Physiologically based kinetic (PBK) modeling as a tool to quantify the role of gut microbial metabolism in the in vivo effects of the foodborne estrogens daidzein and zearalenone

The present thesis focuses on two food borne compounds whose toxicity may be influenced by the gut microbiota. These compounds are daidzein and zearalenone (ZEN), both known to exert estrogenic effects. The isoflavone daidzein represents an important bioactive food constituent in soy products which exerts estrogenicity due to structural similarity to the natural hormone 17β-estradiol (E2) (Niu et al., 2018). The mycotoxin zearalenone is a well-known example of a toxin produced by fungi growing on contaminated crops, showing potential estrogenicity (Drzymala et al., 2015). Both daidzein and ZEN can be metabolized by gut microbiota to metabolites with higher estrogenic potential than their parent compounds, being S-equol (Mayo et al., 2019) and α-zearalenol (α-ZEL) (Zinedine et al., 2007), respectively. Exposure to these microbial metabolites may add to the effects resulting from exposure to the respective parent compounds. The aim of the present thesis was to characterize the role of gut microbial metabolism in the toxicity of daidzein and zearalenone (ZEN) by including gut microbiota in physiologically based kinetic (PBK) models and applying these models for quantitative in vitro to in vivo extrapolations (QIVIVE). The results obtained provide proofs-of-principle for application of this novel approach methodology (NAM) for alternatives in animal testing, characterizing the consequences of the metabolism by the gut microbiota for toxicity of foodborne chemicals in the host without a need for in vivo studies in experimental animals or human intervention studies.