, McKeown- Eyssen 2004 CYP2D6, NAT1,2, and PON1,2 - warning caution the numbers are small, and Schnakenberg 2007 GSTM1 and GSTT1 results applied to 50% of the population.
MCKEOWN-EYSSEN 2004 disputed that of Haley:
"...However our findings differ from those of Haley et al who also observed an association of Gulf War Syndrome with the homozygous R genotype, as we found no corresponding significant association with MCS for the homozygous I. genotype (I.I.) of PON1 55 or for the homozygous R genotype of PON1-192..."
...Neither were there differences between cases and controls in the frequency of the 55I. allele (seen in 66.3% of chromosomes for cases and 63.8% for controls in Table 2, P=0.52 from Fisher's exact test)..."
Berg 2010, with MCS subjects diagnosed by Cullen criteria, found no association of PON1 with MCS.
Concerning other enzymes, MCKEOWN-EYSSEN 2004:
"...our results suggest that individuals with higher CYP2D6 activity (homozygous active) are at increased risk for MCS compared with individuals with two non-functional alleles...however in view of the small numbers , such an association must be viewed cautiously...while differences in NAT2 allele distribution were only marginally significant (table 2), when alleles combine into genotype, rapid acetylators were found at increased risk (table 3)...in view of the small numbers such an association must be viewed cautiously..."
Berg 2010 sank the ship of Haley and Mckeown-Eyssen misapplication to MCS.
"...In conclusion, based upon a considerable number of study participants, we were not able to confirm previous findings of substantial importance of gene variants in CYP2D6, NAT2, PON1, MTHFR, and CCK2R to MCS and self-reported chemical sensitivity..."
"...GSTs are a family of phase 2 enzymes found in all eukaryotic species. They play a critical role in detoxifying both naturally occurring and xenobiotic compounds, including carcinogens, environmental toxins, and reactive oxygen species, by catalyzing the transfer and conjugation of glutathione (Manfredi 2009, Hayes 1995)..."
Over 50% of the population have one or both of the GSTM1 and GSTT1 deletions (Piacentini 2011, Block 2011, Ginsberg 2009, Hayes 1995).
The Schnakenberg study had 521 subjects. None were known to have diagnosed MCS. The subjects filled out a form having 3 choices - not at all a problem, moderate symptoms, or disabling symptoms - in describing their reaction to 10 different exposures: exhaust, smoke, insecticide, gasoline, etc. They were awarded 1, 2, or 3 points in order of severity for each choice so maximum score was 30 and minimum 10.
Those scoring more than 20 were defined as chemically sensitive so that 273 wound up in the "chemically sensitive" group and 248 in the less sensitive group.
Schnakenberg 2007 stated: "...our study subjects were identified by a questionnaire asking for chemical hypersensitivity and not for symptoms of MCS..."
DELUCA 2010 whose case group was diagnosed MCS by Cullen criteria (Cullen 1987), found no significant differences in allele and genotype frequencies of CYP's, UGT, GSTM, GSTT, and GSTP between the MCS and control groups and refer to the studies of Mckeown 2004 and Schnakenberg 2007 as follows:
DELUCA C. ET AL BIOLOGICAL DEFINITION OF MULTIPLE CHEMICAL SENSITIVITY FROM REDOX STATE AND CYTOKINE PROFILING AND NOT FROM POLYMORPHISMS OF XENOBIOTIC- METABOLIZING ENZYMES. TOX AND APPL PHARM 248:285-292 2010:
"...Mckeown-Eyssen et al (2004) suggested also a possible gene-gene interaction between CYP2D6 and N-acetyl transferase 2 (NAT2), with rapid metabolizers for both enzymes showing a substantially elevated risk to develop MCS. The results concerning NAT2 alone or its combination with CYPs found no confirmation in later studies (Schnakenberg et al 2007; Weismuller et al., 2008; Berg et al 2010).
On contrast Schnakenberg et al (2007) suggested that individuals being slow acetylators, and those with homozygously deleted GSTM1 and GSTT1 genes, are significantly more likely to develop MCS syndrome. We did not confirm Schnakenberg's findings, as we did not find any significant differences in GSTs allele or genotype distribution between patients as compared with data previously published in healthy volunteers (table 4) (Garte et al., 2001)..."
In summary, Berg 2010 and Deluca 2010 with diagnosed MCS subjects found genetic variants in detox the same among MCS people as in the general population.
DELUCA 2010 conclude:
"... there exist serious and multiple dysfunctions of chemical defensive systems in MCS patients. These dysfunctions may mainly depend not on genetic defects but on non-genetic modifications of metabolizing/antioxidant enzyme expression and/or activity, mediated by redox active agents such as NO and inflammatory cytokines..."
"...the current research into the genetic contribution to MCS and chemical sensitivity has yielded inconsistent findings, and no result seems to offer an etiologic explanation for a large proportion of patients. A recent finding that the heritability of respiratory symptoms related to perfume, a main complaint in MCS, was 0.35 (Eberling 2009), however encourages further research into the subject... "
B. Inflammatory Cause of Detox Enzyme Dysfunction
"...Phase I reactions form a new or modified functional group or a cleavage (oxidation, reduction, hydrolysis). These are non synthetic - the most important are cytochrome P450 isoenzymes (CYPs) that transfer electrons and catalyze oxidation.
Phase II reactions are synthetic - involving conjugation with an endogenous compound forming metabolites more polar and readily excreted by the kidneys and liver in urine and bile..."
"...(i) LPS (bacterial lipopolysaccharides) induces the release of intermediary cytokines, which, in turn, induce NOS activity in Kupffer cells and hepatocytes; (ii) NO binds to heme iron in cytochromes P450 and prevents oxygen binding, thereby blocking enzyme activity; (iii) NO may also enhance degradation of cytochromes P450 by nitrosylation of heme or thiols in P450 apoprotein or impair transcriptional activation of P450...
...In summary, cytokine induced overproduction of NO could explain attenuation of activity, content, and transcription of cytochromes P450 by a diverse array of immunostimulants..."
STADLER 1994:
"...Inflammatory stimulation of the liver leads to the induction of nitric oxide (NO) biosynthesis. Because NO binds to the catalytic heme moiety of cytochromes P450 (CYPs), we investigated whether NO interferes with specific CYP-dependent metabolic pathways...
...NO synthesis was induced in rat hepatocytes by incubation with a mixture of cytokines and endotoxin. Concurrently, as NO production in hepatocytes increased within 24 hr, a decrease in CYP1A1 dependent benzo[a]pyrene turnover was observed to almost undetectable levels...the inhibition of benzo[a]pyrene turnover by endogenous NO must have been predominantly due to functional inhibition of CYP activity...
...Inhibition of hepatocellular CYP activity by NO was predominantly due to a direct effect on the enzymes. However, NO-dependent inhibition of CYP expression at a transcriptional level was also demonstrated..."
TERLECKY S. ET AL. PEROXISOMES AND AGING. 1763;12:1749-54 2006:
"...there are circumstances in which the tightly regulated balance of hydrogen peroxide producing and degrading activities in peroxisomes is upset - leading to the net production and accumulation of hydrogen peroxide and downstream reactive oxygen species. The factor most essentially involved is catalase, which is missorted in aging, missing or present at reduced levels in certain disease states, and inactivated in response to exposure to specific antibiotics...
...Many individuals worldwide are hypocatalasemic, not due to aging's effects, but rather to a reduction in cellular catalase expression (Eaton 1995, Wen 1988) or stability (Eaton 1995, Crawford 1988)...
...Cells from a hypocatalasemic patient (expressing approximately 25% of normal catalase levels) were found to have accumulated hydrogen peroxide and harbored age-associated pathologies (Wood 2006)..."Deluca 2010 found catalase activity in MCS patients 30% of normal.
Proatherogenic conditions of severe oxidative stress were found in MCS patients due to inflammatory stimulation of blood cell populations with cytokines - elevated NO, glutathione depletion, catalase deficiency, and a fatty acid profile indicating lipid peroxidation - increased SFA with losses in PUFA, N-6, N-3, arachidonic acid and omega 3 (Deluca 2010).
Sensory receptor activation and alveolar macrophage involvement in damaged airway epithelium due to ACA PM - changes in the innate inflammatory immune system (Hogg 2009, Abbas 2007) - result in release of mediators - neuropeptides, cytokines, chemokines, and growth factors (Dantoft 2014, Maes 2012, Deering-Rice 2011, Hazari 2011, Costa 2010, Deluca 2010, Taylor-Clark 2010, Caceres 2009, Anand 2008, Bessac 2008), Nassenstein 2008, Bautista 2006, Inoue 2005, Kobayashi 2005, Veronesi 2001), increase in circulating leukocytes, production of acute phase proteins (Hiraiwa 2014, 2013, Hogg 2009, Goto 2004, Mukae 2001), nitric oxide overproduction (Maes 2012, Deluca 2010, Calderon-Garciduenas 2008), and dysfunction of Phase I and II xenobiotic and antioxidant enzymes in a systemic condition of severe oxidative stress (Deluca 2010, Liptrott 2009, Oslund 2008, Chun 2002, Sterner-Kock 1999, Tinel 1999, Tanabe 1996, Tapner 1996, Nadin 1995, Stadler 1994, Khatsenko 1993).
C. A Genetic Neuroinflammatory Portrait
"...DRG neurons, cultured from BALB/c and B6 neonates, were loaded with Fluo-3 AM and exposed to the prototype irritants, acid pH (5.0, 6.5), or capsaicin (3, 10 μM). Analysis of their increases in intracellular calcium showed that significantly higher numbers of BALB/c neurons responded to these prototype irritants, relative to B6 neurons.
Morphometric analysis of BALB/c neurons, histochemically stained with cobalt to label neurons bearing capsaicin-sensitive receptors, showed a significantly higher level of stained neurons relative to B6 neurons.
Finally, semiquantitative RT-PCR showed a higher expression of VR1 receptor mRNA in DRG and spinal cord taken from neonatal BALB/c mice relative to B6 mice.
Taken together, these data suggest that capsaicin and acid-sensitive irritant receptors, located on somatosensory cell bodies and their nerve fiber terminals, subserve PM-induced airway inflammation and are quantitatively different in responsive and nonresponsive mouse strains..."
"...We have previously shown that the BALB/c mouse strain is responsive to PM-inflammation in contrast to the non-responsive C57/blk (B6) mouse strain.
This differential sensitivity is retained in PM exposed cultures of somatosensory neurons from the dorsal root and trigeminal ganglia that innervate the airways in terms of inflammatory cytokine release.
In the present study, we use RT-PCR, cobalt histochemistry and immunocytochemical techniques to show that the expression of capsaicin (VR1) and Substance P (NK-1) receptors and the release of inflammatory cytokines and neuropeptides are higher in sensory neurons from BALB/c mice relative to the B6 strain.
These data suggest that the strain-specific inflammatory response to PM and other irritants (i.e. capsaicin, acid sensitive) seen in vivo and in vitro models of PM inflammation is subserved by sensory and neuropeptide receptors..."
"...plasma levels of SP (substance P), VIP (vasoactive intestinal peptide), and NGF (nerve growth factor), but not histamine are significantly (p<0.01 by ANOVA) elevated in sMCS patients...
exposure to VOC further increased levels of SP, VIP, and NGF...exposure to VOC also increased plasma histamine levels...
these results indicate that sMCS patients may suffer from ongoing neurogenic inflammation which is aggravated by VOC..."
"...The mechanism by which inflammatory conditions are provoked by chemicals is via chemoreceptors on sensory nerve C-fibers with the release of substance P and other mediators of neurogenic inflammation...progression of inflammation to organ damage is possible to those who continue to be exposed..."
"...after capsaicin provocation the patients showed a significant increase in NGF which was related to capsaicin cough sensitivity...SHR (sensory hypereactivity) is real and measurable, demonstrating a pathophysiology in the airways of these patients compared to healthy subjects..."
"...The findings of the present study indicate that the mechanisms underlying MCS may originate in the sensory nervous system..." - MCS cough occurring in response to capsaicin at concentrations far less (.150) than both the control group (1.120) and the chronic cough group (.630).
"...taken together, the above in vivo and in vitro studies suggested that the variable inflammatory sensitivity to PM observed in different mouse strains (ie Balb/C, B6) related to quantitative differences in the neuropeptide, VR1 (now TRP) receptors and acid sensitive pathways found on sensory neurons that innervate the nasal and upper pulmonary airway. Such data showed how genetically determined differences in sensory neural pathways could influence expressions of PM-induced airway inflammation...genetic differences are thought to underlie these variations and have been experimentally demonstrated for ozone (Kleeberger 1995, Zhang et al 1995), nitrogen dioxide (Holroyd et al 1997), and diesel exhaust (Ichinose et al 1997, Miyabara et al 1998)..."
Heritability of respiratory symptoms has been shown.
"...In conclusion, we found an increased familial occurrence of perfume-related respiratory symptoms where 35% of phenotypic variation was due to additive genetic effects and 65% was due to individual specific environmental effects..."
As mentioned above in Appendix IV, C.G. Jung's Psychological Types (1921) R.F.C. Hall translation published by Princeton University Press, early but highly regarded - written by a principle founder of modern Psychology - and from which can be attributed wide use of the terms introversion and extraversion - is an organization of 8 principle types according to dominance of the feeling, thinking, intuition, or sensation function in either the introverted or extraverted attitude.
Jung further refines the types by recognizing a function of secondary importance - for example introverted intuition (a perceptive function) if in the primary dominant position is paired to either introverted thinking or feeling as the secondary complementary judgement function - making a total of 16 types.
A psychological portrait emerges - cumulative image of typical characteristics - while individual features are effaced.
Occurring with randomly equal distribution and distinctness - Jung concluded the type phenomenon must have a genetic foundation.
Jung 1921 reported hypersensitivity of the sense organs only among the genetically determined introverted intuitives - strongly indicating a shared genetic basis of physiological and psychological features.
R.F.C. Hull Translation
"...extraordinary dependence on sense impressions...this compensates the rarified air of the intuitive's conscious attitude...hypersensitivity of the sense organs..."
D. Neural Pathways: Central Sensitization
Spect hypoactivity, permanent damage to olfactory neuronal pathways, and central sensitization may result from intense, repeated, and sustained input from exposed sensory and olfactory nerves in damaged airway epithelium - alterations in membrane excitability, reductions of inhibitory transmission, increase in synaptic efficacy - and the inflammatory process of translocated ultrafine particles to the brain.
MERCK 1999:
"...A nerve cell (neuron) has two major functions: propagation of an action potential (nerve impulse, signal) along its axon and transmission of this signal from one neuron to another neuron, or to an effector cell to elicit a response...
...Impulse conduction along an axon is electrical, caused by the exchanges of Na+ and K+ ions across the neuronal membrane. In contrast, impulse transmission from one neuron to another neuron or to a non-neuronal effector cell depends on the action of specific neurotransmitters on specific receptors...
...Synapses occur between neuron and neuron and, in the periphery, between neuron and effector...in the CNS more complex arrangements exist...
...The nerve cell body produces enzymes that are involved in the synthesis of most transmitters. The enzymes act on precursor molecules taken up by the neuron to form the neurotransmitter. The neurotransmitter is stored at the nerve terminal in vesicles...
...An action potential arriving at the terminal can activate calcium currents and precipitate the simultaneous release of neurotransmitter molecules from many vesicles by fusing the membrane of the vesicles to that of the nerve terminal. An opening forms through which the molecules are expelled into the synaptic cleft by exocytosis...
...Neurotransmitters diffuse across the synaptic cleft, bind briefly to receptors, and activate them, causing physiologic responses. Depending on the receptor, the response may be excitatory (ie, initiating a new action potential) or inhibitory (ie, inhibiting the development of a new action potential)...
...A neurotransmitter is a chemical that is selectively released from a nerve terminal by an action potential, interacts with a specific receptor on an adjacent structure, and, if received in adequate amounts, elicits a specific physiologic response...
...Neurotransmitter receptors are protein complexes that span the cell membrane..."
"...central sensitization...activity or use dependent form of functional synaptic plasticity that resulted in pain hypersensitivity...triggered by the activity evoked in dorsal horn neurons by input from c-nociceptors...chemical activation of nociceptors by irritant compounds...the TRPA1 channel...TRPV1 channel...
...The key features of acute activity-dependent central sensitization are that it is induced with a short latency (seconds) by intense, repeated, or sustained nociceptor inputs and typically lasts for tens of minutes to several hours in the absence of further nociceptor input..."
...It generally requires activation of NMDA receptors for its induction, and these receptors contribute to its maintenance. Nevertheless, as reviewed above, multiple different triggers can contribute to the establishment of this form of central sensitization: glutamate acting on NMDAR, but also on AMPAR and mGluR, the neuropeptides substance P and CGRP, the kinin bradykinin, as well as BDNF and NO...
...the essence of central sensitization is a constantly changing mosaic of alterations in membrane excitability, reductions in inhibitory transmission, and increases in synaptic efficacy, mediated by many converging and diverging molecular players on a background of phenotypic switches and structural alterations..."
ORRIOLS 2009:
"...MCS patients present brain signal photon emission computed tomography (SPECT) and psychometric scale changes...
...In comparison to controls, cases presented basal brain SPECT hypoperfusion in small cortical areas of the right parietal and both temporal and fronto-orbital lobes. After chemical challenge, cases showed hypoperfusion in the olfactory, right and left hippocampus, right parahippocampus, right amygdala, right thalamus, right and left Rolandic and right temporal cortex regions (p<0.01)...
...Our study showed brain SPECT dysfunction, particularly in those areas involved in odor processing...the pathway that joins the olfactory region to the orbito-frontal cortex through the thalamus is considered to be a control area of olfactory stimuli (Guyton 2000)...The olfactory region is also connected to the limbic system, a highly sensitizable area, which is responsible for vegetative responses and some emotions related to smell (Guyton 2000)...
...Neurologic transmission is a selective process in which excitatory and inhibitory signals control the final information transmitted, inhibitory signals help stabilize nervous system function and prevent excessive intensity and spread of neurologic circuits. Thus, reduced activity of inhibitory neurologic mechanisms can produce much greater excitability and facilitation of nerve stimuli, even in apparently unrelated areas...
...Neurologic dysfunction observed prior to chemical exposure could point to persistent subclinical neurologic changes. In fact, basal SPECT brain cortical hypoactivity was found in our patients. In animal models, inflammation and permanent damage of the olfactory neuronal pathways could result from translocation of inhaled ultrafine particles to the brain (Elder 2006)..."
CALDERON-GARCIDUENAS 2008:
"...Breakdown of the nasal barrier in pollution-exposed subjects may also contribute to brain inflammation by increasing the access of PM to the brain through the olfactory and trigeminal pathways..."
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