1. Naturally occurring mixtures of Alternaria toxins: anti-estrogenic and genotoxic effects in vitro
- Author
-
Hannes Puntscher, Franziska Krüger, Karin Preindl, Georg Aichinger, Benedikt Warth, and Doris Marko
- Subjects
0301 basic medicine ,DNA damage ,Endocrine disruption ,Health, Toxicology and Mutagenesis ,Estrogen receptor ,Toxicology ,medicine.disease_cause ,03 medical and health sciences ,Cell Line, Tumor ,Basic Helix-Loop-Helix Transcription Factors ,Mixture ,medicine ,Humans ,Mode of action ,Emerging mycotoxin ,Estradiol ,030102 biochemistry & molecular biology ,biology ,Chemistry ,Toxin ,Xenoestrogens ,Estrogen Antagonists ,Alternaria ,General Medicine ,Mycotoxins ,Aryl hydrocarbon receptor ,biology.organism_classification ,Comet assay ,030104 developmental biology ,Receptors, Aryl Hydrocarbon ,Biochemistry ,biology.protein ,Alkaline phosphatase ,Mutagens - Abstract
Alternaria molds can produce a variety of different mycotoxins, often resulting in food contamination with chemical mixtures, posing a challenge for risk assessment. Some of these metabolites possess estrogenic properties, an effect whose toxicological relevance is questioned in the light of the strong genotoxic and cytotoxic properties of co-occurring toxins. Thus, we tested a complex extract from A. alternata for estrogenic properties in Ishikawa cells. By assessing alkaline phosphatase activity, we did not observe estrogen receptor (ER) activation at non-cytotoxic concentrations (≤ 10 µg/ml). Furthermore, an extract stripped of highly genotoxic perylene quinones also did not mediate estrogenic effects, despite diminished genotoxic properties in the comet assay (≥ 10 µg/ml). Interestingly, both extracts impaired the estrogenicity of 17β-estradiol (E2) at non-cytotoxic concentrations (5–10 µg/ml), indicating anti-estrogenic effects which could not be explained by the presence of known mycoestrogens. A mechanism for this unexpected result might be the activation of the aryl hydrocarbon receptor (AhR) by Alternaria metabolites, as indicated by the induction of CYP1A1 transcription. While a direct influence on the metabolism of E2 could not be confirmed by LC–MS/MS, literature describing a direct interplay of the AhR with estrogenic pathways points to a corresponding mode of action. Taken together, the present study indicates AhR-mediated anti-estrogenic effects as a novel mechanism of naturally co-occurring Alternaria toxin mixtures. Furthermore, our results confirm their genotoxic activity and raise questions about the contribution of still undiscovered metabolites to toxicological properties.
- Published
- 2019