Discovery in the 1970s

Decades of research around the subject of the dioxin receptor (aryl hydrocarbon receptor) not only permits us an insight into the relationships between exposures to hazardous substances and the occurrence of most severe diseases, but it also explains the cross-generational damage in our genome. As the beginnings of this research are largely unknown to most people, we are going to take a closer look at this issue, not least to appreciate and acknowledge the work of the pioneers in this field.

We do not know whether the medical researchers Nebert and Poland were aware of the dimension of their research activities in the early 1970s. Irrespective of this matter, their work provides the basis for an answer to the questions about the cause of most civilization diseases.

Simply put, Nebert and Poland were concerned with the investigation of the dioxin pollutant metabolism in genetically modified mouse strains (C57BL/6 and DBA/2N) at the beginning of their research work. In doing so they found out that the mouse strains reacted in extremely different ways to the dioxin exposure.

While the members of one mouse family died - as expected - as a result of dioxin poisoning, a much lower toxic effect was observed in the mouse variant that had been genetically modified by means of inbreeding.

A second group of mice that had undergone further genetic modification still by means of inbreeding finally demonstrated a complete dioxin resistance, i.e., the mice were absolutely immune to the most toxic of all toxins, the Seveso dioxin TCDD.

Nebert and his colleagues discovered that the mouse strains differed from each other by an unequally strong production of a certain enzyme (aryl hydrocarbon hydroxylase). The mouse strain that has almost no problem with the dioxin intake is neither capable of distributing this enzyme later referred to as “cytochrome P450 1A1“, nor of generating it.

Besides other researchers, it was chiefly Poland (and Knutson) who identified a certain protein on the cell surface as contact site (receptor) for dioxin and similar hazardous substances in addition to the modified enzyme distribution. And it was Poland, too, who named this receptor “aryl hydrocarbon receptor” for the first time in 1982. (Note: substances that are capable of binding to this receptor are referred to as ligands).

After the works of Nerbert and Poland on the Ah receptor had been published in the early 1970s, the number of the researchers in this field increased substantially around the world.

The 1990s: Cross-generational genetic damage evidenced

Independently of each other, EMA (1994) and Chang (1993), for instance, found out that the diverse capacities to bind to this receptor were caused by a mutation/genetic modification.

In plain language: Since the mid-nineties it is certain that the individual different effects of / sensitivities to hazardous substances are by no means fateful, but must always be ascribed to a prior genetic modification/mutation due to the contact with a ligand.

Thanks to researchers as Ema and Chang it has also been known since the mid-nineties that both cytochrome P450 1A1 and the glutathione-S-transferase expression as well as the genetic constitution undergo permanent, i.e., cross-generational modification after an accordingly high exposure to hazardous substances / ligand binding.

It is not least due to the analysis of the human genome that these pathological genetic modifications could be identified. The said analysis led to an improvement of the technical equipment of many medical scientific institutes and universities in the early to mid 1990s.

Over time, a clear picture emerged on the activities following to the bond of the hazardous substance (dioxin or a similar pollutant) to the dioxin receptor in the organism. Researchers around the world came to the same result: the activation of the Ah receptor through dioxin is always followed by the same reaction sequence globally referred to as “Ah receptor signalling pathway”.

It could be described as a fact that the findings of Nebert and Poland served as important leverage for the investigation and research work of the aryl hydrocarbon receptor . Year after year, thousands of doctoral theses in which PhD students describe the cause / pathogenesis of development damage in early childhood, diabetes or Alzheimer’s disease down to the last detail are composed on the basis of their work.

Key to prevention

However, the real breakthrough for the dioxin receptor research occurred at the beginning of this millennium with the insight that the aryl hydrocarbon receptor signalling pathway not only presents the reason for these diseases, but also the key to the treatment or the prevention of the most serious diseases.

Based on the AhR signalling pathway, the pharmaceutical companies or the medical faculties (with the help of external funding by the pharmaceutical industry) have been developing or - with regard to the side effects - further developing drugs against almost every civilization disease such as Alzheimer’s disease, diabetes, ADS or depression and many more.

As a result, and thanks to Poland, the AhR signalling pathway has not only served as lock, but also as key to the realization of, e.g., the development of a chemotherapy with only few side effects or necessary preventive measures such as a ban of hazardous ingredients in our food, or harmful substances in our flats, our cars, at our workplaces and in our environment.

Note: Many publicists / researchers consider the Ah receptor to be the basic principle, a human-toxicological premise.
In order to emphasize the actual importance of the AhR signalling pathway, the German-speaking toxicologists (Kaina, Dietrich, University of Mainz) even used the term “canonical” (according to the rules) primarily used in the ecclesiastical law in their publication with the title “The aryl hydrocarbon receptor (AhR) in the regulation of cell–cell contact and tumor growth” published in 2010.

There is nothing more to be said with regard to the human-toxicological relevance of the Ah receptor signalling pathway (not only in view of the tumor growth rates).

Sources

Expression of Aryl Hydrocarbon Hydroxylase Induction and Suppression of Tyrosine Aminotransferase Induction in Somatic-Cell Hybrids Proc Natl Acad Sci U S A. 1972 Aug; 69(8): 2179–2183 W. F. Benedict, D. W. Nebert, and E. B. Thompson
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC426895/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC426895/pdf/pnas00134-0189.pdf

Genetic regulation of aryl hydrocarbon hydroxylase induction in the mouse.
Fed Proc. 1972 Jul-Aug;31(4):1315-25. Nebert DW, Gielen JE.
https://www.ncbi.nlm.nih.gov/pubmed/4114109

Ten nucleotide differences, five of which cause amino acid changes, are associated with the Ah receptor locus polymorphism of C57BL/6 and DBA/2 mice
Chang C1, Smith DR, Prasad VS, Sidman CL, Nebert DW, Puga A.
Pharmacogenetics. 1993 Dec;3(6):312-21.
https://www.ncbi.nlm.nih.gov/pubmed/8148872

The aryl hydrocarbon receptor (AhR) in the regulation of cell-cell contact and tumor growth.
Carcinogenesis. 2010 Aug;31(8):1319-28. doi: 10.1093/carcin/bgq028. Epub 2010 Jan 27.
Dietrich C1, Kaina B.
https://www.ncbi.nlm.nih.gov/pubmed/20106901