• Welcome to Phoenix Rising!

    Created in 2008, Phoenix Rising is the largest and oldest forum dedicated to furthering the understanding of and finding treatments for complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), long COVID, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and allied diseases.

    To register, simply click the Register button at the top right.

Gene Expression

Sam7777

Senior Member
Messages
115
I do have mercury toxicity. But that considered, I have met more than enough people who didn't the last 7 years. There were a number well quite a few who had other high exotic metals on their hair tests, as well and not mercury per say. I've met plenty of mold victims as well. And what I take were countless cases of peoples bodies being overwhelmed by various exposure. My father personally I suspect was exposed to heavy chemicals in degreasers for large engines.

My mother was definitely exposed to metals. It would be easy to blame everything on just mercury given what I've seen, but actually I've seen plenty who simply weren't dealing with metals. It's also abundently clear the ME community seems plagued by various viral or bacterial concerns. This is usually EBV or something a long those lines. I do have to emphasize strongly that a HIGH portion of the Lyme's people I've encountered had mercury and metals...

This is the oft toted and oft vilified alternative health concept of people losing their health to a combination of pollution and infection. The medical community and science departments seem invested in conjecture towards environmental health at just about every level, except for the actual departments involved with environmental protection and environmental health and occupational safety research (I speculate it is legally and academically compartmentalized from the biomedical communities to a high degree).

But it's fairly clear, fairly logical that people are being affected by some combination of infection and pollution. Not in a vague sense, but in a very concrete sense. Columbia admits its related to what looks like a lack of recovery from infection. People repeatedly show some sign of auto immunity, EBV, mercury, Lyme's, other metals (again people neglect that its not just Hg), injury by prescriptions,. . . .over and over and over....looks like a skunk smells like a skunk acts like a skunk.....

So we have Fredd's protocol. And there's really a debate going on in the chelation community about the usefulness of genetics at all. I am somewhere in the middle. I think its very clear mercury does bad things, metals do bad things, they affect genes. That doesn't mean the practioner approach to snps is accurate.

Cutler mind you, doesn't really consider genetics at all. He doesn't consider that people could have some sort of bioindividual problem filtering out metals that is directly related to a higher need of nutrients. This is in contrast to the direct fact that some people have simply not gotten better until they treated methylation and mercury.

The concept of genetics and pollution is probably inescapable, because I suspect already, that the people who become ill from amalgams represent a small sub-population genetically. This is at least partly represented by certain alleles such as APOE4, but I would have to imagine there are endless other possible pitfalls.

To Chris Shade's credit, he has at least emphasized that there is a bell curve in the genetic population of people who are exposed and this dictates how well they handle the exposure. I believe the amalgam illness itself is biased towards specific populations.

One of the concepts in Cutler's book is the emphasize on Phase 1 and 2 enzymes; phase 1 is overactive or underactive etc Here's a decent link that explains the general concepts of metabolic detoxification. What you quickly realize is how much more is involved than just methylation, and thus how many areas there are for things to go wrong.
http://www.lifeextension.com/protocols/metabolic-health/metabolic-detoxification/page-01
One of the greatest sources of non-dietary toxicant exposure is the air in the home.5 Building materials (such as floor and wall coverings, particle board, adhesives, and paints) can “off-gas” releasing several toxicants that can be detected in humans.6 For example, a toxic benzene derivative commonly used in disinfectants and deodorizers was detected in 98% of adults in the Environmental Protection Agency’s (EPA) “TEAM” study.7 In another EPA study, three additional toxic solvents were present in 100 percent of human tissue samples tested across the country.8

Newly built or remodeled buildings can have substantial amounts of chemical “off-gassing”, giving rise to what has been called “sick building syndrome.”9 Carpet is an especially big offender, potentially releasing several neurotoxins; in testing of over 400 carpet samples, neurotoxins were present in more than 90 percent of the samples, quantitatively sufficient in some samples to cause death in mice.10 Ironically, shortly after the TEAM report, seventy-one ill employees evacuated the new EPA headquarters in Washington DC complaining claiming health problems, which were eventually attributed to the 27,000 sq. feet of new carpet.11

Carpets also trap environmental toxins; the “Non-Occupational Pesticide Exposure Study” (NOPES) found an average of 12 pesticide residues per carpet sampled, and determined that this route of exposure likely provides infants and toddlers with nearly all of their non-dietary exposure to the notorious pesticides DDT, aldrin, atrazine, and carbaryl.12

I think frankly, that methylation is only part of the picture. Gene expression and not arguably so much snps in and of themselves, and how gene expression is affected by things like carpet fumes and metals is the ultra obvious concern. In this case snps are obviously better to look at than nothing at all, but much like Fredd's protocol the real struggle is understanding what has lowered enzyme function and reduced an entire pathway due to a lack of some molecular input, protein, what have you, and trying to power supplement some missing nutrient. Shade understood this and focused on trying to raise the GTS and Trx1 etc enzymes for glutathione and thioredoxin, but again that's just a slice of the pie.

My biggest suggestion is for people here to start reading and citing journals out of environmental journals. Look at sources for the EPA and OSHA, look at anything you can where you see cases of study on gene expression and dysfunction in the liver. I frankly don't trust biomedicine as an industry all that much as much as I do the environmental fields. I think sources that assume and look for pollutants are ideal.

It's actually really sad, because I've encountered multiple 700 page EPA technical documents where they admit that autopsied dentist had about 50 times as much mercury in the brain as a control. The EPA basically admits that amalgams aren't fantastic, but whatever I suppose.

I do suggest given the recent 70 page thread that people here try the supplement TUDCA, since it seems to be very consistent in enhancing liver function in many of the key manners that R-lipoic acid and the simplified methylation protocol enhance. The fact that body builders are using and abusing TUDCA to get away with steroids and actually benefiting from it is at least a good sign (dumb on their part), but great news for people who didn't voluntarily choose to destroy their liver.

Tauroursodeoxycholic acid (TUDCA) is an ambiphilic bile acid. It is the taurine conjugate form of ursodeoxycholic acid (UDCA). Humans are found to have trace amounts of TUDCA. However, bears contain large amounts of TUDCA in their bile; UDCA and conjugates comprise about 47% of the bile in American black bears and up to 76% in Asiatic bears.[1] TUDCA has been used in ancient Asian pharmacopoeias for its supposed beneficial effects. UDCA is produced in several countries for the treatment ofgallstones and liver cirrhosis. It is not approved by the Food and Drug Administration, in the U.S. while UDCA is approved in the United States for the treatment of primary biliary cirrhosis[2][3]

Anecdotally (well there's also plenty of Chinese authored papers on such plants) Traditional chinese medicine is obsessed with bile function. Many of the best plants affect it to a large degree, predominantly the berberine containing compounds, and things such as Gentian root, Burdock, Magnolia, SkullCap, Buplereum. I feel like that is the direction to go. Frankly, the only thing that's kept me going has been holy basil and magnolia. Without that I would really struggle.

I know what we want: We want specific snps, proteins, ya know specific enzymes that could be pinpointed as causing some failure to control severe inflammation/auto immunity/oxidation. Well, I'm saying you could probably learn a lot studying some of the EPA stuff, some of the stuff in journals like Environmental Health.
 
Last edited:

Sam7777

Senior Member
Messages
115
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1242054/pdf/ehp0109-000071.pdf
Applications of Gene Arrays in Environmental Toxicology: Fingerprints of Gene Regulation Associated with Cadmium Chloride, Benzo(a)pyrene, and Trichloroethylene Matthew Bartosiewicz,1 Sharron Penn,2 and Alan Buckpitt1 1Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California, USA; 2Molecular Dynamics, Sunnyvale, California, USA
Toxicity testing of unknown chemicals currently uses a number of short-term bioassays. These tests are costly and time consuming, require large numbers of animals, and generally focus on a single end point. The recent development of DNA arrays provides a potential mechanism for increasing the efficiency of standard toxicity testing through genome-wide assessments of gene regulation. In this study, we used DNA arrays containing 148 genes for xenobiotic metabolizing enzymes, DNA repair enzymes, heat shock proteins, cytokines, and housekeeping genes to examine gene expression patterns in the liver in response to cadmium chloride, benzo(a)pyrene (BaP), and trichloroethylene (TCE). Dose–response studies were carried out in mice for each chemical; each produced a unique pattern of gene induction. As expected, CdCl2 markedly up-regulated metallothionine I and II (5- to 10,000-fold at the highest doses) and several of the heat shock/stress response proteins and early response genes. In contrast, administration of BaP upregulated only Cyp1a1 and Cyp1a2 genes and produced no significant increases in any of the stress response genes or any of the DNA repair genes present on the array. Likewise, TCEinduced gene induction was highly selective; only Hsp 25 and 86 and Cyp2a were up-regulated at the highest dose tested. Microarray analysis with a highly focused set of genes is capable of discriminating between different classes of toxicants and has potential for differentiating highly noxious versus more subtle toxic agents. These data suggest that use of microarrays to evaluate the potential hazards of unknown chemicals or chemical mixtures must include multiple doses and time points to provide effective assessments of potential toxicity of these substances. Key words: benzo(a)pyrene, cadmium chloride, DNA arrays, gene expression, trichloroethylene. Environ Health Perspect 109:71–74 (2001). [Online 15 December 2000]

http://deepblue.lib.umich.edu/bitstream/handle/2027.42/78717/j.1365-294X.2009.04452.x.pdf?sequence=1
Mercury-associated DNA hypomethylation in polar bear brains via the LUminometric Methylation Assay: a sensitive method to study epigenetics in wildlife J. RICHARD PILSNER,* ALICIA L. LAZARUS,* DONG-HA NAM,† ROBERT J. LETCHER,‡ CHRISTIAN SONNE,§ RUNE DIETZ§ and NILADRI BASU† *Department of Epidemiology, †Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA, ‡Environment Canada, National Wildlife Research Center, Carleton University, Ottawa, ON K1A 0H3, Canada, §National Environmental Research Institute, University of Aarhus, Frederiksborgvej 399, DK-4000 Roskilde, Denmark

Abstract In this paper we describe a novel approach that may shed light on the genomic DNA methylation of organisms with non-resolved genomes. The LUminometric Methylation Assay (LUMA) is permissive for genomic DNA methylation studies of any genome as it relies on the use of methyl-sensitive and -insensitive restriction enzymes followed by polymerase extension via Pyrosequencing technology. Here, LUMA was used to characterize genomic DNA methylation in the lower brain stem region from 47 polar bears subsistence hunted in central East Greenland between 1999 and 2001. In these samples, average genomic DNA methylation was 57.9% ± 6.69 (SD; range was 42.0 to 72.4%). When genomic DNA methylation was related to brain mercury (Hg) exposure levels, an inverse association was seen between these two variables for the entire study population (P for trend = 0.17). After dichotomizing animals by gender and controlling for age, a negative trend was seen amongst male animals (P for trend = 0.07) but no associations were found in female bears. Such sexually dimorphic responses have been found in other toxicological studies. Our results show that genomic DNA methylation can be quantitatively studied in a highly reproducible manner in tissue samples from a wild organism with a non-resolved genome. As such, LUMA holds great promise as a novel method to explore consequential questions across the ecological sciences that may require an epigenetic understanding. Keywords: DNA methylation, ecotoxicology, epigenetics, neurotoxicology, wildlife Received 5 August 2009; revision accepted 22 October 2009

https://www.researchgate.net/profil...io_rerio_)/links/5478a62c0cf293e2da2b29c2.pdf
Comparative Effects of Dietary Methylmercury on Gene Expression in Liver, Skeletal Muscle, and Brain of the Zebrafish (Danio rerio) P. GONZALEZ, Y. DOMINIQUE, J. C. MASSABUAU, A. BOUDOU, AND J. P. BOURDINEAUD* Laboratoire d’Ecophysiologie et Ecotoxicologie des Syste`mes Aquatiques (LEESA), Universite´ Bordeaux 1/UMR CNRS 5805, Place du Dr Peyneau, 33120 Arcachon, France
Effects of dietary methylmercury (MeHg) on gene expression were examined in three organs (liver, skeletal muscle, and brain) of the zebrafish (Danio rerio). Adult male fish were fed over 7, 21, and 63 days on three different diets: one control diet (C0: 0.08 µg of Hg g-1 , dry wt) and two diets (C1 and C2) contaminated by MeHg at 5 and 13.5 µg of Hg g-1 , dry wt. Total Hg and MeHg concentrations were determined in the three organs after each exposure duration, and a demethylation process was evidenced only in the liver. Thirteen genes known to be involved in antioxidant defenses, metal chelation, active efflux of organic compounds, mitochondrial metabolism, DNA repair, and apoptosis were investigated by quantitative real-time RTPCR and normalized according to actin gene expression. Surprisingly, no change in the expression levels of these genes was observed in contaminated brain samples, although this organ accumulated the highest mercury concentration (63.5 ( 4.4 µg g-1 , dry wt after 63 days). This lack of genetic response could explain the high neurotoxicity of MeHg. coxI and cytoplasmic and mitochondrial sod gene expressions were induced early in skeletal muscle and later in liver, indicating an impact on the mitochondrial metabolism and production of reactive oxygen species. Results demonstrated that skeletal muscle was not only an important storage reservoir but was also affected by MeHg contamination. The expression of the metallothionein mt2 and the DNA repair rad51 genes was up-regulated in liver between 21 and 63 days, whereas in skeletal muscle, mt2 remained uninduced, and gadd and rad51 were found to be repressed.

http://ehp.niehs.nih.gov/11338/?utm_source=rss&utm_medium=rss&utm_campaign=11338
Global DNA Hypomethylation Is Associated with High Serum-Persistent Organic Pollutants in Greenlandic Inuit
Jennifer A. Rusiecki,1 Andrea Baccarelli,2 Valentina Bollati,2 Letizia Tarantini,2 Lee E. Moore,3 and Eva C. Bonefeld-Jorgensen4

Background:
Persistent organic pollutants (POPs) may influence epigenetic mechanisms; therefore, they could affect chromosomal stability and gene expression. DNA methylation, an epigenetic mechanism, has been associated with cancer initiation and progression. Greenlandic Inuit have some of the highest reported POP levels worldwide.

Objective:

Our aim in this study was to evaluate the relationship between plasma POPs concentrations and global DNA methylation (percent 5-methylcytosine) in DNA extracted from blood samples from 70 Greenlandic Inuit. Blood samples were collected under the Arctic Monitoring and Assessment Program and previously analyzed for a battery of POPs.

Methods:

We used pyrosequencing to estimate global DNA methylation via Alu and LINE-1 assays of bisulfite-treated DNA. We investigated correlations between plasma POP concentrations and global DNA methylation via correlation coefficients and linear regression analyses.

Results:

We found inverse correlations between percents methylcytosine and many of the POP concentrations measured. Linear regressions, adjusting for age and cigarette smoking, showed statistically significant inverse linear relationships mainly for the Alu assay for p,p′-DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane; β = −0.26), p,p′-DDE [1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene; β = −0.38], β-hexachlorocyclohexane (β = −0.48), oxychlordane (β = −0.32), α-chlordane (β = −0.75), mirex (β = −0.27), sum of polychlorinated biphenyls (β = −0.56), and sum of all POPs (β = −0.48). Linear regressions for the LINE-1 assay showed β estimates of similar magnitudes to those using the Alu assay, however, none was statistically significant.

Conclusions:

This is the first study to investigate environmental exposure to POPs and DNA methylation levels in a human population. Global methylation levels were inversely associated with blood plasma levels for several POPs and merit further investigation.

http://bmcgenomics.biomedcentral.com/articles/10.1186/1471-2164-8-108
Convergence and divergence in gene expression among natural populations exposed to pollution
BMC Genomics20078:108
DOI: 10.1186/1471-2164-8-108

© Fisher and Oleksiak. 2007

Received: 23 November 2006

Accepted: 25 April 2007

Published: 25 April 2007

Abstract
Background
Natural populations of the teleost fish Fundulus heteroclitus tolerate a broad range of environmental conditions including temperature, salinity, hypoxia and chemical pollutants. Strikingly, populations of Fundulus inhabit and have adapted to highly polluted Superfund sites that are contaminated with persistent toxic chemicals. These natural populations provide a foundation to discover critical gene pathways that have evolved in a complex natural environment in response to environmental stressors.

Results
We used Fundulus cDNA arrays to compare metabolic gene expression patterns in the brains of individuals among nine populations: three independent, polluted Superfund populations and two genetically similar, reference populations for each Superfund population. We found that up to 17% of metabolic genes have evolved adaptive changes in gene expression in these Superfund populations. Among these genes, two (1.2%) show a conserved response among three polluted populations, suggesting common, independently evolved mechanisms for adaptation to environmental pollution in these natural populations.

Conclusion
Significant differences among individuals between polluted and reference populations, statistical analyses indicating shared adaptive changes among the Superfund populations, and lack of reduction in gene expression variation suggest that common mechanisms of adaptive resistance to anthropogenic pollutants have evolved independently in multipleFundulus populations. Among three independent, Superfund populations, two genes have a common response indicating that high selective pressures may favor specific responses.
 

Sam7777

Senior Member
Messages
115
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2584160/
Changes in Gene Expression due to Chronic Exposure to Environmental Pollutants
Marjorie F. Oleksiak
Abstract
Populations of the teleost fish Fundulus heteroclitus inhabit and have adapted to highly polluted Superfund sites that are contaminated with persistent toxic chemicals. Populations inhabiting different Superfund sites provide independent contrasts for studying mechanisms of toxicity and resistance due to exposure to environmental pollutants. To identify both shared and unique responses to chronic pollutant exposure, liver, metabolic gene expression in F. heteroclitus populations from each of three Superfund sites (New Bedford Harbor, MA, Newark Bay, NJ, and Elizabeth River, VA) were compared to two flanking reference site populations (9 populations in total). In comparisons to their two clean reference sites, the three Superfund sites had 8 to 32% of genes with altered expression patterns. Between any two Superfund populations, up to 9 genes (4%) show a conserved response, yet among all three populations, there was no gene which had a conserved, altered pattern of expression. Across all three Superfund sites in comparison to all six reference populations, the most significant gene was fatty acid synthase. Fatty acid synthase is involved in the storage of excess energy as fat, and its lesser expression in the polluted populations suggests that the polluted populations may have limited energy stores. In contrast to previous studies of metabolic gene expression in F. heteroclitus, body weight was a significant covariate for many of the genes which could reflect accumulation and different body burdens of pollutants. Overall, the altered gene expression in these populations likely represents both induced and adaptive changes in gene expression.

Keywords: Fundulus heteroclitus, pollution, natural populations, Superfund site, gene expression, microarray

https://lra.le.ac.uk/bitstream/2381/3325/1/expah paper10 Final MR 090806 Archive.pdf
The relationship between biomarkers of oxidative DNA damage, polycyclic aromatic hydrocarbon DNA adducts, antioxidant status and genetic susceptibility following exposure to environmental air pollution in humans Rajinder Singha , Radim J. Sramb , Blanka Binkovab , Ivan Kalinac , Todor A. Popovd , Tzveta Georgievad , Seymour Gartee , Emanuela Taiolif , Peter B. Farmera a Cancer Biomarkers and Prevention Group, Biocentre, University of Leicester, UK b Laboratory of Genetic Ecotoxicology, Institute of Experimental Medicine of Academy of Sciences of the Czech Republic, Prague, Czech Republic c Department of Medical Biology, Medical Faculty University P.J. Šafárik, Košice, Slovak Republic d National Center of Public Health Protection, Sofia, Bulgaria e University of Pittsburgh Cancer Institute, Pittsburgh PA, USA and Genetics Research Institute, Milan, Italy f University of Pittsburgh Cancer Institute, Pittsburgh PA, USA * To whom correspondence should be addressed. E-mail: rs25@le.ac.uk, Phone: (+44) [0]116 223 1827, Fax: (+44) [0]116 223 1840.

Abstract Polycyclic aromatic hydrocarbons (PAHs) appear to be significant contributors to the genotoxicity and carcinogenicity of air pollution present in the urban environment for humans. Populations exposed to environmental air pollution show increased levels of PAH DNA adducts and it has been postulated that another contributing cause of carcinogenicity by environmental air pollution may be the production of reactive oxygen species following oxidative stress leading to oxidative DNA damage. The antioxidant status as well as the genetic profile of an individual should in theory govern the amount of protection afforded against the deleterious effects associated with exposure to environmental air pollution. In this study we investigated the formation of total PAH (bulky) and B[a]P DNA adducts following exposure of individuals to environmental air pollution in three metropolitan cities and the effect on endogenously derived oxidative DNA damage. Furthermore the influence of antioxidant status (vitamin levels) and genetic susceptibility of individuals with regard to DNA damage was also investigated. There was no significant correlation for individuals between the levels of vitamin A, vitamin E, vitamin C and folate with M1dG and 8-oxodG adducts as well as M1dG adducts with total PAH (bulky) or B[a]P DNA adducts. The interesting find from this study was the significant negative correlation between the level of 8-oxodG adducts and the level of total PAH (bulky) and B[a]P DNA adducts implying the that the repair of oxidative DNA damage may be enhanced. This correlation was most significant for those individuals that were non smokers or those unexposed to environmental air pollution. Furthermore the significant inverse correlation between 8-oxodG and B[a]P DNA adducts was confined to individuals carrying the wild type genotype for both the GSTM1 and the 3 GSTT1 gene (separately and interacting). This effect was not observed for individuals carrying the null variant.

https://www.researchgate.net/profil..._pollution/links/09e41513e2422a25ce000000.pdf
Development of mussel mRNA profiling: Can gene expression trends reveal coastal water pollution? Paola Venier a,1, Cristiano De Pitta` a,1, Alberto Pallavicini b, Francesco Marsano c, Laura Varotto a, Chiara Romualdi a, Francesco Dondero c, Aldo Viarengo c, Gerolamo Lanfranchi a,∗ a Department of Biology and CRIBI Biotechnology Centre, University of Padova, Via Bassi 58/B, 35131 Padova, Italy b Department of Biology, University of Trieste, P.le Valmaura 9, 34143 Trieste, Italy c Department of Environmental and Life Science, University of Piemonte Orientale “Amedeo Avogadro”, Via Bellini 25/G, 15100 Alessandria, Italy Received 26 June 2006; received in revised form 21 August 2006; accepted 21 August 2006 Available online 28 September 2006
Abstract Marine bivalves of the genus Mytilus are intertidal filter-feeders commonly used as biosensors of coastal pollution. Mussels adjust their functions to ordinary environmental changes, e.g. temperature fluctuations and emersion-related hypoxia, and react to various contaminants, accumulated from the surrounding water and defining a potential health risk for sea-food consumers. Despite the increasing use of mussels in environmental monitoring, their genome and gene functions are largely unexplored. Hence, we started the systematic identification of expressed sequence tags and prepared a cDNA microarray of Mytilus galloprovincialis including 1714 mussel probes (76% singletons, ∼50% putatively identified transcripts) plus unrelated controls. To assess the potential use of the gene set represented in MytArray 1.0, we tested different tissues and groups of mussels. The resulting data highlighted the transcriptional specificity of the mussel tissues. Further testing of the most responsive digestive gland allowed correct classification of mussels treated with mixtures of heavy metals or organic contaminants (expression changes of specific genes discriminated the two pollutant cocktails). Similar analyses made a distinction possible between mussels living in the Venice lagoon (Italy) at the petrochemical district and mussels close to the open sea. The suggestive presence of gene markers tracing organic contaminants more than heavy metals in mussels from the industrial district is consistent with reported trends of chemical contamination. Further study is necessary in order to understand how much gene expression profiles can disclose the signatures of pollutants in mussel cells and tissues. Nevertheless, the gene expression patterns described in this paper support a wider characterization of the mussel transcriptome and point to the development of novel environmental metrics. © 2006 Elsevier B.V. All rights reserved. Keywords: Mytilus galloprovincialis; cDNA microarray; Coastal water pollution; Gene expression profiles; Heavy metals; Aromatic and chlorinated organic compounds

https://www.researchgate.net/profil...gene_assay/links/0c96052ef9d05d1adf000000.pdf
Aryl hydrocarbon receptor-mediated activity of mutagenic polycyclic aromatic hydrocarbons determined using in vitro reporter gene assay Miroslav Machala a,∗, Jan Vondrácek ˇ a,b, Ludek Bláha ˇ a,c, Miroslav Ciganek a, Jiˇr´ı Necaˇ a a Veterinary Research Institute, 62132 Brno, Czech Republic b Institute of Biophysics, Academy of Sciences of the Czech Republic, 61265 Brno, Czech Republic c RECETOX-TOCOEN & Associates, 63700 Brno, Czech Republic Received 1 February 2001; received in revised form 29 May 2001; accepted 30 May 2001
Abstract Activation of aryl hydrocarbon receptor (AhR) by 30 polycyclic aromatic hydrocarbons (PAHs) was determined in the chemical-activated luciferase expression (CALUX) assay, using two exposure times (6 and 24 h), in order to reflect the metabolization of PAHs. AhR-inducing potencies of PAHs were expressed as induction equivalency factors (IEFs) relative to benzo[a]pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In 24 h exposure assay, the highest IEFs were found for benzo[k]fluoranthene, dibenzo[a,h]anthracene and dibenzo[a,k]fluoranthene (approximately three orders of magnitude lower than TCDD) followed by dibenzo[a,j]anthracene, benzo[j]fluoranthene, indeno[1,2,3-cd]pyrene, and naphtho[2,3-a]pyrene. The 6 h exposure to PAHs led to a significantly higher AhR-mediated activity than the 24 h exposure (generally by two orders of magnitude), probably due to the high rate of PAH metabolism. The strongest AhR inducers showed IEFs approaching that of TCDD. Several PAHs, including some strong mutagens, such as dibenzo[a,l]pyrene, cyclopenta[cd]pyrene, and benzo[a]perylene, elicited only partial agonist activity. Calculation of IEFs based on EC25 values and/or 6 h exposure data is suggested as an alternative approach to estimation of toxic potencies of PAHs with high metabolic rates and/or the weak AhR agonists. The IEFs, together with the recently reported relative mutagenic potencies of PAHs [Mutat. Res. 371 (1996) 123; Mutat. Res. 446 (1999) 1] were combined with data on concentrations of PAHs in extracts of model environmental samples (river sediments) to calculate AhR-mediated induction equivalents and mutagenic equivalents. The highest AhR-mediated induction equivalents were found for benzo[k]fluoranthene and benzo[j]fluoranthene, followed by indeno[1,2,3-cd]pyrene, dibenzo[a,h]anthracene, benzo[a]pyrene, dibenzo[a,j]anthracene, chrysene, and benzofluoranthene. High mutagenic equivalents in the river sediments were found for benzo[a]pyrene, dibenzo[a,e]pyrene, and naphtho[2,3-a]pyrene and to a lesser extent also for benzo[a]anthracene, benzofluoranthene, indeno[1,2,3-cd]pyrene, benzo[j]fluoranthene, dibenzo[a,e]fluoranthene and dibenzo[a,i]pyrene. These data illustrate that AhR-mediated activity of PAHs, including the highly mutagenic compounds, occurring in the environment but not routinely monitored, could significantly contribute to their adverse effects. © 2001 Elsevier Science B.V. All rights reserved. Keywords: PAHs; Aryl hydrocarbon receptor-mediated activity; Mutagenicity; Induction equivalency factors
 

Sam7777

Senior Member
Messages
115
http://www.atsjournals.org/doi/full/10.1165/ajrcmb.19.1.3132#.VrgncvkrLIU
Air Pollution Particles Induce IL-6 Gene Expression in Human Airway Epithelial Cells via NF- κ B Activation
Jacqueline L. Quay, William Reed, James Samet, and Robert B. Devlin

Read More: http://www.atsjournals.org/doi/full/10.1165/ajrcmb.19.1.3132#.VrgncvkrLIU
Fine particles in the air have been associated with increased mortality and morbidity. Particulate air pollution is a complex mixture which varies by region and includes a number of components including residual oil fly ash (ROFA), a byproduct of power plant and industry fuel-oil combustion. Human airway epithelial cells exposed to ROFA release inflammatory cytokines including interleukin (IL)-6, IL-8, and tumor necrosis factor. Expression of these genes is dependent upon pretranscriptional binding of cis regulatory elements, including nuclear factor κB (NF-κB). To investigate the role of NF-κB in the particulate-induced IL-6 response, we exposed human airway epithelial cells (BEAS-2B) to ROFA in vitro. ROFA stimulated a time- and dose-dependent increase in IL-6 messenger RNA (mRNA), which was preceded by the activation of nuclear proteins binding to the NF-κB sequence motif in the IL-6 promoter. Transient transfection of BEAS-2B cells with the 5′ promoter region of the IL-6 gene linked to a luciferase reporter gene confirmed that NF-κB binding is necessary for the transcription of IL-6 mRNA. The IL-6 response was inhibited by the metal chelator deferoxamine and the free radical scavenger N-acetyl-l-cysteine, suggesting that the activation of NF-κB may be mediated through reactive oxygen intermediates generated by transition metals found in ROFA. Activation of NF-κB may therefore be a critical first step in the inflammatory cascade following exposure to particles generated by oil combustion.


Read More: http://www.atsjournals.org/doi/full/10.1165/ajrcmb.19.1.3132#.VrgncvkrLIU


https://www.researchgate.net/profil..._Older_Men/links/00b4951c21b428782d000000.pdf
Prolonged Exposure to Particulate Pollution, Genes Associated with Glutathione Pathways, and DNA Methylation in a Cohort of Older Men Jaime Madrigano,1,2 Andrea Baccarelli,2 Murray A. Mittleman,1,3 Robert O. Wright,2,4 David Sparrow,5,6 Pantel S. Vokonas,5 Letizia Tarantini,7 and Joel Schwartz1,2 1Department of Epidemiology, and 2Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA; 3Cardiovascular Epidemiology Research Unit, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; 4Department of Pediatrics, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts; USA; 5Veterans Administration Normative Aging Study, VA Boston Healthcare System and Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA; 6Channing Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; 7Center of Molecular and Genetic Epidemiology, Istituto Di Ricovero e Cura a Carattere Scientifico, Ca’ Granda Maggiore Policlinico Hospital Foundation and Department of Environmental and Occupational Health, University of Milan, Milan, Italy

Background: DNA methylation is a potential pathway linking environmental exposures to disease. Exposure to particulate air pollution has been associated with increased cardiovascular morbidity and mortality, and lower blood DNA methylation has been found in processes related to cardiovascular morbidity. Objective: We hypothesized that prolonged exposure to particulate pollution would be associated with hypomethylation of repetitive DNA elements and that this association would be modified by genes involved in glutathione metabolism and other host characteristics. Methods: DNA methylation of the long interspersed nucleotide element–1 (LINE-1) and the short interspersed nucleotide element Alu were measured by quantitative polymerase chain reaction pyrosequencing in 1,406 blood samples from 706 elderly participants in the Normative Aging Study. We estimated changes in repetitive element DNA methylation associated with ambient particles (particulate matter ≤ 2.5 µm in aerodynamic diameter), black carbon (BC), and sulfates (SO4), with mixed models. We examined multiple exposure windows (1–6 months) before DNA methylation measurement. We investigated whether this association was modified by genotype and phenotype. Results: An interquartile range (IQR) increase in BC over a 90-day period was associated with a decrease of 0.31% 5-methylcytosine (5mC) (95% confidence interval, 0.12–0.50%) in Alu. An IQR increase in SO4 over a 90-day period was associated with a decrease of 0.27% 5mC (0.02–0.52%) in LINE-1. The glutathione S-transferase mu-1–null genotype strengthened the association between BC and Alu hypomethylation. Conclusion: Prolonged exposure to BC and SO4 particles was associated with hypomethylation of two types of repetitive elements. Key words: air pollution, DNA methylation, epigenetics, gene–environment. Environ Health Perspect 119:977–982 (2011). doi:10.1289/ehp.1002773 [Online 8 March 2011]


http://www.sciencedirect.com/science/article/pii/S0041008X05000876
Metallothionein gene expression in peripheral lymphocytes and renal dysfunction in a population environmentally exposed to cadmium
Abstract
In order to study the validity of metallothionein (MT) gene expression in peripheral blood lymphocytes (PBLs) as a biomarker of cadmium exposure and susceptibility to renal dysfunction, MT mRNA levels were measured using reverse transcription polymerase chain reaction (RT-PCR) in PBLs from residents living in a cadmium-contaminated area. MT mRNA levels were found to increase with the increase of blood cadmium (BCd) and urinary cadmium (UCd) levels. Basal MT mRNA levels were significantly correlated with the logarithm of BCd levels and the logarithm of UCd levels confirming that MT expression in PBLs is a biomarker of cadmium exposure and internal dose. An inverse relationship was observed between in vitro induced MT-mRNA level in PBLs and urinaryN-acetyl-β-d-glucosaminidase (UNAG) suggesting that MT gene expression in PBLs may be used as a biomarker of susceptibility to renal toxicity of cadmium.

Abbreviations
  • BCd, Blood Cadmium level;
  • Cd, Cadmium;
  • Cre, Creatinine;
  • MT, Metallothionein;
  • PBLs,Peripheral Blood Lymphocytes;
  • RT-PCR, Reverse Transcription-Polymerase Chain Reaction;
  • UCd, Urinary Cadmium level;
  • UNAG, Urinary N-acetyl-β-d-glucosaminidase;
  • UCre, Creatinine in urine



https://www.researchgate.net/profil...ed_workers/links/0deec51de5cfb84840000000.pdf
Metallothionein gene expression in peripheral lymphocytes from cadmium-exposed workers Jian Lu,1,2 Taiyi Jin,1,2 Gunnar Nordberg,2 and Monica Nordberg3 1 Department of Occupational Health, Shanghai Medical University, Shanghai 200032, People’s Republic of China 2 Environmental Medicine, Umea University, S-90187 Umea, Sweden 3 Institute of Environmental Medicine, Karolinska Institutet, S-171 77, Stockholm, Sweden

Abstract Metallothionein (MT) plays an important role in the detoxification of cadmium.To investigate the usefulness of MT gene expression in peripheral blood lymphocytes (PBLs) as a biomarker of cadmium exposure and susceptibility, reverse transcriptase–polymerase chain reaction was used to measure the MT gene expression in PBLs from cadmiumexposed workers. Both basal and induced MT expressions were found to increase with increased blood cadmium (BCd) and urinary cadmium (UCd) levels. Both basal and induced MT expression levels were significantly correlated with the logarithm of BCd and the logarithm of UCd levels. The dose-response relationship between internal dose of cadmium and MT expression suggested the validity of MT expression in PBLs as a biomarker of cadmium exposure. In vitro induced MT expression level in PBLs was found to be inversely related to the level of renal dysfunction indicator, urinary N-acetyl-b-D-glucosaminidase (UNAG). The latter finding indicates that MT expression in PBLs may be a useful biomarker of susceptibility to renal toxicity of cadmium. (Presented in part at the International Symposium on MetalBinding Proteins in Biology, Banff, Canada, 1998.)
 

Sam7777

Senior Member
Messages
115
An example of how metaboliic detoxification can be approach is fairly concisely explained by life extension group


I have spent a good portion of 2015 studying R-lipoic specifically to try to distinguish it from Alpha lipoic acid. While they aren't radically different, R-la is in and of itself extremely potent as an anti-oxidant/redox regulator/liver metabolism boosting molecule. It of course depends on what damage is done to the liver and by what compound but I think life extension has the big picture down.

If its mercury or metals you obviously have to watch out for R-la, since it redistributes several heavy metals, which is what happened to me, only with alpha lipoic (I argue that alpha lipoic is a much stronger chelator than R-la, but Shade and Cutler's community refuse to deal with the issue, and Cutler's community has demonized R-la without providing any scientific explanation).

The idea that something like artichoke extract or I3C could make a huge difference for some people isn't a stretch though. Some people have specific blockades or residual pollutants or just weak areas of metabolism, and in other cases it doesn't matter. Certainly with metals nothing will ever change unless you get the metal out.