Multiple Chemical Sensitivity Etiology

Airway Genetics and Ambient Combustion Aerosol

MCS 3ad: MCS Genetics - Likely a Neural Portrait

Expertise from the Most Prestigious Academic, Medical, and Government Research Facilities

Outline

I. Genetics in Detox Enzymes Not Majority Etiology

II. Inflammatory Cause of Detox Enzyme Dysfunction

III. A Genetic Neuroinflammatory Portrait

I. 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.

HALEY R.W. ET AL. ASSOCIATION OF LOW PON1 TYPE Q (TYPE A) ARLESTERASE ACTIVITY WITH NEUROLOGIC SYMPTOM COMPLEXES IN GULF WAR VETERANS. TOXICOL APPLIED PHARMACOL 157: 227-33 1999

MCKEOWN-EYSSEN G. ET AL. CASE CONTROL STUDY OF GENOTYPES IN MULTIPLE CHEMICAL SENSITIVITY: CYP2D6, NAT1, NAT2, PON1, PON2 AND MTHFR. INT J EPIDEM 33:971-78 2004

SCHNAKENBERG E. ET AL. A CROSS SECTIONAL STUDY OF SELF- REPORTED CHEMICAL-RELATED SENSITIVITY IS ASSOCIATED WITH GENE VARIANTS OF DRUG METABOLIZING ENZYMES. ENV H 6:6 2007

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.

BERG 2010: 

"...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..."

BLOCK 2011:

"...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 2011Ginsberg 2009Hayes 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 2007Weismuller et al., 2008Berg 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..."

BERG 2010:

"...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... "

II. Inflammatory Cause of Detox Enzyme Dysfunction

MERCK 1999:

"...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..."

KHATSENKO 1993:

"...(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 2009Abbas 2007) - result in release of  mediators - neuropeptides, cytokines, chemokines, and growth factors (Dantoft 2014, Maes 2012, Deering-Rice 2011, Hazari 2011Costa 2010Deluca 2010Taylor-Clark 2010Caceres 2009Anand 2008Bessac 2008), Nassenstein 2008Bautista 2006Inoue 2005Kobayashi 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 2010Liptrott 2009Oslund 2008Chun 2002Sterner-Kock 1999Tinel 1999Tanabe 1996Tapner 1996Nadin 1995Stadler 1994, Khatsenko 1993).

III. A Genetic Neuroinflammatory Portrait

"...There is no methodology that can comprehensively create a complete list of candidate genes. The potential list of candidate genes is likely impossible to comprehensively select a priori, as genes may play roles in chemical metabolism, cellular toxicity, neurotransmitter metabolism, or could even work indirectly (i.e., disrupt the metabolism of a nutrient involved in brain function)... In addition, it is unlikely that all the relevant genes and regulatory regions that modify the toxicity of ambient pollution are even known. Thus, a candidate gene approach can never comprehensively interrogate all the potential genetic modifiers of environmental toxicants..."
The best insight may be findings from Veronesi 2001, 2000, Roy 2000 at the US EPA Health and Environmental Effects Research Laboratory (NHEERL), and the observations of C.G. Jung reported in 1921 - genetically determined number of receptors and higher release of inflammatory cytokines and neuropeptides.

VERONESI 2000:

"...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..."

ROY 2000: 

"...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..."

KIMATA 2004: 

"...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..." 

MEGGS 1999: 

"...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..."

ORRIOLS 2009:

"...Chemical exposure caused neurocognitive impairment, and SPECT brain dysfunction particularly in odor-processing areas, thereby suggesting a neurogenic origin of MCS..."

MILQVIST 2005: 

"...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..."

NOGAMI 2004:  

"...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).

VERONESI 2001: 

"...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.

ELBERLING 2009:  

"...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..." 

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..."

MCS 3b CAR References

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