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Biological definition of multiple chemical sensitivity from redox state and cytokine profiling and not from polymorphisms of xenobiotic-metabolizing enzymes
Abstract
Multiple chemical sensitivity (MCS) is a poorly clinically and biologically defined environment-associated syndrome. Although dysfunctions of phase I/phase II metabolizing enzymes and redox imbalance have been hypothesized, corresponding genetic and metabolic parameters in MCS have not been systematically examined.
We sought for genetic, immunological, and metabolic markers in MCS.
We genotyped patients with diagnosis of MCS, suspected MCS and Italian healthy controls for allelic variants of cytochrome P450 isoforms (CYP2C9, CYP2C19, CYP2D6, and CYP3A5), UDP-glucuronosyl transferase (UGT1A1), and glutathione S-transferases (GSTP1, GSTM1, and GSTT1). Erythrocyte membrane fatty acids, antioxidant (catalase, superoxide dismutase (SOD)) and glutathione metabolizing (GST, glutathione peroxidase (Gpx)) enzymes, whole blood chemiluminescence, total antioxidant capacity, levels of nitrites/nitrates, glutathione, HNE-protein adducts, and a wide spectrum of cytokines in the plasma were determined.
Allele and genotype frequencies of CYPs, UGT, GSTM, GSTT, and GSTP were similar in the Italian MCS patients and in the control populations. The activities of erythrocyte catalase and GST were lower, whereas Gpx was higher than normal. Both reduced and oxidised glutathione were decreased, whereas nitrites/nitrates were increased in the MCS groups. The MCS fatty acid profile was shifted to saturated compartment and IFNgamma, IL-8, IL-10, MCP-1, PDGFbb, and VEGF were increased.
Altered redox and cytokine patterns suggest inhibition of expression/activity of metabolizing and antioxidant enzymes in MCS. Metabolic parameters indicating accelerated lipid oxidation, increased nitric oxide production and glutathione depletion in combination with increased plasma inflammatory cytokines should be considered in biological definition and diagnosis of MCS.
... The frequency of CYP2C19*2 was the highest in Cyprus (21%) (Mizzi et al., 2016), Romania (20.8%) (Petrović et al., 2020), and Malta (20%) (Mizzi et al., 2016), whereas the Czech Republic (8%) (Mizzi et al., 2016) reported the lowest frequency of all European countries (Table 2). Overall, the CYP2C19*2 allele frequency was slightly more prevalent in Northern and Western European countries, such as Finland (17.5%) (Hilli et al., 2007;Pimenoff et al., 2012), the Faroe Islands (18.8%) (Pedersen et al., 2010), and France (18.4%) (Bertrand-thiébault et al., 2008), compared to Mediterranean countries, namely Italy (10.6%) (de Luca et al., 2010) and Turkey (10.0%) (Gumus et al., 2012). Similar results were also reported in Petrović et al. (2020). ...
... As reported in Petrović et al. (2020), the highest CYP2D6*4 frequency in Europe was observed in the Faroe Islands (33.4%) (Halling et al., 2005). In contrast, frequencies were substantially lower in most Southern European countries, such as Turkey (13.9%) (Aydin et al., 2005), Italy (average of 16.3%) (de Luca et al., 2010;Fuselli et al., 2004;Riccardi et al., 2011;Scordo et al., 2004;Sistonen et al., 2007), and Greece (17.8%) (Arvanitidis et al., 2007). Notably, Finland contradicted this trend with an allele frequency of 10.3% (Pietarinen et al., 2016), which is substantially lower than its neighbouring countries, i.e., Sweden (19.4%) (Ameur et al., 2017;Yamada et al., 1998;Zackrisson et al., 2004Zackrisson et al., , 2010, Norway (21%) (Molden et al., 2002), and Estonia (16.7%) (Petrović et al., 2020). ...
... Allele frequency of the CYP2D6*2, CYP2D6*3, CYP2D6*4, CYP2D6*5, CYP2D6*6, CYP2D6*41 and CYP2D6 duplicates *1xN and *2xN in European countries. -Santander et al., 2012;Fudio et al., 2010;Fuselli et al., 2004;Gómez-Martín et al., 2015;Menoyo et al., 2006) Arygei (Turkey) 1 34 0,412 0,294 0,000 0,088 0,029 0,000 0,147 0,000 0,000 0,029 (Sistonen et al., 2007) Turkish (Turkey) 3 644 0,632 0,000 0,012 0,117 0,015 0,008 0,000 0,012 0,007 0,048 (Aydin et al., 2005;Aynacioglu et al., 1999;Serin et al., 2012) (de Luca et al., 2010;Fuselli et al., 2004;Riccardi et al., 2011;Scordo et al., 2004;Sistonen et al., 2007) (Ameur et al., 2017;Yamada et al., 1998;Zackrisson et al., 2004Zackrisson et al., , 2010) Swiss (Switzerland) 2 221 0,347 0,238 0,038 0,201 0,021 0,006 0,037 0,012 0,008 0,087 (Fuselli et al., 2004;Rebsamen et al., 2009) ...
The cytochrome P450 (CYP) enzymes constitute a large polymorphic family that play a huge role in the metabolism of endogenous compounds and in the metabolization of 70–80% of all clinically prescribed medications. Among them, the CYP2C9, CYP2C19, CYP2D6 and CYP4F2 genes are of clinical relevance, as they are highly polymorphic and implicated in the metabolism of several drugs. These genetic polymorphisms which induce variability in CYPs expression present qualitative and quantitative differences between ethnic groups and geographic regions. This review aims to evaluate the allele frequencies, genotypic distribution and predicted CYP2C9, CYP2C19, CYP2D6 and CYP4F2 genetic variants in the European countries. Therefore, a PubMed and a Web of Science search from 1989 to 2021 on the data on the polymorphic prevalence among European countries of the CYP2C9, CYP2C19, CYP2D6 and CYP4F2 genes was performed. After excluding the duplicates, a total of 1179 studies were found. The results were structured and presented in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The present paper is an overview on the frequency CYP genetic variations, facilitating the prediction of a patient's response to medication and, consequently, enabling the selection of personalized medicine.
... To date, the importance of oxidative stress as an etiopathogenetic mechanism of this condition is widely recognized, in addition to the role of redox status alterations in the development of chronic mild systemic inflammation (5)(6)(7). In previous studies it was demonstrated in the clinical setting how oxidative status and inflammatory markers were elevated in patients with MCS compared with healthy subjects (8)(9)(10)(11)(12). Moreover, almost all patients with MCS are characterized by a genetic background, potentially predisposing them to the development of oxidative/nitrosative stress, given the presence of several single nucleotide polymorphisms (SNPs) in genes coding for enzymes involved in phase I and II detoxification reactions, as well as antioxidant enzymes (9)(10)(11)(13)(14)(15)(16)(17). ...
... Starting from biochemical features of patients with MCS characterized in our previous study (8), the influence of the SOD2 A16V polymorphism on the alterations of selected biomarkers of systemic oxidative damage in patients with MCS compared with healthy subjects were evaluated in the present study. (20) and the Quick Environment Exposure Sensitivity Inventory (QEESI) score (21), adapted for local application. ...
... In the last two decades several studies have provided evidence for a correlation between MCS and chemical defense system alterations, occurring in the presence of gene polymorphisms of detoxification phase I (CYPs) and phase II enzymes (GST, NAT and UGT, amongst others), as well as antioxidant enzymes SOD2 and GPX (5,(9)(10)(11)(12)(13)(14)(15)(16)(17) highlighted the relevance of oxidative stress in this syndrome. In particular, a reduction of CAT and GST enzyme activities, associated with glutathione reduction, increased GPx activity, PUFA-depleted profiles of erythrocyte membranes, and specifically altered pro-inflammatory plasma cytokine patterns have been shown in a MCS cohort as a whole (8,9). Moreover, in our previous study, it was reported that there was a significantly higher frequency of polymorphisms in genes coding for CYP enzymes in patients with MCS compared with controls. ...
Chronically increased oxidative stress has been reported in patients with multiple chemical sensitivity (MCS). Recently, a single nucleotide polymorphism of the gene coding for mitochondrial superoxide dismutase (SOD2), namely the missense substitution A16V (C47>T) resulting in alteration of SOD2 enzyme activity, has been reported to be associated with MCS. However, the influence of SOD2 A16V genetic background on redox status of patients with MCS has not yet been investigated. Here, the results of a retrospective analysis aimed to evaluate the role of the SOD2 A16V polymorphism in the alterations of antioxidant defense markers as well as fatty acid (FA) composition of erythrocyte membranes in 67 patients with MCS matched with 55 healthy controls is reported. The mutated SOD2 V16 variant was observed more frequently in the MCS group compared with the control group, and this difference was statistically significant. The most common genotype in both groups was the heterozygous SOD2 AV16 variant, whereas the mutated SOD2 VV16 variant was more frequently observed in the MCS group, although the difference was not significant. The MCS cohort showed significantly depleted levels of plasma total antioxidant activity, ubiquinol, erythrocyte reduced glutathione and membrane polyunsaturated FA levels, coupled with significant increases in glutathione peroxidase activity, likely accounting for sustained detoxification from lipoperoxides. Notably, the highest levels of oxidative stress were found in patients with MCS bearing the genotype SOD2 AA16, whereas intermediate levels were found in patients bearing the heterozygous AV16 genotype. Healthy subjects bearing the SOD2 AA16 genotype also showed increased oxidative stress compared with carriers of other SOD2 genotypes. Despite the need for further confirmations in larger cohorts, due to MCS population genetic heterogeneity, these preliminary findings suggest that SOD2 defective activity makes certain patients with MCS more susceptible to developing oxidative stress following a chronic daily exposure to pro-oxidant insults.
... To date the proposed etiopathogenetic mechanism involves an aberrant activation of the vicious cycle N-methyl-d-aspartate (NMDA)-nitric oxide/peroxynitrite triggered by various chemical agents, that ultimately lead to oxidative stress and activation of pro-inflammatory transcription factors [8]. Indeed, dramatically increased levels of reactive oxygen and nitrogen species (ROS, RNS), as well as pro-inflammatory cytokines and the presence of autoimmune antibodies, have been reported in MCS patients compared with healthy subjects [9][10][11][12][13][14]. Moreover, a link has been suggested between MCS and inherited or acquired defects in genes coding for enzymes involved in xenobiotic metabolism phase I and II, antioxidant defense, lipid metabolism and one-carbon pathway [11,12,[15][16][17][18][19][20][21]. ...
... In the last decade, literature data provided evidence for the association of MCS with increased oxidative/nitrosative stress and inflammation [9][10][11][12][13][14], likely resulting from defects in xenobiotic metabolism and antioxidant enzyme defenses [26]. A chronic imbalance in redox homeostasis promotes the development of inflammation mainly through the dysregulation of immune response cells and the activation of pro-inflammatory transcription factors [27]. ...
... Moreover, IL-4 plays a role in antagonizing pathogenic Th1 responses [40]. The increased IL-4 serum levels observed in MCS patients recruited for this study and in other studies [9,10], and the here observed significant positive correlation with IFN-γ levels, suggest a compensative reaction to buffer the increase of IFN-γ production. ...
Systemic inflammation and immune activation are striking features of multiple chemical sensitivity (MCS). The rs2298383 SNP of ADORA2A gene, coding for adenosine receptor type 2A (A2AR), has been involved in aberrant immune activation. Here we aimed to assess the prevalence of this SNP in 279 MCS patients and 238 healthy subjects, and its influence on ADORA2A, IFNG and IL4 transcript amounts in peripheral blood mononuclear cells of randomly selected patients (n = 70) and controls (n = 66) having different ADORA2A genotypes. The ADORA2A rs2298383 TT mutated genotype, significantly more frequent in MCS patients than in controls, was associated with a three-fold increased risk for MCS (O.R. = 2.86; C.I. 95% 1.99–4.12, p < 0.0001), while the CT genotype, highly prevalent among controls, resulted to be protective (O.R. = 0.33; C.I. 95% 0.224–0.475, p < 0.0001). Notably, ADORA2A mRNA levels were significantly lower, while IFNG, but not IL4, mRNA levels were significantly higher in TT MCS patients compared with controls. A significant negative correlation was found between ADORA2A and both IFNG and IL4, while a significant positive correlation was found between IFNG and IL4. These findings suggest that A2AR defective signaling may play a relevant role in PBMC shift towards a pro-inflammatory phenotype in MCS patients.
... The genetic risk related to phase I and II enzymes involved in xenobiotic detoxification, olfactory, and neurodegenerative diseases play a necessary along the pathophysiological route of the disease. This tends to confirm previous hypotheses suggesting the inherited and acquired dysfunction of the chemical defensive system as a molecular basis for MCS complaints (8)(9)(10). ...
... The polymorphism in genes encoding both metabolizing enzymes and the receptors and transcriptional factors regulating their expression, may account for the existing interindividual variations in xenobiotics metabolizing activity, and it has been suggested as a possible mechanism underlying MCS (9). On the other hand, individual peculiarity of adaptive response to chemical stressors at the epigenetic level through the direct interaction of these substances and their metabolites with biologically important molecules and cellular membranes may also play an important role in the disease pathogenesis. ...
... Dysregulation of the immune system has frequently been proposed as a pathophysiological mechanism likely to play a role in the etiology (9,16) and common MCS symptom-triggering compounds, such as formaldehyde, hydrocarbons and organochlorines, have been shown to suppress immune system functioning in humans (17). However, immunological testing has failed to reveal any consistent pattern of reactivity or abnormalities indicative of common immunological deficiency in MCS (18,19). ...
Multiple chemical sensitivity (MCS) is increasingly widespread disease, characterized by non-specific and recurring symptoms from various organs associated with exposure to common chemicals, even if inhaled at low concentrations, usually harmless for normal people. MCS is not yet well recognized from common point of view and for this reason affected patients risk marginalization and their symptoms are often trivialized. It is actually a devastating chronic disease that affects not only the patients in the daily routine but partly conditions their survival. Despite more than 50 years of research, the action mechanisms of MCS is still undefined. In this study we examine the theories about the etiopathogenesis of multiple chemical sensitivity that include genetic susceptibility factors, immunological factors, neurological factors and psychiatric factors. Since no specific diagnostic markers are currently available for the MCS, the diagnosis can only be supposed on the basis symptomatic criteria and patient's medical history. However new biochemical markers and diagnostic imaging techniques have emerged, useful to postulate at least the clinical-diagnostic hypothesis of MCS and in this paper we discuss a list of biomarkers studied for the diagnosis of MCS, based on the available scientific literature. At last but not least, we propose four-levels MCS tests that could help the clinician in the diagnosis of the pathology both through the use of quantifiable serological parameters, both through diagnostic tools, genetic testing and through clinical observation of symptoms.
... Among the vast literature regarding the gene polymorphisms involved in MCS, the overall approach is, at least, to define the individual genetic profiles of enzymes involved in body detoxification from xenobiotics such as phase I metabolism cytochrome P450 monoxygenases (CYP450), phase II metabolism glutathione-S-transferase (GST) and N-acetyl-transferase (NAT2), antioxidant defense, namely mitochondrial superoxide dismutase (SOD2), paraoxonase 1 and 2 (PON1, PON2), endothelial and inducible nitric oxide synthase (NOS2, NOS3) as well as folate cycle/methylation (MTHFR) [10,31,[39][40][41][42][43][44][45][46]. The hypothesis underlying the above cited investigations was the fact that the extreme individual sensitivity in MCS patients could be related to the inherited impairment in xenobiotics/endobiotics metabolism and to a vicious cycle [47] including peroxynitrite overproduction and lipid peroxidation, possibly not coped by the impairment in SOD, catalase, glutathione peroxidase, and NOS enzyme activities [48]. Int. ...
... The resulting individual phenotype is characterized by a reduced antioxidant defense, potentially leading to increased susceptibility to oxidative stress. The observed increased prevalence of defects in antioxidant enzymes confirms previous results [10,40,51,52] and may provide a mechanistic explanation for reported MCS features of oxidative stress [48]. ...
... In particular, when paying attention to both the regression model and the Pareto chart highlighting respective t-values accounting for significant impact on LQrv, such a multifactorial model was hierarchically contributed to by genetic factors (phase I and phase II classes scores), environmental (chemical compound exposures), and anamnestic characteristics (presence of previous surgery events) of the patients. This tends to confirm previous hypotheses suggesting the inherited and acquired dysfunction of the chemical defensive system as a molecular basis for MCS complaints [42,48]. Indeed, adequate body response to environmental toxicants presumably requires proper function of the xenobiotic detoxification pathways. ...
Genetic polymorphisms as well as environmental exposures to chemical compounds, iatrogenic, psychological, and physical trauma may play a pathophysiological role in multiple chemical sensitivity (MCS) olfactory complaints, given that xenobiotic metabolism is influenced by sequence variations in genes of metabolizing enzymes. Thus, the aim of the present study was to depict—by means of multiple regression analysis—how different genetic conditions, grouped according to their function as well as clinical background and environmental exposure may interfere with those olfactory complaints referred by MCS patients. Therefore, MCS patients after gene polymorphism sequencing, the olfactory-related quality of life score—calculated by means of the Questionnaire of Olfactory Disorder in forty-six MCS patients—have been found to significantly rely on the phase I and II enzymes score and exposure to previous compounds and surgical treatments. The present work—implementing for the first time a genetic-acquired factors model on a regression analysis—further reinforces those theories, positing MCS as a complex, multifactorial, disease in which the genetic risk related to phase I and II enzymes involved in xenobiotic detoxification, olfactory, and neurodegenerative diseases play a necessary, but probably not sufficient role, along the pathophysiological route of the disease.
... I pazienti con la MCS spesso presentano comorbidità come disturbi digestivi (ad es. sindrome dell'intestino irritabile), malattie della tiroide, asma, allergie o astenia [6] . La sensibilità chimica risulta quindi essere una condizione acquisita, con un possibile substrato di iperossidazione riferibilie a poliallelismo mutazione, delezioni geniche. ...
... La patogenesi della malattia può essere ricondotta ad una massiva reazione allo stress ossidativo e nitrosativo, ad infiammazione neurogena e sistemica cronica [5] , rottura della barriera emato-encefalica (BBB), ad un metabolismo anormale degli xenobiotici [3] ed insufficienti capacità detossificanti. Si induce quindi iperattivazione di numerosi recettori sensoriali con un impatto sul metabolismo e sul sistema immunitario oltre che sul sistema nervoso centrale a causa della reazione allo stress ossidativo [6,7] , il quale può esprimersi in multiformi patologie. In questa sindrome, sono coinvolte sostanze come: contaminanti quali pesticidi, biocidi, metaboliti e tossine [7,8] , profumi, deodoranti, detergenti, fumo di tabacco, superfici verniciate di recente, tappeti in plastica e adesivi, composti organici volatili (COV -VOC), come formaldeide, 2-etilesanolo, inchiostro fresco, gas di scarico o polvere di strada. ...
... La tabella contiene un numero di biomarcatori che sono di uso corrente per altri utilizzi, ma non sono ancora stati sfruttati nella valutazione dei pazienti con la MCS. In tutti i pazienti con MCS, è possibile trovare indicazioni per livelli (o attività) ridotte di GSH (glutatione) e CAT (catalasi) e GST (glutatione transferasi) [4,6] . ...
Per taluni è un condizionamento comportamentale, reattivo a condizioni ambientali, sensibilizzanti filtrate dall'apparato olfattivo. Per altri è semplicemente un "allarme fisiologico difettoso". In effetti, la iper-sensibilità chimica multipla (MCS) non è ancora ben riconosciuta sotto il profilo diagnostico e per questo motivo i pazienti affetti rischiano l' emarginazione e i loro sintomi vengono spesso banalizzati.
... In most of the epidemiological studies people are recruited following interviews and through the compilation of different kinds of questionnaires [51][52][53][54][55][56][57][58][59][60] or standardized questionnaire as the EESI or QEESI [61][62][63][64][65][66][67][68][69][70][71][72][73][74], CGES [75], Huppe [76], Environmental medicine questionnaire (EMQ), or chemical sensitivity scale for sensory hyper-reactivity (CSS-SHR) [50,77], Chemical Odor Intolerance Index (CII) [78,79]. Sometimes the syndrome has been diagnosed by doctors without pointing out the diagnostic procedure [80,81]. ...
... In this scenario the sensitivity to substances may also be caused by different polymorphisms involved in the detoxification of xenobiotics, which could lead to an accumulation of oxidizing substances and subsequent damage. In some studies [69,72,74] various polymorphisms of Cyp 450 (Cyp 2C9, Cyp 2C19, Cyp 2D6 etc) were analyzed, including also glutathione transferase and peroxidase (GSTM, GSTT, GSTP), aldehyde dehydrogenase, superoxide dismutase (SOD 2 ) and paraoxonase (PON1) [69,73,74]. The SOD 2 polymorphism [69] and a specific variant of NOS 3 [67] seem to be associated with the syndrome and increased levels of oxidative stress. ...
... In this scenario the sensitivity to substances may also be caused by different polymorphisms involved in the detoxification of xenobiotics, which could lead to an accumulation of oxidizing substances and subsequent damage. In some studies [69,72,74] various polymorphisms of Cyp 450 (Cyp 2C9, Cyp 2C19, Cyp 2D6 etc) were analyzed, including also glutathione transferase and peroxidase (GSTM, GSTT, GSTP), aldehyde dehydrogenase, superoxide dismutase (SOD 2 ) and paraoxonase (PON1) [69,73,74]. The SOD 2 polymorphism [69] and a specific variant of NOS 3 [67] seem to be associated with the syndrome and increased levels of oxidative stress. ...
... In most of the epidemiological studies people are recruited following interviews and through the compilation of different kinds of questionnaires [51][52][53][54][55][56][57][58][59][60] or standardized questionnaire as the EESI or QEESI [61][62][63][64][65][66][67][68][69][70][71][72][73][74], CGES [75], Huppe [76], Environmental medicine questionnaire (EMQ), or chemical sensitivity scale for sensory hyper-reactivity (CSS-SHR) [50,77], Chemical Odor Intolerance Index (CII) [78,79]. Sometimes the syndrome has been diagnosed by doctors without pointing out the diagnostic procedure [80,81]. ...
... In this scenario the sensitivity to substances may also be caused by different polymorphisms involved in the detoxification of xenobiotics, which could lead to an accumulation of oxidizing substances and subsequent damage. In some studies [69,72,74] various polymorphisms of Cyp 450 (Cyp 2C9, Cyp 2C19, Cyp 2D6 etc) were analyzed, including also glutathione transferase and peroxidase (GSTM, GSTT, GSTP), aldehyde dehydrogenase, superoxide dismutase (SOD 2 ) and paraoxonase (PON1) [69,73,74]. The SOD 2 polymorphism [69] and a specific variant of NOS 3 [67] seem to be associated with the syndrome and increased levels of oxidative stress. ...
... In this scenario the sensitivity to substances may also be caused by different polymorphisms involved in the detoxification of xenobiotics, which could lead to an accumulation of oxidizing substances and subsequent damage. In some studies [69,72,74] various polymorphisms of Cyp 450 (Cyp 2C9, Cyp 2C19, Cyp 2D6 etc) were analyzed, including also glutathione transferase and peroxidase (GSTM, GSTT, GSTP), aldehyde dehydrogenase, superoxide dismutase (SOD 2 ) and paraoxonase (PON1) [69,73,74]. The SOD 2 polymorphism [69] and a specific variant of NOS 3 [67] seem to be associated with the syndrome and increased levels of oxidative stress. ...
Objective:
Systematic bibliography analysis of about the last 17 years on multiple chemical sensitivity (MCS) was carried out in order to detect new diagnostic and epidemiological evidence. The MCS is a complex syndrome that manifests as a result of exposure to a low level of various common contaminants. The etiology, diagnosis, and treatment are still debated among researchers.
Method:
Querying PubMed, Web of Science, Scopus, Cochrane library, both using some specific MESH terms combined with MESH subheadings and through free search, even by Google.
Results:
The studies were analyzed by verifying 1) the typology of study design; 2) criteria for case definition; 3) presence of attendances in the emergency departments and hospital admissions, and 4) analysis of the risk factors.
Outlook:
With this review, we give some general considerations and hypothesis for possible future research.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0.
... Furthermore, in accordance with the emerging view on MCS (Van den Bergh et al. 2010), a biopsychosocial perspective on CI was adopted: Not only general health markers were assessed prior to the experimental whole-body exposure to ammonia (e.g., lung and olfactory function), but also parameters which have been found to be specifically altered in MCS. These parameters included (a) negative affect, perceived stress, and somatoform symptom levels (Papo et al. 2006;Skovbjerg et al. 2015); (b) cognitive-emotional information processing (Witthöft et al. 2009); and (c) plasma cytokine levels, plasma growth factor levels, and erythrocyte membrane fatty acid profiles (De Luca et al. 2010. This in-depth characterization of participants was performed in order to better understand the relation between self-reported CI and MCS and the importance of CI-related differences at baseline for exposure-related effects. ...
... Venous blood samples were collected in EDTA and serum tubes (total collected volume per participant: 29.7 ml). A certified clinical laboratory (DIN EN ISO 15189) analyzed inflammation markers C-reactive protein and alkaline phosphatase in blood, while suggested MCS-specific plasma biomarkers (De Luca et al. 2010) were analyzed at the central scientific unit Analytical Chemistry of the Leibniz Research Centre for Working Environment and Human Factors, Dortmund, Germany. ...
... However, our results concerning nasal TNF-α need to be interpreted with caution. In contrast to the predictions of the neurogenic inflammation theory and the nitric oxide/peroxynitrite theory of MCS, nasal substance P, plasma inflammatory cytokines, and fatty acid profiles of erythrocyte membranes were comparable Table 4 Reaction times (RT) and error rates (Err %) in the 3-back task and for the compatible and incompatible trials of the response inhibition (RI) task in the control group and the experimental group between the two groups (De Luca et al. 2010;Meggs 1993;Pall 2003). Furthermore, a significant difference between the two groups regarding nasal TNF-α only emerged if olfactory function was statistically controlled. ...
Purpose:
Healthy individuals differ in self-reported chemical intolerance (CI). It is unclear whether this inter-individual variability impacts well-being and performance in environmental and occupational settings with chemical exposures. So far, operational definitions and questionnaires of CI have either emphasized physical symptoms or affective/behavioral disruption. In contrast, this study focused on healthy individuals who reported strong CI which generalized to awareness, physiology, affect, and behavior. We investigated whether generalized self-reported CI is associated with hyper-reactivity and reduced cognitive functioning due to chemosensory-mediated distraction during ammonia exposure.
Methods:
An online sample (N = 321) answered established CI questionnaires. Based on the convergent self-reports in these questionnaires, healthy women with generalized CI and healthy female control participants were selected (total N = 26). Baseline characterization was performed using implicit association, lung and olfactory function tests, health-related self-reports, plasma inflammatory and metabolic markers. Performance in neurobehavioral tasks, perceptual ratings, nasal inflammatory, neuroendocrine, and autonomic nervous system reactivity were examined by means of a 75-min whole-body challenge to ammonia (stepwise increase: 0-10 ppm).
Results:
Correlational analyses confirmed the multidimensionality of CI. Participants with generalized self-reported CI exhibited better olfactory function and reported stronger pungency during the challenge than controls. Cognitive performance and physiological response to the challenge were comparable between the two groups.
Conclusions:
Self-reports of CI are complex and not easily assessed by unidimensional questionnaires. While generalized self-reported CI is associated with altered chemosensory processing, it seems unlikely that it modulates health effects and cognitive functioning during chemical exposure.
... SRI symptoms include multi-organ systemic and skin events, chronic muscular fatigue, asthma, as well as neurological, gastrointestinal, cardiac, and autoimmune disorders [5,6]. ...
... SRIs diagnosis is based on the Cullen's inclusion anamnestic criteria [7], and results from the modified QEESI (Quick Environmental Exposure and Sensitivity Inventory), a multistep questionnaire that determines the levels of sensitization to chemical triggers as well as the life impact, and scores the type, localization and severity of symptoms after exposure [8]. Indeed, a modified QEESI score of 10 common environmental exposures and 10 major symptoms enables the differential diagnosis of MCS and SMCS (suspected MCS): full diagnosis (20 ≤ Score ≤ 30) or strongly suspected diagnosis, that is subjects fulfilling diagnostic criteria only partially (10 ≤ Score ≤ 20), or subjects not fulfilling diagnostic criteria (0 ≤ Score ≤ 10) [6,8]. ...
... Recent advances have highlighted the role of inherited or acquired impairment of xenobiotic metabolism in the individual hypersensitivity to xenobiotics and toxic endogenous metabolites. Alterations of this system may lead to incomplete removal of toxins or/and to excessive generation of toxic by-products, leading to redox state impairment, inflammation and cell damage [6,9,10]. Notably, erythrocyte catalase and glutathione-S-transferase (GST) activities, antioxidant potential as well as reduced glutathione (GSH) content, have been found to be lower in SRI patients than in healthy subjects [6]. ...
Aims:
Oxidative stress increase is a key event for development of sensitivity-related illnesses (SRIs). The aim of this work was to evaluate the influence of genetic variants in antioxidant enzymes on oxidative stress development in SRIs.
Main methods:
Glutathione peroxidase (GPx1) rs1800668 genotype, as well as glutathione, ubiquinone, and DNA damage were assessed in 34 SRI patients and 36 healthy subjects.
Key findings:
Total glutathione, reduced/oxidized glutathione, and ubiquinone were significantly decreased in cases compared with controls, while DNA fragmentation was significantly increased in patients. However, these differences were not associated to GPx1 genetic background.
Significance:
GPx1 rs1800668 polymorphism does not play a major role in SRI-related oxidative stress development.
... En muchos casos, las personas afectadas declaran la aparición de los primeros síntomas tras una exposición aguda importante, en ocasiones relacionada con una sustancia química olorosa (un evento desencadenante). Más tarde, la aparición de síntomas similares o nueva sintomatología ocurre tras exposiciones a niveles bajos, casi despreciables, de sustancias químicas tan variadas como las contenidas en perfumes, pinturas, productos de limpieza, tintas, moquetas y otros compuestos orgánicos (desencadenantes en bajas dosis) 23,24,25,26,27 . ...
... En el caso de la SQM se han encontrado las siguientes comorbilidades: la tiroiditis autoinmune, el asma bronquial, el reflujo esofágico, el colon irritable y la esteatosis hepática (la más frecuente de entre las hepatopatías). Entre las patologías psiquiátricas, estarían: el trastorno mixto ansioso-depresivo, los ataques de pánico y los trastornos obsesivo-compulsivos 24 . ...
... comidas, medicaciones, alcohol), calidad de vida y posible existencia del fenómeno de enmascaramiento, de forma tal que usadas en conjunto, las escalas resultantes proveen una sensibilidad del 92% y una especificidad del 95% en la diferenciación de personas afectadas por SQM respecto a los controles. Algunos autores han establecido sus casos con cuestionarios que emplean grupos de preguntas del QEESI con o sin modificaciones 24,87,90 . · Existen, finalmente, otro tipo de cuestionarios que evalúan la gravedad de la sensibilidad química ambiental, pero no sintomatología específica 88, 91, 92, 93, y variables tanto para el estudio de la exposición como de la sintomatología 87. ...
SÍNTESIS
Como resultado de las búsquedas realizadas se localizaron 1.350 referencias. De
todas ellas, en la AETS se seleccionaron 10 estudios que trataban sobre epidemiología
y 16 relacionados con la sintomatología clínica y morbilidades asociadas a la SQM.
No se localizó ningún artículo sobre tratamiento que cumpliera los criterios establecidos.
Las tablas de resultados de estos artículos se presentan en los Anexos
III y IV.
La calidad metodológica de los estudios seleccionados sobre datos clínicos y de
comorbilidad de la SQM ha sido, en general, baja por lo que la calidad de la evidencia
científica asignada a los mismos, siguiendo la clasificación acordada por SIGN,
ha sido en la mayoría de nivel 3. Hay dos estudios5, 6 de casos-controles, y solo un
trabajo7 con una calidad metodológica considerablemente mejor (nivel 2++) que
recoge el estudio de provocación en pacientes con asignación randomizada, doble
ciego, y que incluía un grupo control.
Estos estudios incluyeron un número relativamente pequeño de personas, entre 28
y 291, con un número medio de 103,2, y metodológicamente fueron muy diferentes
entre sí. Así, la mayoría fueron series de casos; en seis estudios se incluyeron también
controles emparejados; solo en cinco trabajos se mencionó que la selección
de pacientes fue de manera consecutiva; dos fueron retrospectivos, obteniendo los
datos de la revisión de las historias clínicas de los pacientes; uno fue multicéntrico;
uno era un estudio de provocación; dos trabajos presentaron resultados de seguimiento
de los pacientes durante varios años; y en dos realizaron encuestas por
teléfono. Los cuestionarios empleados también fueron diferentes de unos estudios
a otros: en algunos trabajos se empleó el QEESI©, en otros, el SF-36, el SIP u otros
de orden físico o psicológico.
Los trabajos más rigurosos metodológicamente han encontrado resultados que o
bien ponen en duda la relación entre los factores desencadentes y la enfermedad
o bien concluían que la relación no podía demostrarse. En uno de estos trabajos8
no se encontró relación entre las sustancias químicas y los síntomas mencionados
por los pacientes, ni tampoco evidencia sobre una posible exposición inicial ni de
posteriores exposiciones desencadenantes. En el estudio de provocación controlado
y doble ciego, en el que no se encontraron diferencias entre ambos grupos,
sus autores7 concluyeron que en la mayoría de los casos, se debía cuestionar la
veracidad de los cuadros de SQM y considerar, en su lugar, otras patologías físicas
y psiquiátricas.
Igual que en los estudios que analizan la prevalencia de la SQM, hay gran variabilidad
en la definición de caso y en los criterios utilizados para definir las personas
enfermas de SQM. En seis estudios se dice de forma expresa que utilizaron la definición
de caso derivada de la reunión de consenso de 19999 tres de los trabajos
utilizaron los criterios de Cullen10 para definir la enfermedad, en otro estudio se
utilizó la definición de caso de Nethercott11 y en otro la del International Programme
on Chemical Safety (IPCS)12. En los demás, no se especificó.
Los trabajos seleccionados proceden de varios países: 10 de EEUU, 4 de Alemania,
3 de España, 3 de Canadá, 1 de Italia, 1 de Japón, 1 de Gran Bretaña y 1 de Suecia.
En este sentido hay que mencionar la restricción en el idioma de publicación de los
estudios a inglés y español, lo que supone una limitación de esta revisión.
A pesar de que se ha realizado una exhaustiva búsqueda utilizando las fuentes
de información de mayor reconocimiento en el ámbito de las ciencias de la salud,
es preciso reconocer que otra limitación de esta revisión es la relacionada con la
selección de esas fuentes de información y publicaciones científicas y con la capacidad
de acceso a las mismas, por lo que es probable que no se hayan identificado
algunos documentos que pudieran contener datos y resultados de interés. Además,
es muy posible que algunas personas afectadas hayan sido incluidas en varios trabajos
del mismo equipo de investigadores publicados en diferentes años, pero ante
la dificultad para confirmarlo y separar los resultados, y dado el número escaso de
artículos seleccionados, se prefirió no considerar ésto motivo de exclusión de los
artículos para esta revisión.
En cuanto a las revisiones sobre SQM analizadas, cuatro de ellas fueron revisiones
narrativas y dos, revisiones sistemáticas de la literatura. En una de estas últimas13
se dice que cuando el enmascaramiento se realiza de forma correcta, los pacientes
con SQM no son capaces de diferenciar entre estímulos verdaderos y placebo, por
lo que consideran que el patrón de reacción de estos pacientes podría deberse a
las creencias o expectativas previas a la exposición.
... Several theories on the pathophysiology of MCS have been investigated, including increased responses in the CNS, the impairment of the immune, olfactory, and respiratory systems, behavioral conditioning, and psychiatric disorders [14,15]. The organ systems affected in MCS and FSD are the same organs that perform important processes to maintain optimal metabolic health. ...
... Nevertheless, disturbances in metabolic health and the examination of more traditional biochemical markers in relation to the pathophysiology of MCS is poorly described in the literature. One study found differences in the fatty acid profile in the erythrocyte membranes when comparing MCS patients with controls [14] ,whereas another study found no differences in fasting glucose, insulin, or insulin resistance (measureed by HOMA-index) [16]. When looking into other FSDs, metabolic disturbances have been reported in both fibromyalgia, chronic fatigue syndrome, and IBS, which were found to be associated with metabolic syndrome when comparing cases with healthy controls [17][18][19]. ...
Multiple chemical sensitivity (MCS) is a multisystem syndrome, and limited knowledge of its pathophysiology exists. Based on the population-based Danish cohort DanFunD, this study investigated metabolic health in people with MCS compared to individuals who did not have MCS. From 9656 cohort participants aged 18–76 years old, 1.95% were categorized as MCS individuals with comorbid functional somatic disorders (MCS + FSD, n = 188), and 1.13% were categorized as MCS without functional somatic disorders (MCS ÷ FSD, n = 109). MCS was characterized based on three criteria: the experience of symptoms upon exposure to common odors and airborne chemicals, symptoms related the central nervous systems and others organ symptoms, and significant impact on every day, social, and occupational life. The remaining study population without MCS or any other functional somatic disorders were regarded as controls. We used adjusted multiple linear regression with link-function to evaluate the associations between lipid and glucose metabolism markers and MCS. We also tested the odds ratio of metabolic syndrome in MCS. Results did not point to statistically significant associations between lipid biomarkers or metabolic syndrome and both MCS groups compared to the controls. We found that MCS individuals may be more insulin resistant and that MCS ÷ FSD may have an impaired glucose metabolism when compared to controls.
... In the last five years, MCS knowledge has rapidly incremented and clinical manifestations [9][10][11][12][13][14][15][16][17][18][19][20], triggers [21][22][23][24][25][26][27] and a patient category at risk [28][29][30][31] have been identified. These contribute to the understanding of the MCS pathogenesis [10,21,[32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] and assists in the design of dedicated MCS screening questionnaires [49][50][51][52][53][54] (Table 1). ...
... Metabolism perturbations due to or provoked by environmental exposures are currently under evaluation and the preliminary data suggest abnormalities in the detoxification metabolism (i.e., glutathione transferase, catalase, superoxide dismutase), energetic metabolism (i.e., intracellular adenosine triphosphate (ATP) in erythrocytes and platelets) and inflammatory response (pro-inflammatory serum cytokines) [43,87,105,[109][110][111][112][113][114]. These promising biomarkers evaluated on serum, whole blood and peripheral blood mononuclear cells (PBMCs) are detected with methods validated only in experimental conditions and are not applicable to daily clinical practice. ...
Multiple chemical sensitivity (MCS) is a multisystem, recurrent, environmental disorder that flares in response to different exposures (i.e., pesticides, solvents, toxic metals and molds) under the threshold limit value (TLV) calculated for age and gender in the general population. MCS is a syndrome characterized by cutaneous, allergic, gastrointestinal, rheumatological, endocrinological, cardiological and neurological signs and symptoms. We performed a systematic review of the literature to summarize the current clinical and therapeutic evidence and then oriented an eDelphi consensus. Four main research domains were identified (diagnosis, treatment, hospitalization and
emergency) and discussed by 10 experts and an MCS patient. Thus, the first Italian MCS consensus had the double aim: (a) to improve MCS knowledge among healthcare workers and patients by standardizing the clinical and therapeutic management to MCS patients; and (b) to improve and shed light on MCS misconceptions not supported by evidence-based medicine (EBM).
... MCS pathogenesis can be traced back to an exaggerated response to oxidative and nitrosative stress, chronic neurogenic and systemic inflammation [4], altered blood brain barrier (BBB) permeability, abnormal xenobiotic metabolism and insufficient detoxifying capacity [5]. The resulting hyper-activation of sensory receptors has an impact on metabolic pathways, the immune system and the central nervous system (CNS), linked to oxidative stress [6,7], and can result in multiple pathological manifestations. In MCS, contaminants, such as pesticides, biocides, heavy metals, metabolites, mycotoxins, perfumes, detergents, volatile organic compounds, such as formaldehyde, 2-ethylhexanol and dust [7,8], play a role in triggering the symptoms. ...
... Relying on the compromised detoxification system, studies on chemically hypersensitive populations have been focused mainly on the genetic panel of these patients. The allelic variants of cytochrome P450 isoforms (CYP2C9, CYP2C19, CYP2D6, and CYP3A5), glutathione S-transferases (GSTP1, GSTM1 and GSTT1), and antioxidants [catalase, superoxide dismutase (SOD)] were studied in MCS subjects compared to healthy controls (HC) [17] and catalase and GST enzyme activities were found to be lower in MCS [6,17]. GST polymorphisms may reduce glutathione conjugation, a key protective mechanism against oxidative damage. ...
Multiple chemical sensitivity (MCS) is characterised by non-specific and recurring symptoms affecting multiple organs and associated with exposure to chemicals, even at low concentrations, which are, under normal circumstances, harmless to the general population. Symptoms include general discomfort, cardiovascular instability, irritation of the sensory organs, breath disorders, hypersensitivity affecting the skin and epithelial lining of the gut, throat and lungs, anxiety, and learning and memory loss. Chemical intolerance is a key distinguishing feature of MCS, limiting considerably patients’ lifestyle with serious social, occupational and economic implications. Since no specific diagnostic markers are currently available for chemical intolerance, the diagnosis relies on clinical symptoms. Despite the formulation of several hypotheses regarding the pathophysiology of MCS, its mechanisms remain undefined. A person-centred care approach, based on multidisciplinary and individualised medical plans, has shown promising results. However, more definite treatment strategies are required. We have reviewed the main experimental studies on MCS pathophysiology, focusing on the brain networks involved, the impact of environmental pollution on the olfactory system and the correlation with other pathologies such as neurodegenerative diseases. Finally, we discuss treatment strategies targeting the olfactory system.
... In this regard, although in literature it is reported that 26 genes are implicated in the pathogenesis of MCS, 21 but only a few of these are important. 22 This group includes mutations of the catalase coding gene (CAT C262T homozygosity polymorphism) and of the gene encoding glutathione transferase (polymorphism with a null genotype of the GSTT1 gene and heterozygosity polymorphism of the GSTP1 A313G gene) that seem to increase cellular oxidative stress after exposure to certain xenobiotics [23][24][25] and to facilitate the onset of bronchial hyperactivity and asthmatic-like symptoms in patients with MCS. 26,27 On the other hand, particular polymorphisms of the CYP2D6 gene give the carrier a slow metaboliser phenotype, which leads to increased blood concentrations of the same xenobiotics and the consequent oxidative stress. ...
... Similar but not conclusive results were previously reported in studies that have investigated genotype in patients with IEI/MCS. 24,[48][49][50][51][52][53][54] Various mutations of antioxidant genes (GST, CAT, OGG1) and the slow CYP 2D6 phenotype have favored the maintenance of high blood and tissue levels of aromatic compounds, as evidenced by the notable presence of DNA-Hippuric acid adducts on the gene NAP2, and the triggering of inflammatory responses by inhalation or contact with such agents. With regard to the latter, high concentrations of such metabolite precursors such as benzalkonium or benzyl benzoate have been associated with death from acute asthma attack. ...
In this case of idiopathic environmental intolerance, a little known disease characterized by many symptoms of irritation due to exposure to several toxic compounds, genetic analysis could be helpful in case of differential diagnosis issue. In this case of idiopathic environmental intolerance, a little known disease characterized by many symptoms of irritation due to exposure to several toxic compounds, genetic analysis could be helpful in case of differential diagnosis issue.
... Diplotypes' and AS' distribution in the analyzed sample was compared with data from other Italian studies using the Analysis of variance (ANOVA) test [26][27][28][29][30]. ...
... No statistically significant differences were found in the distributions based on gender or geographical location. Our results regarding the allelic and genotype distribution were in accordance with previous studies about European and Italian populations, even if gPMs were less represented in our population sample [26][27][28][29][30]. In general, the most frequent alleles were *1 (38.5%), *2 (17.5%), and *41 (12 %). ...
Background
A proper antalgic treatment is based on the use of titrated drugs to provide adequate relief and a good tolerability profile. Therapies have a variable effectiveness among subjects depending on medical and genetic conditions. CYP2D6 variations determine a different clinical response to most analgesic drugs commonly used in daily clinical practice by influencing the drugs’ pharmacokinetics. This study was a monocentric clinical trial exploring the CYP2D6 variants in 100 patients with a diagnosis of chronic pain.
Methods
DNA was extracted to evaluate the genotype and to classify patients as normal-fast (gNMs-F), normal-slow (gNMs-S), ultrarapid (gUMs), intermediate (gIMs), and poor metabolizers (gPMs) using the Activity Score (AS). Information on therapies and general side effects experienced by patients was collected. Nongenetic co-factors were evaluated to examine the discrepancy between metabolic profile predicted from genotype (gPh) and metabolic profile (phenocopying).
Results
The distribution of our data underlined the prevalence of the gNMs-F (67%), whereas gNMs-S were 24%, gIMs 6%, gPMs 3%, and no gUMs were found, resulting in 33% of patients with reduced metabolic activity. In the analyzed population sample, 86% and 56% of patients, respectively, took at least one or two drugs inhibiting in vitro activity of the CYP2D6 enzyme.
Conclusions
Over one-third of the enrolled patients showed altered CYP2D6 enzymatic metabolic activity, with a risk of phenocopying potentially due to polypharmacology.
Trial registration
ClinicalTrials.gov ID: NCT03411759.
... The importance of glutathione has also been demonstrated in cases involving multiple chemical sensitivity, where reduced levels of glutathione and other antioxidants in patients suffering from MCS were found (19). Moreover, glutathione depletion along with increased plasma inflammatory cytokines have been proposed as useful parameters in diagnosing MCS (20). Thus, defining the role of inflammation in MCS may contribute to a better understanding of this condition and may provide insights into potential treatments and/or prevention. ...
... The valence status of metals may also be relevant in regard to the redox activity and antioxidant status in the lung (30). Moreover, De Luca and coworkers found that increased inflammatory cytokines and glutathione depletion along with other markers of altered redox status are defining characteristics of patients with MCS (20). Although we did not observe a change in total glutathione levels between experimental groups, a change in reduced glutathione ratios was observed indicating an alteration in redox status and oxidative stress. ...
Aim of study:
Metal contaminants contribute to adverse human health effects via acute and chronic exposures. Acute metal exposures followed by prolonged secondary metal exposures may elicit exaggerated inflammatory responses in certain individuals. The aim of this study is to determine whether repeated pulmonary exposures to zinc chloride (ZnCl2) alter subsequent responses to zinc or cerium exposures.
Materials and methods:
Rats were intratracheally (IT) instilled with physiologic saline (n = 24) or 0.05 mg/kg ZnCl2 (n = 16) twice weekly for 4 weeks. Four days after last dosing, the saline group was divided into three subgroups, each IT-instilled with either saline, ZnCl2 or CeCl3 (both at 0.1 mg/kg). The ZnCl2 pre-instilled rats were divided into two subgroups, each instilled with 0.1 mg/kg ZnCl2 or CeCl3. Biomarkers of lung injury/inflammation were assessed in bronchoalveolar lavage (BAL) fluid collected 24 hours later. Oxidative stress was evaluated as total and reduced glutathione in BAL.
Results:
Increases in inflammatory cells, LDH, albumin, leptin, MCP-1, IP-10, fractalkine, TNFα and RANTES were observed in rats instilled with multiple PBS and then with 0.1 mg/kg ZnCl2 and CeCl3. However, rats pre-exposed repeatedly to 0.05 mg/kg ZnCl2 and then challenged with 0.1 mg/kg ZnCl2 or CeCl3 showed even more eosinophils, lymphocytes, and increased concentrations of hemoglobin and MIP-1α. Significant reduction in GSH/GSSG ratios in BAL in response to all ZnCl2 or CeCl3 exposures indicated oxidative stress.
Conclusion:
Previous exposure to zinc ions increases responsiveness to subsequent exposures to zinc and cerium ions. These findings suggest enhanced sensitization possibly due to a reduction in antioxidant defenses.
... Theoretically such susceptibility could explain why some subjects are particularly suffering from EHS and/or MCS and not others. A genetic predisposition including gene variants of drug-metabolizing enzymes has been reported for MCS (149-151) but this has not been confirmed (152,153), suggesting that to define MCS biologically, redox state and cytokine profiling should be considered instead (153). ...
... Theoretically such susceptibility could explain why some subjects are particularly suffering from EHS and/or MCS and not others. A genetic predisposition including gene variants of drug-metabolizing enzymes has been reported for MCS (149-151) but this has not been confirmed (152,153), suggesting that to define MCS biologically, redox state and cytokine profiling should be considered instead (153). ...
Much of the controversy over the causes of electro-hypersensitivity (EHS) and multiple chemical sensitivity (MCS) lies in the absence of both recognized clinical criteria and objective biomarkers for widely accepted diagnosis. Since 2009, we have prospectively investigated, clinically and biologically, 1216 consecutive EHS and/or MCS-self reporting cases, in an attempt to answer both questions. We report here our preliminary data, based on 727 evaluable of 839 enrolled cases: 521 (71.6%) were diagnosed with EHS, 52 (7.2%) with MCS, and 154 (21.2%) with both EHS and MCS. Two out of three patients with EHS and/or MCS were female; mean age (years) was 47. As inflammation appears to be a key process resulting from electromagnetic field (EMF) and/or chemical effects on tissues, and histamine release is potentially a major mediator of inflammation, we systematically measured histamine in the blood of patients. Near 40% had a increase in histaminemia (especially when both conditions were present), indicating a chronic inflammatory response can be detected in these patients. Oxidative stress is part of inflammation and is a key contributor to damage and response. Nitrotyrosin, a marker of both peroxynitrite (ONOO°-) production and opening of the blood-brain barrier (BBB), was increased in 28% the cases. Protein S100B, another marker of BBB opening was increased in 15%. Circulating autoantibodies against O-myelin were detected in 23%, indicating EHS and MCS may be associated with autoimmune response. Confirming animal experiments showing the increase of Hsp27 and/or Hsp70 chaperone proteins under the influence of EMF, we found increased Hsp27 and/or Hsp70 in 33% of the patients. As most patients reported chronic insomnia and fatigue, we determined the 24 h urine 6-hydroxymelatonin sulfate (6-OHMS)/creatinin ratio and found it was decreased (
... In addition, some intermediate activity variants occur frequently in Europe, including CYP2D6*41, CYP2D6*10, CYP2D6*9 and CYP2D6*17 with a prevalence of 9.4, 1.57, 2.76 and 0.39%, respectively. Based on the data from the Tuscans in Italy cohort and from several additional small series [43,48,49], these loss of function and intermediate function variants seem to also be highly prevalent in Italy. Marked differences have been observed between Northern Italy, where loss of function alleles are more represented, and Central and Southern Italy, where the prevalence of intermediate variants is higher [45]. ...
Background: Pharmacogenomic factors affect the susceptibility to drug–drug interactions (DDI). We identified drug interaction perpetrators among the drugs prescribed to a cohort of 290 older adults and analysed the prevalence of gene polymorphisms that can increase their interacting potential. We also pinpointed clinical decision support systems (CDSSs) that incorporate pharmacogenomic factors in DDI risk evaluation. Methods: Perpetrator drugs were identified using the Drug Interactions Flockhart Table, the DRUGBANK website, and the Mayo Clinic Pharmacogenomics Association Table. Allelic variants affecting their activity were identified with the PharmVar, PharmGKB, dbSNP, ensembl and 1000 genome databases. Results: Amiodarone, amlodipine, atorvastatin, digoxin, esomperazole, omeprazole, pantoprazole, simvastatin and rosuvastatin were perpetrator drugs prescribed to >5% of our patients. Few allelic variants affecting their perpetrator activity showed a prevalence >2% in the European population: CYP3A4/5*22, *1G, *3, CYP2C9*2 and *3, CYP2C19*17 and *2, CYP2D6*4, *41, *5, *10 and *9 and SLC1B1*15 and *5. Few commercial CDSS include pharmacogenomic factors in DDI-risk evaluation and none of them was designed for use in older adults. Conclusions: We provided a list of the allelic variants influencing the activity of drug perpetrators in older adults which should be included in pharmacogenomics-oriented CDSSs to be used in geriatric medicine.
... Additional file 1: Table S1 lists selected MC mediators involved in neuroinflammation (after Theoharides et al. [56][57][58][59]. Many investigators have documented neuroinflammation and inflammatory mediators in CI [53,[60][61][62]. ...
Background
This paper explores the relationship between chemical intolerance (CI) and mast cell activation syndrome (MCAS). Worldwide observations provide evidence for a two-stage disease process called toxicant-induced loss of tolerance (TILT) as a mechanism for CI. TILT is initiated by a major exposure event or a series of lower-level exposures. Subsequently, affected individuals report that common chemical inhalants, foods, and drugs (i.e., various xenobiotics) trigger multi-system symptoms.
Purpose
To determine whether MCAS provides a plausible biological mechanism for CI/TILT.
Methods
Using the validated Quick Environmental Exposure and Sensitivity Inventory (QEESI), we compared patients diagnosed with MCAS (n = 147) to individuals who reported chemical intolerances (CI/TILT) following various exposures (n = 345) and to healthy controls (n = 76). Using ANOVA, we compared QEESI scores across groups. Clinical scores for the MCAS patient group were used to predict CI status using logistic regression.
Results
More than half (59%) of the MCAS group met criteria for CI. A logistic regression model illustrates that as the likelihood of patients having MCAS increased, their likelihood of having CI/TILT similarly increased, to a near-perfect correspondence at the high ends of the QEESI and clinical MCAS scores. Symptom and intolerance patterns were nearly identical for the CI and MCAS groups.
Discussion
We present data suggesting that xenobiotic activation of mast cells may underlie CI/TILT. The strikingly similar symptom and intolerance patterns for MCAS and TILT suggest that xenobiotics disrupt mast cells, leading to either or both of these challenging conditions. Faced with patients suffering from complex illness affecting multiple organ systems and fluctuating inflammatory, allergic, and dystrophic symptoms, clinicians can now ask themselves two questions: (1) Could MCAS be at the root of these problems? (2) Could environmental exposures be driving MC activation and mediator release? Increasing our understanding of the connection between TILT and MCs has the potential to expose a new link between environmental exposures and illness, offering new opportunities for improving individual and public health.
Conclusion
The close correspondence between QEESI scores and symptom patterns for MCAS and TILT patients supports xenobiotic-driven mast cell activation and mediator release (i.e., MCAS) as a plausible unifying biological mechanism for CI/TILT, with profound implications for medicine, public health, and regulatory toxicology.
... Previous studies have failed to show consistent findings related to immunological parameters [26]. Luca et al. reported that IFN-gamma, IL-8, IL-10, MCP-1, PDGFbb, and VEGF were significantly increased in the plasma compared to healthy controls [27]. Dantoft et al. found that plasma levels of IL-1-beta, IL-2, IL-4, and IL-6 were significantly increased in IEI, whereas IL-13 was downregulated [28]. ...
A subset of adult-onset asthma patients attribute their symptoms to damp and moldy buildings. Symptoms of idiopathic environmental intolerance (IEI) may resemble asthma and these two entities overlap. We aimed to evaluate if a distinct clinical subtype of asthma related to damp and moldy buildings can be identified, to unravel its corresponding pathomechanistic gene signatures, and to investigate potential molecular similarities with IEI. Fifty female adult-onset asthma patients were categorized based on exposure to building dampness and molds during disease initiation. IEI patients (n = 17) and healthy subjects (n = 21) were also included yielding 88 study subjects. IEI was scored with the Quick Environmental Exposure and Sensitivity Inventory (QEESI) questionnaire. Inflammation was evaluated by blood cell type profiling and cytokine measurements. Disease mechanisms were investigated via gene set variation analysis of RNA from nasal biopsies and peripheral blood mononuclear cells. Nasal biopsy gene expression and plasma cytokine profiles suggested airway and systemic inflammation in asthma without exposure to dampness (AND). Similar evidence of inflammation was absent in patients with dampness-and-mold-related asthma (AAD). Gene expression signatures revealed a greater degree of similarity between IEI and dampness-related asthma than between IEI patients and asthma not associated to dampness and mold. Blood cell transcriptome of IEI subjects showed strong suppression of immune cell activation, migration, and movement. QEESI scores correlated to blood cell gene expression of all study subjects. Transcriptomic analysis revealed clear pathomechanisms for AND but not AAD patients. Furthermore, we found a distinct molecular pathological profile in nasal and blood immune cells of IEI subjects, including several differentially expressed genes that were also identified in AAD samples, suggesting IEI-type mechanisms.
... These findings have not been completely consistent [273,274] however, a regression analysis published in 2019 reinforces the concept that a genetic risk related to phase I and II liver enzymes involved in xenobiotic detoxification can play a role in the pathophysiological route towards sensitization to olfactory compounds in MCS [275]. Nevertheless, even in the absence of an abnormality among detoxification polymorphisms, oxidative stress and systemic inflammation are universally observed in MCS patients [276,277]. There is also evidence suggesting that the BBB may be dysfunctional in MCS [278], which would enable greater chemical exposures in the CNS. ...
The World Health Organization lists air pollution as one of the top five risks for developing chronic non-communicable disease, joining tobacco use, harmful use of alcohol, unhealthy diets and physical inactivity. This review focuses on how host defense mechanisms against adverse airborne exposures relate to the probable interacting and overlapping pathophysiological features of neurodegeneration and multiple chemical sensitivity. Significant long-term airborne exposures can contribute to oxidative stress, systemic inflammation, transient receptor subfamily vanilloid 1 (TRPV1) and subfamily ankyrin 1 (TRPA1) upregulation and sensitization, with impacts on olfactory and trigeminal nerve function, and eventual loss of brain mass. The potential for neurologic dysfunction, including decreased cognition, chronic pain and central sensitization related to airborne contaminants, can be magnified by genetic polymorphisms that result in less effective detoxification. Onset of neurodegenerative disorders is subtle, with early loss of brain mass and loss of sense of smell. Onset of MCS may be gradual following long-term low dose airborne exposures, or acute following a recognizable exposure. Upregulation of chemosensitive TRPV1 and TRPA1 polymodal receptors has been observed in patients with neurodegeneration, and chemically sensitive individuals with asthma, migraine and MCS. In people with chemical sensitivity, these receptors are also sensitized, which is defined as a reduction in the threshold and an increase in the magnitude of a response to noxious stimulation. There is likely damage to the olfactory system in neurodegeneration and trigeminal nerve hypersensitivity in MCS, with different effects on olfactory processing. The associations of low vitamin D levels and protein kinase activity seen in neurodegeneration have not been studied in MCS. Table 2 presents a summary of neurodegeneration and MCS, comparing 16 distinctive genetic, pathophysiological and clinical features associated with air pollution exposures. There is significant overlap, suggesting potential comorbidity. Canadian Health Measures Survey data indicates an overlap between neurodegeneration and MCS (p < 0.05) that suggests comorbidity, but the extent of increased susceptibility to the other condition is not established. Nevertheless, the pathways to the development of these conditions likely involve TRPV1 and TRPA1 receptors, and so it is hypothesized that manifestation of neurodegeneration and/or MCS and possibly why there is divergence may be influenced by polymorphisms of these receptors, among other factors.
... MCS is not rare and epidemiological studies suggest it can affect up to 13% of the population (12,13). The pathogenic mechanism is also not understood but possible roles of inflammatory cytokines, immune cell abnormalities, metabolic vulnerability to oxidative stress, and neural sensitization have been suggested (14)(15)(16)(17)(18)(19). Genetic polymorphisms of the superoxide dismutase 2 gene have also been proposed to increase the risk of being affected by the condition (20). ...
Small fiber neuropathy (SFN) is characterized by the involvement of Aδ and C fibers leading to sensory, mainly pain, and/or autonomic symptoms. Multiple chemical sensitivity syndrome (MCS) is an incompletely defined condition characterized by the onset of various symptoms in patients after exposure to several chemical substances. Pain is a common symptom in these patients. In this study, we report the histological and clinical data of a cohort of 21 patients who had been diagnosed as having MCS and who were referred to us with the suspicion of SFN because of chronic pain. All patients underwent neurological clinical examination, (including scales for pain and autonomic disorders), and a skin biopsy. Age-matched healthy subjects were used as controls for the skin biopsies. Nerve conduction studies and serum screening to exclude possible causes of peripheral neuropathy were also performed. Skin biopsies disclosed a somatic SFN in all patients. Although the majority (18 out of 21) of patients also had autonomic symptoms. we found sparing of autonomic innervation in the biopsies. These observations suggest that chronic pain in MCS could be secondary to the presence of somatic SFN, although more data are needed to confirm these observations.
... [10,11] The pathogenic mechanism is still not understood; a possibile role of in ammatory cytokines, immune cell abnormalities, metabolic vulnerability to oxidative stress and neural sensitization have been suggested. [12][13][14][15][16][17] Genetic polymorphisms of the superoxide dismutase (SOD) 2 gene has also been proposed to increase the risk of being affected by the condition. [18] Moreover, polymorphisms involving the gene encoding for CYP2D6 and NAT-2 (two enzymes involved in drugs metabolism) have also being reported as factors which increase the likelihood of being affected by MCS. ...
Small fiber neuropathy (SFN) is characterised by an involvement of Aδ and C-fibres leading to sensory, mainly pain, and/or autonomic symptoms. Multiple chemical sensitivity syndrome (MCS) is a still not fully defined condition characterised by the arising of different symptoms after exposure to several chemical substances. Pain is often complained by patients affected by MCS. In this study we report the histological and clinical data of a cohort of patients referred to our attention for the suspect of SFN because of chronic pain, who had also received a previous diagnosis of MCS. We studied a total of 21 patients; all patients underwent neurological clinical examination (including scales for pain and autonomic disorders) and skin biopsy. Age matched healthy were used as controls for skin biopsy data. In addition, nerve conduction studies and serum screening to exclude possible causes of peripheral neuropathy were also performed. Skin biopsy disclosed a somatic SFN in all patients. Notwithstanding the majority (18 out of 21) of patients complained also of autonomic symptoms we found a sparing of autonomic innervation on skin biopsy. Chronic pain in MCS could be secondary to the presence of a somatic SFN although larger studies are needed to confirm our observation.
... In this regard, patients often refer to respiratory and allergy specialists and their MCS symptoms can be often misdiagnosed as asthma or allergic conditions, which can lead to vain medical investigations [7]. MCS patients showed immunological alterations, including high levels of IFN-gamma, IL-10, IL-8, MCP-1, VEGF, and PDGF [44]. Despite this, studies have failed to reveal significant changes to provide diagnostic immunological tests or to monitor disease progression [45]. ...
Multiple Chemical Sensitivity (MCS) is a chronic and/or recurrent condition with somatic, cognitive, and affective symptoms following a contact with chemical agents whose concentrations do not correlate with toxicity in the general population. Its prevalence is not well defined; it mainly affects women between 40 and 50 years, without variations in ethnicity, education and economic status. We aimed to assess the core symptoms of this illness in a sample of Italian patients. Two physicians investigated different symptoms with a checklist compilation in 129 patients with MCS (117 women). We conducted a categorical Principal Component Analysis (CATPCA) with Varimax rotation on the checklist dataset. A typical triad was documented: hyperosmia, asthenia, and dyspnoea were the most common symptoms. Patients also frequently showed cough and headache. The CATPCA showed seven main factors: 1, neurocognitive symptoms; 2, physical (objective) symptoms; 3, gastrointestinal symptoms; 4, dermatological symptoms; 5, anxiety-depressive symptoms; 6, respiratory symptoms; 7, hyperosmia and asthenia. Patients showed higher mean prevalence of factors 7 (89.9%), 6 (71.7%), and 1 (62.13%). In conclusion, MCS patients frequently manifest hyperosmia, asthenia, and dyspnoea, which are often concomitant with other respiratory and neurocognitive symptoms. Considering the clinical association that is often made with anxiety, more studies are necessary on the psychosomatic aspects of this syndrome. Further analytical epidemiological studies are needed to support the formulation of aetiological hypotheses of MCS.
... This condition would cause an overreaction of the organism with particular implication of the central nervous system, limbic hyperactivity [2,6] and other apparatuses and systems also following exposures to different classes of substances. It is under investigation if, due to particular metabolic polymorphisms in detoxification enzymes [7,8] and/or due to subsequent epigenetic modifications, these subjects would no longer be able to adequately detoxify their organisms, with an increase in free radicals (hydroxyls and nitroso compounds) capable of causing inflammatory processes in different organs and ...
On the international scene, Multiple Chemical Sensitivity (MCS) is defined, by several experts, as a multisystem syndrome that develops following chronic exposures to low doses of common chemical contaminants. Its general characteristics are, however, the object of conflicting opinions and a source of debate and research aimed at the appropriate nosological and therapeutic frameworks. In the face of a potentially debilitating trend, both in the occupational and in the economical and social sphere, the scientific community has not so far found an agreement. This problem leads patients and their associations to periodically claim some requests. The syndrome is also taken into consideration at a political level, especially due to the close connection with the problems related to environmental pollution and to decision making in the field of control and prevention. For these reasons we believe that an appropriate widespread surveillance network for MCS should be set up in Italy, capable of intercepting possible cases, analyzing them at a multidisciplinary level, and following their evolution.
... We present for the first time all genetic variants of CYP2D6 including SNVs and SVs in 136 Kinh Vietnamese subjects. Our newly obtained data provide important knowledge for determin- Chinese Han 1954 0.4 b 6.0 42.9 -0.9 0.0 0.6 -- [15] Japanese 1017 --42.7 ------ [16] Korean 448 0.8 b 6.2 44.1 -0.5 ---- [17] Thai 288 0.7 4.3 a 44.6 -1.0 -16.4 d -- [18] Indian 881 9.3 -------- [19] Europe Hungarians 431 18.1 d -2.4 c ------ [20] Italian 218 17.7 d 0.0 d ------- [21] Macedonia 184 18.7 d 9.1 2.7 c ------ [22] Greek 283 17. [35] Middle East Iranian 100 12.5 d 3.0 a 9.0 c ------ [36] Saudi Arabians 192 ----0.3 ---- [37] a P < .05 ...
CYP2D6 genetic variations could result in alteration of CYP2D6 enzyme activity, leading to dissimilarity among individuals in regard of drug metabolism.
This study aims to detect all genetic variants, allele, and genotype frequencies of CYP2D6 gene in 136 unrelated healthy Kinh Vietnamese volunteers. All single nucleotide variants (SNVs) and structural variations (SVs) of CYP2D6 gene were identified by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) assay.
Totally, 30 SNVs and 9 SVs including a whole gene deletion, 8 hybrid structures, and tandem arrangements were identified. Of the 7 novel SNVs detected, the 3157G>T (R329L) substitution was predicted to be deleterious by PROVEAN; the 3851G>A (W358X) variant resulted in a truncated protein; and the 2988G>A variant located in the intron 6 was predicted to be capable of modifying splicing motif by Human Splicing Finder. We determined 29 different genotypes of CYP2D6 from 136 individuals. The most common alleles were the CYP2D6∗10 (43.75%), ∗1 (18.75%), and tandem arrangement ∗36-∗10 (12.13%).
This study provides best information on CYP2D6 polymorphism comprising the newly discovered SNVs, structural variations, and their frequencies in Kinh Vietnamese. These new data would be valuable in view of precise dosing of CYP2D6 metabolized drugs and giving better treatment outcome.
... Second, no objective measurement was used for diagnosing MCS. Although some studies have identified abnormalities in cerebral blood flow as well as mutations in several genes and metabolic enzymes in MCS [50][51][52][53], these are not considered evidence-based indicators of MCS at present. We used the QEESI to define patients with MCS as this tool has been internationally validated [9,[11][12][13]. ...
Introduction
Multiple chemical sensitivity (MCS) is characterized by recurrent nonspecific symptoms that are attributed to exposure to trace levels of environmental agents. Although the clinical symptoms of MCS have been described in several studies, the risk factors for this condition remain unclear. Our aim was to clarify the risk factors for MCS and the association between MCS and birth by caesarean section.
Methods
We conducted a nationwide case-control study of Japanese individuals (aged 20–65 years) with physician-diagnosed MCS (183 cases) and without MCS (345 controls). The study participants were selected from among 150,000 people in a web-based research panel with approximately 1,000,000 registrants. They completed an online survey including questions on their sociodemographic characteristics, birth history (i.e., birth by caesarean section), and other potential risk factors for MCS. Multivariate logistic regression analysis was employed to determine the association between sociodemographic characteristics and the risk of MCS.
Results
The proportions of case and control subjects who were born by caesarean section were 39.9 and 7.0%, respectively. The association between birth by caesarean section and MCS was significant even after adjusting for potential confounders (adjusted odds ratio: 6.15; 95% confidence interval: 3.13–12.1). A history of agricultural work, mouth breathing, ≥11 vaccinations in the past 10 years, and residing in a new home (< 1 year-old) ≥3 times were also significantly associated with MCS.
Conclusion
Our data indicate an epidemiological link between MCS and birth by caesarean section. Moreover, we show that factors other than chemical exposure may be associated with the development of MCS.
Electronic supplementary material
The online version of this article (10.1186/s12940-018-0438-2) contains supplementary material, which is available to authorized users.
... 6 • Over-consumption of oxygen, due to increased cardiac load which generates free radicals in mitochondrial respiratory chain, coupled with oxidative phosphorylation in the mitochondria and depletion of ATP. 7,8 • In addition, dietary habits as lipid rich diets, with high dietary saturated fatty acids (SFA) which stimulate intracellular mechanisms, leading to oxidative stress through variousbiochemical pathways, such as superoxide generation from NADPH oxidases, glyceraldehyde autoxidation, protein kinase C (PKC) activation, and polyol pathway. 8 Moreover, consumption of diet poor in fruits and vegetables; since fruits and vegetables contain antioxidant as vitamin C and A that protect the body from oxidative injury. ...
... Similar processes may have also contributed to the differential distribution observed in northern Italy for two of our analysed CYP genes. Numerous pharmacogenetic studies about the Italian population published in the literature so far (Caccamo et al., 2013;De Luca et al., 2010;Serrano et al., 2011) were mainly focused on the clinical aspects rather than on the population distribution patterns. Although our study consists of a relatively reduced number of analysed individuals, the adopted sampling strategy took into account both ancestral and geographical origins for a better representation of the Italian genetic structure. ...
Background: Environmental conditions and past migratory events may have shaped genetic heterogeneity of clinically relevant enzymes involved in the phase I metabolism of the most common therapeutic drugs.
Aim: To investigate the genetic variability of CYP2D6, CYP2B6, CYP2C19 and CYP2C9 across the Italian Peninsula, by sampling only ancestrally and geographically homogeneous individuals from northern, central and southern Italy.
Subjects and methods: A total of 25 SNPs were genotyped in 174 unrelated Italian individuals by means of multiplex PCR and minisequencing reactions. CYP2D6 genotypic data were used to predict phenotypes and the phylogenetic relationships among reconstructed haplotypes were represented by means of a Median Joining Network.
Results: Pairwise Fisher Exact tests revealed significant differences between northern and southern Italy in the distribution of CYP2C19 genotypes, with the CYP2C19*2 allele appearing over-represented in northern Italy. Likewise, significant differences in the distribution of CYP2D6 genotypes (*4/*3, *4/*4 and *6/*4) responsible for the poor metabolizer phenotype were observed in northern with respect to both central and southern Italy.
Conclusions: The north–south structuring pattern showed by CYP2D6 and CYP2C19 underline how a deeper knowledge of the geographic distribution of alleles may improve clinical practice and help to avoid hypothetical bias in drug trials.
... Numerous studies revealed that the responses of the immune system to Hg could be a factor in the development of various autoimmune diseases (Sterzl et al., 1999;Hybenova et al., 2010). Also, remarkable overexpression of pro-inflammatory cytokines like interferon (IFN)gamma was reported in the multiple chemical sensitivity individuals (De Luca et al., 2010), indicating metal-induced inflammation could be a critical risk factor in the majority of metal-sensitized patients (Stejskal et al., 2013). It has been suggested that Hg-induced autoimmunity could result from the generation of autoreactive T cells and a defect at the T suppressor level in HgCl 2 -injected Brown-Norway (BN) rats (Pelletier et al., 1988). ...
... MCS is a condition when a person experiences a complex array of recurrent unspecific symptoms attributable to low dosages of chemicals that are well tolerated by most people (11). Although many biomarkers of inflammation can be detected, there is no single-specific diagnostic laboratory test to diagnose MCS at the moment (12). The diagnosis of MCS can be only established by questionnaire and applying varying clinical definitions (13)(14)(15). ...
A great variety of non-specific symptoms may occur in patients living or working in moisture-damaged buildings. In the beginning, these symptoms are usually reversible, mild, and present irritation of mucosa and increased morbidity due to respiratory tract infections and asthma-like symptoms. Later, the disease may become chronic and a patient is referred to a doctor where the assessment of dampness and mold hypersensitivity syndrome (DMHS) often presents diagnostic challenges. Currently, unanimously accepted laboratory tests are not yet available. Therefore, the diagnosis of DMHS is clinical and is based on the patient’s history and careful examination. In this publication, I reviewed contemporary knowledge on clinical presentations, laboratory methods, and clinical assessment of DMHS. From the literature, I have not found any proposed diagnostic clinical criteria. Therefore, I propose five clinical criteria to diagnose DMHS: (1) the history of mold exposure in water-damaged buildings, (2) increased morbidity to due infections, (3) sick building syndrome, (4) multiple chemical sensitivity, and (5) enhanced scent sensitivity. If all the five criteria are met, the patient has a very probable DMHS. To resolve the current problems in assigning correct DMHS diagnosis, we also need novel assays to estimate potential risks of developing DMHS.
... In 2010, De Luca and team found that MCS patients produced high levels of IFNgamma, IL-8, IL-10, and VEGF with lower levels of glutathione S-transferase and glutathione when compared to control populations. [205] Emerging research on this SRI state confirms that elevated nitrotyrosine (a peroxynitrite marker) is a potential disease biomarker for this condition [206] -a finding which provides clues as to the pathological metabolic dysfunction that characterizes this hypersensitivity state. Reduction of the total body load of toxicants foreign to the body has been associated with resolution of the SRI state and normalization of tolerance. ...
Background:
Recent evidence highlights the reality of unprecedented human exposure to toxic chemical agents found throughout our environment - in our food and water supply, in the air we breathe, in the products we apply to our skin, in the medical and dental materials placed into our bodies, and even within the confines of the womb. With biomonitoring confirming the widespread bioaccumulation of myriad toxicants among population groups, expanding research continues to explore the pathobiological impact of these agents on human metabolism.
Methods:
This review was prepared by assessing available medical and scientific literature from Medline as well as by reviewing several books, toxicology journals, government publications, and conference proceedings. The format of a traditional integrated review was chosen.
Results:
Toxicant exposure and accrual has been linked to numerous biochemical and pathophysiological mechanisms of harm. Some toxicants effect metabolic disruption via multiple mechanisms.
Conclusions:
As a primary causative determinant of chronic disease, toxicant exposures induce metabolic disruption in myriad ways, which consequently result in varied clinical manifestations, which are then categorized by health providers into innumerable diagnoses. Chemical disruption of human metabolism has become an etiological determinant of much illness throughout the lifecycle, from neurodevelopmental abnormalities in-utero to dementia in the elderly.
... It has been suggested that inflammation of the upper airways affect perceived sensory irritation (Shusterman et al., 2003). There is also some empirical support for neurogenic inflammation in chemical sensitivity and building related intolerance (Dantoft et al., 2013;De Luca et al., 2010;Sahlberg et al., 2010;Zhang et al., 2010) and inflammation have been suggested to influence the sensitivity of the TRPA1 channel (Bessac and Jordt, 2008). It would therefore be interesting to include sensitive individuals in future studies that might alter the level of detectability and perceived intensity due to acrolein exposure identified in this study. ...
The aim of the study was to examine the time dependence on sensory irritation detection following exposure to threshold levels of acrolein, in humans. The exposures occurred in an exposure chamber and the subjects were breathing fresh air through a mask that covered the nose and mouth. All participants participated in four exposure conditions, of which three consisted of a mixture of acrolein and heptane and one of only heptane. Exposure to acrolein at a concentration half of the TLV-C lead to sensory irritation. The perceived sensory irritation resulted in both increased detectability and sensory irritation after about 6.8 minutes of exposure in 58% of the participants. The study confirm the previously suggested LOAEL of about 0.34 mg/m3 for eye irritation due to acrolein exposure. The sensory irritation was still significant 10 minutes after exposure. These results have implications for risk assessment and limit setting in occupational hygiene.
... Moreover, our observation of similar cytokine and chemokine levels in upper airways of MCS subjects and controls after low-dose n-butanol exposure, despite MCS subjects experiencing a deviating reaction to the exposure session, implies that symptom elicitation in MCS takes place without localized secretion of immunological mediators from epithelial and immune cells in the upper airways. Likewise, our finding underpins that previous reports of elevated cytokine levels within circulating blood [14,20] is without involvement of upper airway inflammatory mediators being secreted and transferred into peripheral circulation. ...
... Moreover, our observation of similar cytokine and chemokine levels in upper airways of MCS subjects and controls after low-dose n-butanol exposure, despite MCS subjects experiencing a deviating reaction to the exposure session, implies that symptom elicitation in MCS takes place without localized secretion of immunological mediators from epithelial and immune cells in the upper airways. Likewise, our finding underpins that previous reports of elevated cytokine levels within circulating blood [14,20] is without involvement of upper airway inflammatory mediators being secreted and transferred into peripheral circulation. ...
Background
Multiple Chemical Sensitivity (MCS) is a chronic condition characterized by reports of recurrent symptoms in response to low level exposure to various chemical substances. Recent findings suggests that dysregulation of the immune system may play a role in MCS pathophysiology.
Objectives
The aim of this study was to examine baseline and low dose n -butanol-induced upper airway inflammatory response profiles in MCS subjects versus healthy controls.
Method
Eighteen participants with MCS and 18 age- and sex-matched healthy controls were enrolled in the study. Epithelial lining fluid was collected from the nasal cavity at three time points: baseline, within 15 minutes after being exposed to 3.7 ppm n -butanol in an exposure chamber and four hours after exposure termination. A total of 19 cytokines and chemokines were quantified. Furthermore, at baseline and during the exposure session, participants rated the perceived intensity, valence and levels of symptoms and autonomic recordings were obtained.
Results
The physiological and psychophysical measurements during the n -butanol exposure session verified a specific response in MCS individuals only. However, MCS subjects and healthy controls displayed similar upper airway inflammatory mediator profiles (P>0.05) at baseline. Likewise, direct comparison of mediator levels in the MCS group and controls after n -butanol exposure revealed no significant group differences.
Conclusion
We demonstrate no abnormal upper airway inflammatory mediator levels in MCS subjects before or after a symptom-eliciting exposure to low dose n -butanol, implying that upper airways of MCS subjects are functionally intact at the level of cytokine and chemokine production and secretory capacity. This suggests that previous findings of increased cytokine plasma levels in MCS are unlikely to be caused by systemic priming via excessive upper airway inflammatory processes.
A third of 1990-1 Gulf-deployed personnel developed drug/chemical-induced multisymptom illness, “Gulf War illness” (GWI). Veterans with GWI (VGWI) report increased drug/exposure adverse effects (AEs). Using previously collected data from a case-control study, we evaluated whether the fraction of exposures that engendered AEs (“AE Propensity”) is increased in VGWI (it was); whether AE Propensity is related to self-rated “chemical sensitivity” (it did); and whether specific exposures “predicted” AE Propensity (they did). Pesticides and radiation exposure were significant predictors, with copper significantly “protective”—in the total sample (adjusted for GWI-status) and separately in VGWI and controls, on multivariable regression. Mitochondrial impairment and oxidative stress (OS) underlie AEs from many exposures irrespective of nominal specific mechanism. We hypothesize that mitochondrial toxicity and interrelated OS from pesticides and radiation position people on the steep part of the curve of mitochondrial impairment and OS versus symptom/biological disruption, amplifying impact of new exposures. Copper, meanwhile, is involved in critical OS detoxification processes.
Multiple chemical sensitivity (MCS) is a complex medical condition associated with low dose chemical exposures. MCS is characterized by diverse features and common comorbidities, including fibromyalgia, cough hypersensitivity, asthma, and migraine, and stress/anxiety, with which the syndrome shares numerous neurobiological processes and altered functioning within diverse brain regions. Predictive factors linked to MCS comprise genetic influences, gene-environment interactions, oxidative stress, systemic inflammation, cell dysfunction, and psychosocial influences. The development of MCS may be attributed to the sensitization of transient receptor potential (TRP) receptors, notably TRPV1 and TRPA1. Capsaicin inhalation challenge studies demonstrated that TRPV1 sensitization is manifested in MCS, and functional brain imaging studies revealed that TRPV1 and TRPA1 agonists promote brain-region specific neuronal variations. Unfortunately, MCS has often been inappropriately viewed as stemming exclusively from psychological disturbances, which has fostered patients being stigmatized and ostracized, and often being denied accommodation for their disability. Evidence-based education is essential to provide appropriate support and advocacy. Greater recognition of receptor-mediated biological mechanisms should be incorporated in laws, and regulation of environmental exposures.
Background
Chemical Intolerance (CI) is characterized by multi-system symptoms initiated by exposures to environmental toxins. Symptoms include fatigue, headache, mood changes, musculoskeletal pain, gastro-intestinal issues, difficulties with memory/concentration. With mixed results, researchers have used targeted genetic approaches to understand the genetic pathways associated with CI. This study is the first to apply a genome-wide untargeted exploratory approach.
Methods
A high-density genotyping platform was used to perform a hypothesis-free search for genetic variants associated with CI in a set of 200 participants. Each CI patient was verified using a validated survey. The association between CI and SNPs was obtained using SOLAR (Sequential Oligogenic Linkage Analysis Routines). Gene-Chemical-Disease interactions were determined using the DisGeNET Database.
Results
Several associated SNPs/genes were identified with either increased or decreased risk of CI. Four chemicals were found to alter gene expression (bisphenol A, valproic acid, aflatoxin B, and benzo(a)pyrene). There were common adverse health effects associated with the genes and the chemicals that influence them, including inflammation, gastrointestinal and immune system disorders, nervous system diseases, and intellectual disabilities.
Discussion
This study supports evidence of novel genetic components associated with CI that may interact with common ubiquitous chemical and drug exposures affecting gene expression. The identified health consequences are common to individuals with CI and implies gene/chemical exposure interactions that may influence the development or exacerbation of symptoms associated with CI. The identified chemicals affecting these genes are ubiquitous environmental toxins, entering the body through air, food, and water, suggesting the need for greater public health policy efforts.
Background:
Psychosocial and physical stressors can elicit the stress response, co-ordinated by interactions between neuroendocrine and inflammatory processes. The central role of the immune system, specifically low-grade systemic inflammation, is sometimes overlooked in work-related stress research.
Objective:
To review evidence that work-related psychosocial and physical stressors can stimulate a low-grade systemic inflammation which, through interactions with the neurohormonal systems, may impact on the well-being and productivity of workers.
Methods:
Literature searches were performed by databases and by hand. Databases used included Interface - EBSCOhost Research Databases; PsycINFO; Academic Search Complete; Africa-Wide Information; CINAHL; E-Journals; MEDLINE and PsycARTICLES.
Results:
Psychosocial stressors, infections, poor indoor air quality, musculoskeletal injuries and chemicals can stimulate a low-grade systemic inflammation that may adversely affect workers' mental and physical health, as well as productivity. The psychological and physical effects caused by infection-induced inflammation are generally referred to as sickness behaviour and those caused by poor indoor air quality as sick building syndrome.
Conclusions:
Stressor-induced low-grade systemic inflammation can be a causal factor in the physical and behavioural symptoms of work-related stress. It is therefore important that those involved with the health of workers be cognisant of inappropriate or chronic low-grade inflammation as a potential health hazard.
Background
Worldwide observations provide evidence for a two-stage disease process called Toxicant-Induced Loss of Tolerance (TILT), described in this journal in the first of two related papers. The disease process is initiated by a major exposure event, or a series of lower level exposures (Stage I, Initiation). Subsequently, affected individuals report that common chemical inhalants, foods, and drugs trigger multisystem symptoms (Stage II, Triggering). Given that foods and drugs also are comprised of chemicals, we refer to these intolerances simply as “chemical intolerance” (CI). In this second, companion paper we propose mast cell sensitization and mediator release as a plausible and researchable biological explanation for TILT.
Methods
Using the Quick Environmental Exposure and Sensitivity Inventory (QEESI), we compared patients diagnosed with mast cell activation syndrome (MCAS) (n = 147) to individuals who reported chemical intolerances following various exposures (n = 345), and to controls (n = 76). We compared QEESI scores using ANOVA across groups. Clinical scores for the MCAS patient group were used to predict CI status using logistic regression.
Results
As the likelihood of patients’ having CI increased, their likelihood of having MCAS similarly increased, to a near-perfect correspondence at the high ends of the QEESI and clinical MCAS scores. Symptom patterns were near-identical for CI and MCAS groups.
Conclusion
The close correspondence between QEESI scores for MCAS and TILT patients supports mast cell sensitization and mediator release as a plausible biological mechanism underlying both conditions, with implications for medicine, environmental health, and regulatory toxicology.
Multiple chemical sensitivity (MCS), also known as idiopathic environmental intolerance, has been described as a chronic acquired disorder characterized by nonspecific symptoms in multiple organ systems and is associated with exposure to low-level chemicals. The name was established by Cullen, in 1987, although the name and diagnostic criteria are still under debate even now. A number of hypotheses concering the etiology and pathogenesis of MCS have been proposed, including impairmens of neurological, immunological and psychological systems. However, research on the possible mechanisms underlying MCS is far from complete. The name and diagnostic criteria of its history as well as theoretical and experimental mechanisms underlying MCS are reviewed here.
Objectives:
This study investigated comorbidity in chemical intolerance (CI) and building- related intolerance (BRI) with (i) chronic sinusitis, chronic obstructive pulmonary disease, allergic and non-allergic asthma and allergic rhinitis, and (ii) airway inflammatory symptoms.
Methods:
Data from two population-based questionnaire surveys, the Västerbotten and Österbotten Environmental Health Studies was used. The participants were categorized as CI or BRI and referents, and binary logistic regression analysis was applied.
Results:
Prevalence rates for the case groups were 7.2-40.0% for diseases and 24.3-68.9% for symptoms, whereas adjusted odds ratios (ORs) were 3.4-26.1 for diseases and 3.3-17.0 for symptoms, all being significantly higher than unity. Prevalence rates and ORs were in general higher in BRI than in CI.
Conclusions:
Inflammatory airway diseases and symptoms are associated with CI and BRI which encourages further research regarding underlying mechanisms and treatments.
Oxylipins and endocannabinoids play important biological roles, including effects upon inflammation. It is not known whether the circulating levels of these lipids are affected by inhalation of the environmental pollutant acrolein. In the present study, we have investigated the consequences of low-level exposure to acrolein on oxylipin, endocannabinoid and related lipid levels in the plasma of healthy individuals and individuals with chemical intolerance (CI), an affliction with a suggested inflammatory origin. Participants were exposed twice (60 minutes) to heptane and a mixture of heptane and acrolein. Blood samples were collected before exposure, after and 24 hours post-exposure. There were no overt effects of acrolein exposure on the oxylipin lipidome or endocannibinoids detectable in the bloodstream at the time points investigated. No relationship between basal levels or levels after exposure to acrolein and CI could be identified. This implicates a minor role of inflammatory mediators on the systemic level in CI.
Objectives
To investigate the pathophysiological pathways leading to symptoms elicitation in multiple chemical sensitivity (MCS) by comparing gene expression in MCS participants and healthy controls before and after a chemical exposure optimised to cause symptoms among MCS participants. The first hypothesis was that unexposed and symptom-free MCS participants have similar gene expression patterns to controls and a second hypothesis that MCS participants can be separated from controls based on differential gene expression upon a controlled n-butanol exposure.
Design
Participants were exposed to 3.7 ppm n-butanol while seated in a windowed exposure chamber for 60 min. A total of 26 genes involved in biochemical pathways found in the literature have been proposed to play a role in the pathogenesis of MCS and other functional somatic syndromes were selected. Expression levels were compared between MCS and controls before, within 15 min after being exposed to and 4 hours after the exposure.
Settings
Participants suffering from MCS and healthy controls were recruited through advertisement at public places and in a local newspaper.
Participants
36 participants who considered themselves sensitive were prescreened for eligibility. 18 sensitive persons fulfilling the criteria for MCS were enrolled together with 18 healthy controls.
Outcome measures
17 genes showed sufficient transcriptional level for analysis. Group comparisons were conducted for each gene at the 3 times points and for the computed area under the curve (AUC) expression levels.
Results
MCS participants and controls displayed similar gene expression levels both at baseline and after the exposure and the computed AUC values were likewise comparable between the 2 groups. The intragroup variation in expression levels among MCS participants was noticeably greater than the controls.
Conclusions
MCS participants and controls have similar gene expression levels at baseline and it was not possible to separate MCS participants from controls based on gene expression measured after the exposure.
Introduction:
Growing exposure of human skin to environmental and occupational hazards, to numerous skin care/beauty products, and to topical drugs led to a biomedical concern regarding sustainability of cutaneous chemical defence that is essential for protection against intoxication. Since skin is the largest extra-hepatic drug/xenobiotic metabolising organ where redox-dependent metabolic pathways prevail, in this review, publications on metabolic processes leading to redox imbalance (oxidative stress) and its autocrine/endocrine impact to cutaneous drug/xenobiotic metabolism were scrutinised. Areas covered: Chemical and photo-chemical skin barriers contain metabolic and redox compartments: their protective and homeostatic functions. The review will examine the striking similarity of adaptive responses to exogenous chemical/photo-chemical stressors and endogenous toxins in cutaneous metabolic and redox system; the role(s) of xenobiotics/drugs and phase II enzymes in the endogenous antioxidant defence and maintenance of redox balance; redox regulation of interactions between metabolic and inflammatory responses in skin cells; skin diseases sharing metabolic and redox problems (contact dermatitis, lupus erythematosus, and vitiligo) Expert opinion: Due to exceptional the redox dependence of cutaneous metabolic pathways and interaction of redox active metabolites/exogenous antioxidants with drug/xenobiotic metabolism, metabolic tests of topical xenobiotics/drugs should be combined with appropriate redox analyses and performed on 3D human skin models.
Clinical practice sometimes brings to face with situations quite peculiar, potentially dangerous for the patient's life. In the great majority of cases, pathologies associated with each other (cardiovascular, respiratory, neurological), while in other cases we can treat rare diseases or syndromes. It's considered exceptional the simultaneous presence of "rare" pathologies in a single patient. This exceptionality has been a push to treat a patient as a “unique” asking for help to deeper studies of pharmacogenetics. Our case reports the management of a patient with Ehlers- Danlos syndrome (EDS) and Multiple Chemical Sensitivity (MCS), undergoing a total thyroidectomy. We found several problems, and we tried to find effective solutions for the management of the patient during the whole peri-operative process, from a clinical, pharmacological and also from a surgical point of view.
Chemical defensive system consisting of bio-sensoring, transmitting, and responsive elements has been evolved to protect multi-cellular organisms against environmental chemical insults (xenobiotics) and to maintain homeostasis of endogenous low molecular weight metabolites (endobiotics). Both genetic and epigenetic defects of the system in association with carcinogenesis and individual sensitivity to anti-tumor therapies have been intensely studied. Recently, several non-tumor human pathologies with evident environmental components such as rather rare functional syndromes (multiple chemical sensitivity, chronic fatigue, Persian Gulf, and fibromyalgia now collectively labeled as idiopathic environmental intolerances) and common diseases (vitiligo and systemic lupus erythematosus) have become subjects of the research on the impaired metabolism and detoxification of xenobiotics and endogenous toxins. Here, we collected and critically reviewed epidemiological, genetic, and biochemical data on the involvement and possible role of cytochrome P450 super family enzymes, glutathione-S-transferase isozymes, catechol-O-methyl-transferase, UDP-glucuronosyl transferases, and proteins detoxifying inorganic and organic peroxides (catalase, glutathione peroxidase, and peroxiredoxin) in the above pathologies. Genetic predisposition assessed mainly by single nucleotide polymorphism and gene expression analyses revealed correlations between defects in genes encoding xenobiotic-metabolizing and/or detoxifying enzymes and risk/severity of these syndromes/diseases. Proteome analysis identified abnormal expression of the enzymes. Their functions were affected epigenetically leading to metabolic impairment and, as a consequence, to the negative health outcomes shared by some of these pathologies. Data obtained so far suggest that distinct components of the chemical defensive system could be suitable molecular targets for future pathogenic therapies.
In this study, we find that CD45RO+ memory populations of CD4+ T lymphocytes express the vascular endothelial growth factor (VEGF) receptors KDR and Flt-1 at both the mRNA and protein levels. Furthermore, by Western blot analysis, we find that VEGF increases the phosphorylation and activation of ERK and Akt within CD4+CD45RO+ T cells. These VEGF-mediated signaling responses were inhibited by a KDR-specific small interfering RNA in a VEGF receptor-expressing Jurkat T cell line and by SU5416, a pharmacological KDR inhibitor, in CD4+CD45RO+ T cells. We also find that VEGF augments mitogen-induced production of IFN-gamma in a dose-dependent manner (p < 0.001) and significantly (p < 0.05) increases directed chemotaxis of this T cell subset. Collectively, our results for the first time define a novel function for VEGF and KDR in CD45RO+ memory T cell responses that are likely of great pathophysiological importance in immunity.
Naive CD4(+) T cells give rise to T-helper-cell subsets with functions that are tailored to their respective roles in host defence. The specification of T-helper-cell subsets is controlled by networks of lineage-specifying transcription factors, which bind to regulatory elements in genes that encode cytokines and other transcription factors. The nuclear context in which these transcription factors act is affected by epigenetic processes, which allow programmes of gene expression to be inherited by progeny cells that at the same time retain the potential for change in response to altered environmental signals. In this Review, we describe these epigenetic processes and discuss how they collaborate to govern the fate and function of T helper cells.
Myocardial phospholipids serve as primary reservoirs of arachidonic acid (AA), which is liberated through the rate-determining hydrolytic action of cardiac phospholipases A2 (PLA2s). A predominant PLA2 in myocardium is calcium-independent phospholipase A2beta (iPLA2beta), which, through its calmodulin (CaM) and ATP-binding domains, is regulated by alterations in local cellular Ca2+ concentrations and cardiac bioenergetic status, respectively. Importantly, iPLA2beta has been demonstrated to be activated by ischaemia through elevation of the concentration of myocardial fatty acyl-CoA, which abrogates Ca2+/CaM-mediated inhibition of iPLA2beta. AA released by PLA2-catalysed hydrolysis of phospholipids serves as a precursor for eicosanoids generated by pathways dependent on cyclooxygenases (COX), lipoxygenases (LOX), and cytochromes P450 (CYP). Eicosanoids initiate and propagate diverse signalling cascades, primarily through their interaction with cellular receptors and ion channels. However, during pathologic states such as ischaemia or congestive heart failure, eicosanoids contribute to multiple maladaptive changes including inflammation, alterations of cellular growth programmes, and activation of multiple transcriptional events leading to the deleterious sequelae of these pathologic states. This review summarizes the central roles of myocardial PLA(2)s in eicosanoid signalling in the heart, the major COX, LOX, and CYP pathways of eicosanoid generation in the myocardium, and the effects of important eicosanoids on receptor-, ion channel-, and transcription-mediated processes that facilitate cardiac hypertrophy, mediate ischaemic preconditioning, and precipitate arrhythmogenesis in response to pathologic stimuli.
We evaluated glutathione transferase (GST) activities and the levels of glutathionylated hemoglobin in the RBC of 42 workers exposed to 1,3-butadiene in a petrochemical plant, using 43 workers not exposed to 1,3-butadiene and 82 foresters as internal and external controls, respectively. Median 1,3-butadiene exposure levels were 1.5, 0.4, and 0.1 microg/m3 in 1,3-butadiene-exposed workers, in workers not directly exposed to 1,3-butadiene, and in foresters, respectively. In addition, we determined in the peripheral blood lymphocytes of the same individuals the presence of GST polymorphic genes GSTT1 and GSTM1 and the distribution of GSTP1 allelic variants. Comparing the mean values observed in petrochemical workers with those of control foresters, we found a marked decrease of GST enzymatic activity and a significant increase of glutathionylated hemoglobin in the petrochemical workers. A weak but significant negative correlation was found between levels of 1,3-butadiene exposure and GST activity, whereas a positive correlation was found between 1,3-butadiene exposure and glutathionylated hemoglobin. A negative correlation was also observed between GST activity and glutathionylated hemoglobin. No influence of confounders was observed. Using a multiple linear regression model, up to 50.6% and 41.9% of the variability observed in glutathionylated hemoglobin and GST activity, respectively, were explained by 1,3-butadiene exposure, working setting, and GSTT1 genotype. These results indicate that occupational exposure to 1,3-butadiene induces an oxidative stress that impairs the GST balance in RBC, and suggest that GST activity and glutathionylated hemoglobin could be recommended as promising biomarkers of effect in petrochemical workers.
Cystic fibrosis is characterized by recurring pulmonary exacerbations that lead to the deterioration of lung function and eventual lung failure. Excessive inflammatory responses by airway epithelia have been linked to the overproduction of the inflammatory cytokine IL-6 and IL-8. The mechanism by which this occurs is not fully understood, but normal IL-1beta mediated activation of the production of these cytokines occurs via H2O2 dependent signaling. Therefore, we speculated that CFTR dysfunction causes alterations in the regulation of steady state H2O2. We found significantly elevated levels of H2O2 in three cultured epithelial cell models of CF, one primary and two immortalized. Increases in H2O2 heavily contributed to the excessive IL-6 and IL-8 production in CF epithelia. Proteomic analysis of three in vitro and two in vivo models revealed a decrease in antioxidant proteins that regulate H2O2 processing, by > or =2 fold in CF vs. matched normal controls. When cells are stimulated, differential expression in CF versus normal is enhanced; corresponding to an increase in H2O2 mediated production of IL-6 and IL-8. The cause of this redox imbalance is a decrease by approximately 70% in CF cells versus normal in the expression and activity of the transcription factor Nrf-2. Inhibition of CFTR function in normal cells produced this phenotype, while N-acetyl cysteine, selenium, an activator of Nrf-2, and the overexpression of Nrf-2 all normalized H2O2 processing and decreased IL-6 and IL-8 to normal levels, in CF cells. We conclude that a paradoxical decrease in Nrf-2 driven antioxidant responses in CF epithelia results in an increase in steady state H2O2, which in turn contributes to the overproduction of the pro-inflammatory cytokines IL-6 and IL-8. Treatment with antioxidants can ameliorate exaggerated cytokine production without affecting normal responses.
The compound 4-hydroxynonenal (4-HNE) is the major aldehyde formed during lipid peroxidation of omega-6-polyunsaturated fatty acids and has been suggested to regulate inflammatory responses because it inhibits tumor necrosis factor (TNF) mRNA production in the human monocytic cell line THP-1. Here we demonstrate that 4-HNE inhibits TNF and interleukin-1beta production in human monocytes in response to lipopolysaccharide. The main action of 4-HNE occurred at the pretranscriptional level; there was no effect on TNF mRNA production or stability when 4-HNE was added after stimulation. The mechanism of action of 4-HNE appears to be downstream of lipopolysaccharide-receptor binding. In the human monocytic MonoMac 6 cell line, 4-HNE caused selective inhibition of the activity of the mitogen-activated protein kinases p38 and ERK1/ERK2, but not JNK. However, in monocytes, the activities of all three kinases were inhibited, suggesting that the effects of 4-HNE were exerted at points upstream of ERK1/ERK2 and JNK as the levels of the phosphorylated kinases were reduced. In contrast, p38 phosphorylation was not inhibited, suggesting that 4-HNE affects kinase activity. 4-HNE also inhibited nuclear factor-kappaB activation in monocytes. In view of the roles of p38, ERK1/ERK2, JNK, and nuclear factor-kappaB in inflammation, the data suggest that 4-HNE, at nontoxic concentrations, has anti-inflammatory properties, most likely through an effect on these signaling molecules, and could lead to the development of novel treatments for inflammatory diseases.
In the present study, we studied the signal transduction mechanism that is involved in the expression of c-Jun protein evident after exposure of rat liver epithelial RL34 cells to the major end product of oxidized fatty acid metabolism, 4-hydroxy-2-nonenal (HNE). HNE treatment of the cells resulted in depletion of intracellular glutathione (GSH) and in the formation of protein-bound HNE in plasma membrane. In addition, HNE strongly induced intracellular peroxide production, suggesting that HNE exerted oxidative stress on the cells. Potent expression of c-Jun occurred within 30 min of HNE treatment, which was accompanied by a time-dependent increase in activator protein-1 (AP-1) DNA binding activity. We found that HNE caused an immediate increase in tyrosine phosphorylation in RL34 cells. In addition, HNE strongly induced phosphorylation of c-Jun N-terminal kinases (JNK) and p38 mitogen-activated protein kinases and also moderately induced phosphorylation of extracellular signal-regulated kinases. The phosphorylation of JNK was accompanied by a rapid and transient increase in JNK and p38 activities, whereas changes in the activity of extracellular signal-regulated kinase were scarcely observed. GSH depletion by L-buthionine-S, R-sulfoximine, a specific inhibitor of GSH biosynthesis, only slightly enhanced peroxide production and JNK activation, suggesting that HNE exerted these effects independent of GSH depletion. This and the findings that (i) HNE strongly induced intracellular peroxide production, (ii) HNE-induced JNK activation was inhibited by pretreatment of the cells with a thiol antioxidant, N-acetylcysteine, and (iii) H2O2 significantly activated JNK support the hypothesis that pro-oxidants play a crucial role in the HNE-induced activation of stress signaling pathways. In addition, we found that, among the inhibitors of tyrosine kinases, cyclooxygenase, and Ca2+ influx, only quercetin exerted a significant inhibitory effect on HNE-induced JNK activation. In light of the JNK-dependent induction of c-jun transcription and the AP-1-induced transcription of xenobiotic-metabolizing enzymes, these data may show a potential critical role for JNK in the induction of a cellular defense program against toxic products generated from lipid peroxidation.
To describe the prevalence and correlates of reports about sensitivities to chemicals, questions about chemical sensitivities were added to the 1995 California Behavior Risk Factor Survey (BRFS). The survey was administered by telephone to 4,046 subjects. Of all respondents, 253 (6.3%) reported doctor-diagnosed "environmental illness" or "multiple chemical sensitivity" (MCS) and 643 (15.9%) reported being "allergic or unusually sensitive to everyday chemicals." Sensitivity to more than one type of chemical was described by 11.9% of the total sample population. Logistic regression models were constructed. Hispanic ethnicity was associated with physician-diagnosed MCS (adjusted odds ratio (OR) = 1.82, 95% confidence interval (CI) 1.21-2.73). Female gender was associated with individual self-reports of sensitivity (adjusted OR = 1.63, 95% CI 1.23-2.17). Marital status, employment, education, geographic location, and income were not predictive of reported chemical sensitivities or reported doctor diagnosis. Surprising numbers of people believed they were sensitive to chemicals and made sick by common chemical exposures. The homogeneity of responses across race-ethnicity, geography, education, and marital status is compatible with a physiologic response or with widespread societal apprehensions in regard to chemical exposure.
Using the International Project on Genetic Susceptibility to Environmental Carcinogens (GSEC) database containing information on over 15,000 control (noncancer) subjects, the allele and genotype frequencies for many of the more commonly studied metabolic genes (CYP1A1, CYP2E1, CYP2D6, GSTM1, GSTT1, NAT2, GSTP, and EPHX) in the human population were determined. Major and significant differences in these frequencies were observed between Caucasians (n = 12,525), Asians (n = 2,136), and Africans and African Americans (n = 996), and some, but much less, heterogeneity was observed within Caucasian populations from different countries. No differences in allele frequencies were seen by age, sex, or type of controls (hospital patients versus population controls). No examples of linkage disequilibrium between the different loci were detected based on comparison of observed and expected frequencies for combinations of specific alleles.
Symptoms, and especially those without clear underlying medical explanations, account for a large percentage of clinical encounters. Many unexplained symptoms have been organized by patients and practitioners into syndromes such as chronic fatigue syndrome, multiple chemical sensitivity, sick building syndrome, Gulf War syndrome, and the like. All these syndromes are defined solely on the basis of symptoms rather than by medical signs. Some of the above-described conditions overlap strongly with explained conditions such as asthma. The relationship of such symptoms and syndromes to environmental exposure is often sharply debated, as is the distinction between the various syndromes. This leads to problems of what type of research should be conducted and who should conduct it. It is time to develop a comprehensive research agenda to sort out nomenclature, epidemiology, and environmental causation for these conditions, moving toward comprehensive and effective public health and clinical approaches.
This review describes the three mammalian glutathione transferase (GST) families, namely cytosolic, mitochondrial, and microsomal GST, the latter now designated MAPEG. Besides detoxifying electrophilic xenobiotics, such as chemical carcinogens, environmental pollutants, and antitumor agents, these transferases inactivate endogenous alpha,beta-unsaturated aldehydes, quinones, epoxides, and hydroperoxides formed as secondary metabolites during oxidative stress. These enzymes are also intimately involved in the biosynthesis of leukotrienes, prostaglandins, testosterone, and progesterone, as well as the degradation of tyrosine. Among their substrates, GSTs conjugate the signaling molecules 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) and 4-hydroxynonenal with glutathione, and consequently they antagonize expression of genes trans-activated by the peroxisome proliferator-activated receptor gamma (PPARgamma) and nuclear factor-erythroid 2 p45-related factor 2 (Nrf2). Through metabolism of 15d-PGJ2, GST may enhance gene expression driven by nuclear factor-kappaB (NF-kappaB). Cytosolic human GST exhibit genetic polymorphisms and this variation can increase susceptibility to carcinogenesis and inflammatory disease. Polymorphisms in human MAPEG are associated with alterations in lung function and increased risk of myocardial infarction and stroke. Targeted disruption of murine genes has demonstrated that cytosolic GST isoenzymes are broadly cytoprotective, whereas MAPEG proteins have proinflammatory activities. Furthermore, knockout of mouse GSTA4 and GSTZ1 leads to overexpression of transferases in the Alpha, Mu, and Pi classes, an observation suggesting they are part of an adaptive mechanism that responds to endogenous chemical cues such as 4-hydroxynonenal and tyrosine degradation products. Consistent with this hypothesis, the promoters of cytosolic GST and MAPEG genes contain antioxidant response elements through which they are transcriptionally activated during exposure to Michael reaction acceptors and oxidative stress.
Previously we have reported in vitro evidence suggesting that that H2O2 may support wound healing by inducing VEGF expression in human keratinocytes (C. K. Sen et al., 2002, J. Biol. Chem.277, 33284-33290). Here, we test the significance of H2O2 in regulating wound healing in vivo. Using the Hunt-Schilling cylinder approach we present the first evidence that the wound site contains micromolar concentrations of H2O2. At the wound site, low concentrations of H2O2 supported the healing process, especially in p47(phox)- and MCP-1-deficient mice in which endogenous H2O2 generation is impaired. Higher doses of H2O2 adversely influenced healing. At low concentrations, H2O2 facilitated wound angiogenesis in vivo. H2O2 induced FAK phosphorylation both in wound-edge tissue in vivo and in human dermal microvascular endothelial cells. H2O2 induced site-specific (Tyr-925 and Tyr-861) phosphorylation of FAK. Other sites, including the Tyr-397 autophosphorylation site, were insensitive to H2O2. Adenoviral gene delivery of catalase impaired wound angiogenesis and closure. Catalase overexpression slowed tissue remodeling as evidenced by a more incomplete narrowing of the hyperproliferative epithelium region and incomplete eschar formation. Taken together, this work presents the first in vivo evidence indicating that strategies to influence the redox environment of the wound site may have a bearing on healing outcomes.
The cytokine tumor necrosis factor alpha (TNF-alpha) is a primary inflammatory mediator after liver injury. Several cytokines impair the regulation of cytochrome P450 (CYP) genes in liver, but the specificity of these effects remains unclear. This study investigated the effects of recombinant murine TNF-alpha on the expression of specific constitutive CYPs in male rat liver.
Microsomal steroid hydroxylation was used to indicate the activities of specific CYPs after TNF-alpha treatment and immunoblotting to correlate CYP activities with protein contents. CYP messenger RNA levels were measured by solution hybridization.
Testosterone 2 alpha/16 alpha- and 6 beta-hydroxylations, mediated respectively by CYPs 2C11 and 3A2, were decreased after TNF-alpha treatment, whereas 7 alpha-hydroxylation (CYP 2A1) was unchanged. Similarly, progesterone 2 alpha/16 alpha- (CYP 2C11) and 6 beta-hydroxylations (CYP 3A2), but not 21-hydroxylation (CYP 2C6), were decreased after TNF-alpha treatment. 2C11 and 3A2 apoproteins and messenger RNAs, but not 2A1 apoprotein, were decreased after TNF-alpha treatment; changes in messenger RNAs were evident 4 hours after treatment.
TNF-alpha down-regulates CYPs 2C11 and 3A2 in male rat liver at a pretranslational level, whereas two other constitutive CYPs, 2A1 and 2C6, seem refractory to TNF-alpha. Thus, impaired CYP regulation by TNF-alpha resembles the combined effects of autologous interferons (on 3A2) and interleukins (on 2C11).
It has been reported that iron overload in β-thalassemia leads to an enhanced generation of reactive oxygen species and to oxidative stress. We have studied the oxidant/antioxidant imbalance in the blood of 48 transfusion-dependent β-thalassemic patients (TLP) (17 males, 31 females, 11–22 year), under chelation therapy, and in 40 sex and age matched healthy controls (CTR). Plasma and lymphocyte levels of vitamin E (Vit E), ubiquinol (CoQ10H2), ubiquinone (CoQ10), plasma concentrations of vitamin A (Vit A), β-carotene, lycopene, vitamin C (Vit C), total thiols, fatty acid patterns of phospholipids (PL-FA), and plasma and urinary markers of lipoperoxidation (TBA-RM, conjugated dienes, and azelaic acid (AZA), as well as the urinary levels of catecholamine and serotonin metabolites, were evaluated by gas chromatography-mass spectrometry (GC-MS), HPLC and spectrophotometry. Routine laboratory blood analyses were performed on the same samples; 39/48 TLP were HCV positive. Blood samples were collected just before transfusion, the 24 h urine samples the day before. Our results clearly showed that a severe oxidative stress occurs in the plasma of TLP in comparison with CTR. In fact, the levels of lipophilic antioxidants and ascorbate were severely depleted: CoQ10H2 (-62.5%), total CoQ10 (-35.1%), Vit E (-43.8%, β-carotene (-31.1%), lycopene (-63.7%), Vit A (-35.9%), Vit C (-23.1%). The impairment of the antioxidant status was associated with elevated plasma levels of by-products of lipoperoxidation and urinary concentrations of catecholamine metabolites and of AZA, indicating a high degree of both neurological stress and lipoperoxidation. A significant positive correlation was found between vitamin E and non-transferrin-bound iron (NTBI) (r = -0.81; p < 0.001), while no correlation was found between antioxidant depletion and ferritin serum levels, average blood consumption, or the presence of clinical complications. The administration of selective antioxidants along with an appropriate diet might represent a promising way of counteracting oxidative damage and its deleterious effects on the progression of the disease.
4-Hydroxynonenal (HNE) is one of several lipid oxidation products that may have an impact on human pathophysiology. It is an important second messenger involved in the regulation of various cellular processes and exhibits antiproliferative and differentiative properties in various tumor cell lines. The mechanisms by which HNE affects cell growth and differentiation are only partially clarified. Because microRNAs (miRNAs) have the ability to regulate several cellular processes, we hypothesized that HNE, in addition to other mechanisms, could affect miRNA expression. Here, we present the results of a genome-wide miRNA expression profiling of HNE-treated HL-60 leukemic cells. Among 470 human miRNAs, 10 were found to be differentially expressed between control and HNE-treated cells (at p < 0.05). Six miRNAs were down-regulated (miR-181a*, miR-199b, miR-202, miR-378, miR-454-3p, miR-575) and 4 were up-regulated (miR-125a, miR-339, miR-663, miR-660). Three of these regulated miRNAs (miR-202, miR-339, miR-378) were further assayed and validated by quantitative real-time RT-PCR. Moreover, consistent with the down-regulation of miR-378, HNE also induced the expression of the SUFU protein, a tumor suppressor recently identified as a target of miR-378. The finding that HNE could regulate the expression of miRNAs and their targets opens new perspectives on the understanding of HNE-controlled pathways. A functional analysis of 191 putative gene targets of miRNAs modulated by HNE is discussed.
Multiple chemical sensitivity (MCS) is characterised by adverse effects due to exposure to low levels of chemical substances. Various genes, especially genes of importance to the metabolism of xenobiotic compounds, have been associated with MCS, but findings are inconsistent. The purpose of this study was to investigate genetic susceptibility factors for MCS and self-reported chemical sensitivity in a population sample. Ninety six MCS patients and 1,207 controls from a general population divided into four severity groups of chemical sensitivity were genotyped for variants in the genes encoding cytochrome P450 2D6, arylamine N-acetyltransferase 2, paraoxonase 1, methylene tetrahydrofolate reductase, and the cholecystokinin 2 receptor. No hypotheses were consistently confirmed. An apparent association between number of active cytochrome P450 2D6 alleles and MCS status was not statistically significant (OR=1.2, p=0.28). Fast arylamine N-acetyltransferase 2 metaboliser status was associated with severity of chemical sensitivity only in the most severely affected group in the population sample (OR=3.1, p=0.04). The cholecystokinin 2 receptor allele with 21 CT repeats was associated with MCS when compared in post hoc analyses with all individuals from the population sample (p=0.02). Genetic variants in paraoxonase 1 and methylene tetrahydrofolate reductase were not associated with MSC or with self-reported chemical sensitivity in the population sample. Our results suggest that variants in the genes examined are of less importance to MCS than previously reported or that gene-environment interactions or significant degrees of genetic heterogeneity in MCS underlie inconsistent findings in the literature.
Oxidative stress due to increased epidermal levels of H(2)O(2) with consequent inhibition of catalase activity is generally accepted as a leading cytotoxic mechanism of melanocyte loss in vitiligo. Keratinocyte-derived cytokines are considered key factors in the maintenance of melanocyte structure and functions. We hypothesized that abnormal redox control may lead to impaired cytokine production by keratinocytes, thus causing noncytotoxic defects in melanocyte proliferation and melanogenesis. We found significantly suppressed mRNA and protein expression of glutathione-S-transferase (GST) M1 isoform, and higher-than-normal levels of both 4-hydroxy-2-nonenal (HNE)-protein adducts and H(2)O(2) in the cultures of keratinocytes derived from unaffected and affected skin of vitiligo patients, and in their co-cultures with allogeneic melanocytes. GST and catalase activities, as well as glutathione levels, were dramatically low in erythrocytes, whilst HNE-protein adducts were high in the plasma of vitiligo patients. The broad spectrum of major cytokines, chemokines, and growth factors was dysregulated in both blood plasma and cultured keratinocytes of vitiligo patients, when compared to normal subjects. Exogenous HNE added to normal keratinocytes induced a vitiligo-like cytokine pattern, and H(2)O(2) overproduction accompanied by adaptive upregulation of catalase and GSTM1 genes, and transient inhibition of Erk1/2 and Akt phosphorylation. Based on these results, we suggest a novel GST-HNE-H(2)O(2)-based mechanism of dysregulation of cytokine-mediated keratinocyte-melanocyte interaction in vitiligo.
Psoriasis is a chronic recurrent inflammatory disorder of the skin. Clinical subtypes include psoriasis vulgaris (PV), psoriatic arthropathy, and erythrodermic psoriasis. Aim of this study was to analyse relevant inflammatory mediators in the plasma of patients with distinct subtypes of active psoriasis, and in the scales of mild-to-moderate PV patients, and correlation to disease severity. Compared to healthy controls (n=10), patients affected by very severe forms of psoriasis (n=30) were characterized by increased plasma levels of IL-4, IL-6, MCP-1, VEGF and in particular PDGFbb. Each group with severe psoriasis had distinct characteristic features of plasma cytokine profile. Mild-to-moderate PV patients (n=35) showed higher levels of IL-4, IL-6, IL-10, and IL-13 when compared to healthy controls. No correlation was found between PV severity assessed by PASI (Psoriasis Area and Severity Index) and levels of these mediators. By contrast, disease severity correlated to scale levels of IP-10. For the first time, we found exaggerated circulating levels of the pro-angiogenic PDGFbb and VEGF in severe psoriasis. Evidence that the severity of skin symptoms correlated exclusively with scale levels of IP-10, but not with any up-regulated inflammatory mediator in plasma, suggests that distinct skin-independent processes contribute to the circulating cytokine profile in psoriasis.
The function of transporters in peripheral blood mononuclear cells (PBMC) has been characterized, but less is known about cytochrome P450 (CYP) enzyme function in these cells. Given that cytokines are dysregulated in many diseases, the purpose of this work was to assess the impact of cytokines on the expression of CYPs, transporters and chemokine receptors in PBMC.
Human PBMC were incubated with cytokines for 48 h. ATP-binding cassette (ABC)B1, ABCC1, ABCC2, CYP2B6, CYP3A4, CXCR4 and CCR5 expression were measured by quantitative polymerase chain reaction and flow cytometry at 0, 4, 8, 24 and 48 h. Enzyme activity was assessed using fluorescent probes.
We show here functional activity of CYP3A4 and CYP2B6 in PBMC. Furthermore, cytokines had a significant impact on the mRNA and protein expression of all proteins. For example, interleukin-2 (IL-2) had a marked impact on ABCB1 mRNA (% control 4745 +/- 11961) and protein (% control 200 +/- 57). Increases in drug efflux transporter expression, in response to cytokines, resulted in reduced cellular accumulation of digoxin [decrease of 17% and 26% for IL-2 and interferon-gamma (IFNgamma) respectively] and saquinavir (decrease of 28% and 30% for IL-2 and IFNgamma respectively). The degree to which drug transporter and chemokine receptor expression changed in response to cytokines was positively correlated (e.g. ABCB1 and CXCR4, r(2) = 0.545).
These data have important implications for diseases in which cytokines are dysregulated and for which pharmacological intervention targets immune cells.
The immune system is a sensitive target for aryl hydrocarbon receptor (AHR)-mediated transcriptional regulation. Most of the cells that participate in immune responses express AHR protein, and many genes involved in their responses contain multiple DRE sequences in their promoters. However, the potential involvement of many of these candidate genes in AHR-mediated immunomodulation has never been investigated. Many obstacles to understanding the transcriptional effects of AHR activation exist, owing to the complexities of pathogen-driven inflammatory and adaptive immune responses, and to the fact that activation of AHR often influences the expression of genes that are already being regulated by other transcriptional events in responding cells. Studies with TCDD as the most potent, non-metabolized AHR ligand indicate that AHR activation alters many inflammatory signals that shape the adaptive immune response, contributing to altered differentiation of antigen-specific CD4(+) T helper (TH) cells and altered adaptive immune responses. With TCDD, most adaptive immune responses are highly suppressed, which has been recently linked to the AHR-dependent induction of CD4(+)CD25(+) regulatory T cells. However activation of AHR by certain non-TCDD ligands may result in other immune outcomes, as a result of metabolism of the ligand to active metabolites or to unknown ligand-specific effects on AHR-mediated gene transcription. Based on studies using AHR(-/-) mice, evidence for a role of endogenous AHR ligands in regulation of the immune response is growing, with bilirubin and lipoxinA4 representing two promising candidates.