Aryl hydrocarbon receptor - In plain language: Dioxin receptor
Author: Peter Röder
An employee of the chemical giant DOW Chemicals once described the aryl hydrocarbon receptor as the most researched object in the history of medicine. Although Dr. Alan Poland, the (major) discoverer of the Ah receptor, has never been adequately honoured for his discovery that was first published in 1976, his work presents the key element of modern medical research.
After Poland had supplied the scientific evidence that mice (strain C57BL/6) whose Ah receptor had been removed via inbreeding were almost immune to the most toxic of all substances, namely dioxin, the relationship between the hazardous substance and most of the so-called civilization diseases has been broken down (genetically) almost completely on the basis of this knowledge in the last 40 years (primarily taking the example of dioxin).
Simply put, it were the missing changes in the mice without Ah receptor that have supported science and the pharmaceutical industry in meticulously breaking down and understanding the relationship between hazardous substance and diseases such as breast cancer, diabetes or prenatal abnormal neural development.
There is no pharmaceutical company worldwide and no university with medical research faculties that does not conduct research or develop drugs on the basis of the Ah receptor signalling pathway.
During their research activities the scientists have come across a cornucopia of new findings. On the other hand, they have still been unable to provide a satisfactory explanation of the actual purpose of this mighty receptor. In contrast to all other receptors in the area of the nervous system or the sexual hormones, science has not found any natural function of this receptor to date.
In view of the fact that an appropriately strong activation of the Ah receptor, e.g., through dioxins, chemotherapy, chemical flame inhibitors or epichlorohydrin, an ubiquitously used solvent (annual German production 260,000 t) does not only trigger potentially lethal diseases (cancer, autoimmune disease), but also causes severe cross-generational genetic changes, the second primary function of the Ah receptor, namely the generation of fertility disorders, prevents the transfer of the genetic defects to the next generation. The same applies to the consequential genetic damage by inbreeding.
Proper consideration of this matter points to the conclusion that this receptor had proven to be extremely useful in the developmental period of our planet, i.e., when the air was fraught with polycyclic aromatic hydrocarbons, soot particles and similar pollutants from volcanoes and the atmosphere had been so thin that it could not detain hard radiation.
Organisms / creatures deviating from their natural shape and form due to these genotoxic impacts were incapable of transferring these genetic defects. This was the guarantor for the preservation of the species.
So-called wildtype mice have no problems in producing healthy offspring, whereas this is impossible for the so-called KO mice (inbreeding/C57BL/6 AhR negative). In most cases, their offspring is born with massive malformations, if at all viable.
Vietnam, or the genotoxic effects of the dioxin-contaminated defoliant “Agent Orange” on the Vietnamese people must be stated to be the most dreadful example of this active potential. Numerous children have been born there with massive malformations to this very day.
In sum, the aryl hydrocarbon receptor decides on the weal and woe of almost every form of life on this planet. When an organism of a person or another creature is not exposed to hazardous substances that activate this receptor, there is a great chance of having produced healthy offspring and of gently passing away naturally in old age, spared from cancer and Alzheimer’s disease.
Now, since this receptor - almost equal to a higher being - decides on the “weal and woe” or the “well or waste”, it is internally referred to as “WOW receptor” in this text.
Using the available knowledge for prevention purposes
As head of the scientific research work, department of human toxicology, I became increasingly aware of the extreme importance of this receptor after more than two and a half years.
In my opinion a logic approach requires the major focus to be put on prevention - in addition to an understanding of the development of civilization diseases and their treatment - if we are really interested in the further existence of our species.
In the era of the internet, the assertion that the aryl hydrocarbon receptor is most probably the most researched object in the history of medicine can be checked by everyone at any time with help of a simple search.
The links are listed below, arranged by subject area, and provide a small but extremely impressing insight into the actual significance of this receptor.
In light of this fact it is no wonder that every pharmaceutical company, every university with a chair of medicine situated on this planet is involved in the conduction of research and development activities based on this signalling pathway. Nor is a surprise that - on closer inspection - almost each and every Nobel prize in medicine has involved a direct or indirect relationship with the Ah receptor signalling pathway in recent years. No object on this planet has presented a direct or indirect dissertation subject that was chosen as often as this one.
The omission to use this knowledge for the purpose of prevention presents a crime against almost every species on this planet.
If we consider our future to be important for us, hazardous substances capable of activating this receptor must be subject to rigorous control prior to being released for trade.
Dr. Alan Poland - the pioneer in this field of research
Studies on the mechanism of toxicity of the chlorinated dibenzo-p-dioxins.
Environ Health Perspect. 1973 Sep;5:245-51.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1474979/
2,3,7,8-Tetrachlorodibenzo-p-dioxin: environmental contaminant and molecular probe.
Fed Proc. 1976 Oct;35(12):2404-11.
https://www.ncbi.nlm.nih.gov/pubmed/134910
An estimate of the maximum in vivo covalent binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin to rat liver protein, ribosomal RNA, and DNA.
https://www.ncbi.nlm.nih.gov/pubmed/476664
http://cancerres.aacrjournals.org/content/39/9/3341.full-text.pdf (Fulltext PDF)
Basic knowledge on the aryl hydrocarbon receptor
wikiepedia > https://en.wikipedia.org/wiki/Aryl_hydrocarbon_receptor
Timing is everything: Consequences of transient and sustained AhR activity
Biochem Pharmacol. 2009 Mar 15; 77(6): 947–956.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2751579/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2751579/pdf/nihms145092.pdf
The Aryl Hydrocarbon Receptor Complex and the Control of Gene Expression
Crit Rev Eukaryot Gene Expr. 2008; 18(3): 207–250.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583464/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583464/pdf/nihms64064.pdf
An Aryl Hydrocarbon Receptor Odyssey to the Shores of Toxicology: The Deichmann Lecture, International Congress of Toxicology-XI
Toxicol Sci (2007) 98 (1): 5-38
https://academic.oup.com/toxsci/article/98/1/5/1664877/An-Aryl-Hydrocarbon-Receptor-Odyssey-to-the-Shores
https://academic.oup.com/toxsci/article-pdf/98/1/5/4680785/kfm096.pdf
Persistent Binding of Ligands to the Aryl Hydrocarbon Receptor
Toxicol Sci (2007) 98 (1): 99-109
https://academic.oup.com/toxsci/article/98/1/99/1663027/Persistent-Binding-of-Ligands-to-the-Aryl
https://academic.oup.com/toxsci/article-pdf/98/1/99/4676516/kfm085.pdf
Lehrbuch der Toxikologie 2. Auflage 2002 Hrsg. Marquardt und Schäfer WVGmbH Stuttgart
Ligands = (hazardous) substances that activate the aryl hydrocarbon receptor
POTENCY AND SPECIES SPECIFICITY OF ARYL HYDROCARBON RECEPTOR LIGANDS
Doktorarbeit Richard J.Wall, University of Nottingham July 2012
eprints.nottingham.ac.uk/12798/1/PhD_thesis.pdf
Examples for the aetiology of so-called civilization diseases based on the AhR signalling pathway
Prenatal developmental deficits / prenatal neuronal (mal-)development
Over-expression of AhR (aryl hydrocarbon receptor) induces neural differentiation of Neuro2a cells: neurotoxicology study
Environ Health. 2006; 5: 24.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1570454/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1570454/pdf/1476-069X-5-24.pdf
Gene-Chemical Interactions in the Developing Mammalian Nervous System: Effects on Proliferation, Neurogenesis and Differentiation
Neurotoxicology. 2010 Sep; 31(5): 589–597.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2934892/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2934892/pdf/nihms210049.pdf
Expression of Aryl Hydrocarbon Receptor in Human Placentas and Fetal Tissues
J Histochem Cytochem. 2010 Aug; 58(8): 679–685.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2907273/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2907273/pdf/679.pdf
The Caenorhabditis elegans aryl hydrocarbon receptor, AHR-1, regulates neuronal development Developmental Biology Volume 270, Issue 1, 1 June 2004, Pages 64–75
http://www.sciencedirect.com/science/article/pii/S0012160604001198
Effects of Prenatal Exposure to Endocrine Disrupters on Cerebral Cortex Development
Multi-System Endocrine Disruption Research and Perspectives in Endocrine Interactions pp 43-49
http://link.springer.com/chapter/10.1007/978-3-642-22775-2_3
Immunologic and Neurodevelopmental Susceptibilities of Autism
Neurotoxicology. 2008 May; 29(3): 531–544.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2475601/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2475601/pdf/nihms55471.pdf
Autism
Host-microbiome interactions: the aryl hydrocarbon receptor and the central nervous system
http://link.springer.com/article/10.1007/s00109-016-1486-0
http://link.springer.com/content/pdf/10.1007%2Fs00109-016-1486-0.pdf
DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders?
Environ Epigenet. 2016 Mar; 2(1): dvv012.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4856164/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4856164/pdf/nihms756677.pdf
Association of Aryl Hydrocarbon Receptor-Related Gene Variants with the Severity of Autism Spectrum Disorders
Front Psychiatry. 2016; 7: 184.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110561/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110561/pdf/fpsyt-07-00184.pdf
Support for calcium channel gene defects in autism spectrum disorders
https://molecularautism.biomedcentral.com/articles/10.1186/2040-2392-3-18
https://molecularautism.biomedcentral.com/track/pdf/10.1186/2040-2392-3-18?site=molecularautism.biomedcentral.com
Cancer
Sunitinib, a tyrosine kinase inhibitor, induces cytochrome P450 1A1 gene in human breast cancer MCF7 cells through ligand-independent aryl hydrocarbon receptor activation.
https://www.ncbi.nlm.nih.gov/pubmed/23288144
Aryl hydrocarbon receptor/cytochrome P450 1A1 pathway mediates breast cancer stem cells expansion through PTEN inhibition and β-Catenin and Akt activation
Molecular Cancer201716:14 DOI: 10.1186/s12943-016-0570-y
https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-016-0570-y
https://molecular-cancer.biomedcentral.com/track/pdf/10.1186/s12943-016-0570-y?site=molecular-cancer.biomedcentral.com
Autoimmune diseases
The aryl hydrocarbon receptor: a perspective on potential roles in the immune system
Immunology. 2009 Jul; 127(3): 299–311.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2712099/pdf/imm0127-0299.pdf
The aryl hydrocarbon receptor: a molecular pathway for the environmental control of the immune response
Immunology. 2013 Mar; 138(3): 183–189
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3573271/pdf/imm0138-0183.pdf
The Role of AhR in Autoimmune Regulation and Its Potential as a Therapeutic Target against CD4 T Cell Mediated Inflammatory Disorder
nt J Mol Sci. 2014 Jun; 15(6): 10116–10135
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4100143/pdf/ijms-15-10116.pdf
The roles of aryl hydrocarbon receptor in immune responses
Int Immunol (2013) 25 (6): 335-343
https://academic.oup.com/intimm/article/25/6/335/733829/The-roles-of-aryl-hydrocarbon-receptor-in-immune
https://academic.oup.com/intimm/article-pdf/25/6/335/2186716/dxt011.pdf
Aryl hydrocarbon receptor and experimental autoimmune arthritis.
Semin Immunopathol. 2013 Nov;35(6):637-4
https://www.ncbi.nlm.nih.gov/pubmed/23982178
Transplant medicine
Environmental Exposures- The Missing Link in Immune Responses After Transplantation.
Am J Transplant. 2016 May;16(5):1358-64
https://www.ncbi.nlm.nih.gov/pubmed/26696401
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4844852/pdf/nihms-744712.pdf
Prevention / therapeutic application
Application Resveratrol / Metformin - breast cancer risk / autoimmune diseases
Metformin suppresses CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating aryl hydrocarbon receptor expression.
Toxicol Appl Pharmacol. 2014 Oct 1;280(1):138-48
https://www.ncbi.nlm.nih.gov/pubmed/25110054
Metformin inhibits 7,12-dimethylbenz[a]anthracene-induced breast carcinogenesis and adduct formation in human breast cells by inhibiting the cytochrome P4501A1/aryl hydrocarbon receptor signaling pathway.
Toxicol Appl Pharmacol. 2015 Apr 15;284(2):217-26
https://www.ncbi.nlm.nih.gov/pubmed/25697376
Effects of metformin on Sirt1, Nrf2 and AhR expression in cancer cells
Department of Pharmacy Graduate School Chungnam National University
A Dissertation for the Degree of Doctor of Philosophy
Autor; Minh Truong Do Advisor Hye Gwang Jeong August 2014
http://lrc.tnu.edu.vn/upload/collection/brief/43413_189201493932dominhtruong.pdf
Aryl hydrocarbon receptor/cytochrome P450 1A1 pathway mediates breast cancer stem cells expansion through PTEN inhibition and β-Catenin and Akt activation
Molecular Cancer201716:14
DOI: 10.1186/s12943-016-0570-y
https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-016-0570-y
https://molecular-cancer.biomedcentral.com/track/pdf/10.1186/s12943-016-0570-y?site=molecular-cancer.biomedcentral.com
Hypertension
Metformin Reverses Development of Pulmonary Hypertension via Aromatase Inhibition
Hypertension. 2016;68:00-00.
http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.116.07353/-/DC1
Autoimmune reaction / diabetes
Use of natural AhR ligands as potential therapeutic modalities against inflammatory disorders
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4076843/
Resveratrol protects against polychlorinated biphenyl-mediated impairment of glucose homeostasis in adipocytes
J Nutr Biochem. 2013 Dec; 24(12): 2168–2174.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066417/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066417/pdf/nihms-527453.pdf
Chemotherapy / Resveratrol
Development of cardiac hypertrophy by sunitinib in vivo and in vitro rat cardiomyocytes is influenced by the aryl hydrocarbon receptor signaling pathway.
Arch Toxicol. 2014 Mar;88(3):725-38.
https://www.ncbi.nlm.nih.gov/pubmed/24247421
Autoimmune encephalomyelitis
Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor
Global Research & Development, Teva Pharmaceutical Industries Ltd.,
www.pnas.org/cgi/doi/10.1073/pnas.1607843113
Microbiome
Host-microbiome interactions: the aryl hydrocarbon receptor and the central nervous system
Journal of Molecular medicine Jan 2017, Volume 95 pp 29-39
https://link.springer.com/article/10.1007/s00109-016-1486-0
https://link.springer.com/content/pdf/10.1007%2Fs00109-016-1486-0.pdf
Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522678/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522678/pdf/srep12689.pdf
Antiviral / AIDS HIV
Constitutive aryl hydrocarbon receptor signaling constrains type I interferon–mediated antiviral innate defense Nature Immunology 17, 687–694 (2016)
http://www.nature.com/ni/journal/v17/n6/abs/ni.3422.html
The aryl hydrocarbon receptor is a modulator of anti-viral immunity
Biochem Pharmacol. 2009 Feb 15; 77(4): 642653.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662440/
Constitutive aryl hydrocarbon receptor signaling constrains type I interferon-mediated antiviral innate defense.
Nat Immunol. 2016 Jun;17(6):687-94
https://www.ncbi.nlm.nih.gov/pubmed/27089381
New insights into the aryl hydrocarbon receptor as a modulator of host responses to infection
Semin Immunopathol. 2013 Nov; 35(6)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3808126/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3808126/pdf/nihms-518589.pdf
German authors / Research i.S. Aryl hydrocarbon receptor
Professor Esser / IUF Leibniz-Institut für umweltmedizinische Forschung gGmbH (Leibniz Research Institute for Environmental Medicine)
AG (Prof.) Esser: Rolle des AhR in der Immuntoxikologie
http://www.iuf-duesseldorf.de/ag-esser-43.html
Publications:
The aryl hydrocarbon receptor in T cells contributes to sustaining oral tolerance against ovalbumin in a mouse model.
Biljes D, Hammerschmidt-Kamper C, Merches K, Esser C:
EXCLI J 16: 291-301, 2017. doi: 10.17179/excli2017-168
Esser C: The Aryl Hydrocarbon Receptor in Immunity: Tools and Potential. In: Cuturi MC, Anegon I (Hrsg.): Suppression and Regulation of Immune Responses, Methods and Protocols, Volume II. Humana press, New York, 2016. ISBN 978-1-4939-3138-5.
Esser C, Rannug A: The Aryl Hydrocarbon Receptor in Barrier Organ Physiology, Immunology, and Toxicology. Pharmacol Rev 67(2): 259-279, 2015. [pubmed]
Professor Schrenk / Technical University of Kaiserslautern
AG (Prof.) Schrenk Biological responses mediated by the dioxin receptor
https://www.chemie.uni-kl.de/en/ag-schrenk/research/
Publications:
Consensus toxicity factors for polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls combining in silico models and extensive in vitro screening of AhR-mediated effects in human and rodent cells.
https://www.ncbi.nlm.nih.gov/pubmed/25654323
The 2005 World Health Organization Re-evaluation of Human and Mammalian Toxic Equivalency Factors for Dioxins and Dioxin-like Compounds
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2290740/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2290740/pdf/nihms18967.pdf
