In their lifetime, humans are exposed to hundreds of thousands of contaminants, both synthetic and natural. Usually, they are not hazardous to health, but, for example, exposure that occurs at a sensitive gestational age can lead to changes that become evident only in adulthood or even future generations. The discipline that studies these adverse health effects of chemical substances found in our food and surroundings is called toxicology. At the department, dioxins and the AH receptor, which serves as the mediator of dioxin toxicity, constitute a key research topic.
Of the contaminants occurring in our environment and food, among the toxicologically most significant group are substances known as persistent organic pollutants (POP). As the name suggests, they are chemicals that persist in nature for a long time and tend to accumulate in the food chain. Dioxins constitute one key POP group. There are a large number of dioxin derivatives, of which the most toxic (especially TCDD) engender even at low levels of exposure an exceptionally high number of various biochemical and toxic responses. In humans, their elimination half-life is very long (several years), and epidemiological evidence has been obtained of their possible link to, for example, diabetes, hypothyroidism, cardiovascular diseases and, in children, changes in the timing of puberty as well as cognitive changes. In a risk assessment published in 2019 by the European Food Safety Authority (EFSA), declining sperm concentration in semen was found to be the most sensitive of the dioxin responses on which sufficient evidence has been obtained. In that regard, the mean exposure on the population level currently exceeds the tolerable upper intake level broadly across Europe, even though the background levels of dioxin have decreased markedly in the past 30 years.
While dioxins are among the most extensively investigated contaminant chemicals in the world, knowledge of their mechanisms of toxicity remains insufficient. What is known, however, is that the AH (aryl hydrocarbon) receptor (AHR) is needed to mediate their effects. AHR is a transcription factor that is activated when ligands, such as dioxin, bind with it, after which the receptor alters the expression of the genes it regulates. AHR is an evolutionarily well-conserved protein molecule that dates back more than 600 million years, whose physiological effects have only recently started to be uncovered. It has proven to be a key immune response regulator and a protector of the integrity of bodily interfaces. Through the analysis of AHR knockout mice, the receptor has been found to contribute to the growth of many organs and tissues, stem cell differentiation, the adaptation of the circadian rhythm, the maintenance of disease tolerance and – according to our latest discovery – the development of obesity. At the department, we are currently investigating AHR’s role in energy balance as well as interaction between AHR and retinoids. Our findings shed new light on the physiological duties of AHR and increase understanding of the mechanisms of toxicity of dioxins and other chemicals whose effect is mediated by AHR.