Mycotoxin Alternariol (AOH) Affects Viability and Motility of Mammary Breast Epithelial Cells

Abstract

Mycotoxins are present in everyday diet as common food and feed pollutants. A part of them is still concerned as so-called emerging mycotoxins. Due to the lack of toxicity data, the safety limits and detail molecular mechanism have been not established yet for all of them. Alternariol (AOH), as one of these mycotoxins, produced by Alternaria species, is so far reported as an estrogenic, genotoxic, and immunomodulatory agent; however, its direct effect on human health is not known. Especially, in the case of hormone-dependent tissues which are sensitive to both endogenic, as well as external estrogenic agents, it might be crucial to assess the effect of AOH. Thus, this study evaluated how exposure to AOH affects viability and motility of the human normal mammary gland epithelial in vitro model. We observed that AOH significantly affects viability of cells in a time- and dose-dependent manner. Moreover, the induction of oxidative stress, DNA damage, and cell cycle arrest in the G2/M cell cycle phase was observed. The motility of 184A1 cells was also significantly affected. On the molecular level, AOH induced antioxidative stress response via activation of Nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway agents, as well as decrease in the phosphorylation of protein kinase B (Akt) and p44/42 (ERK 1-2) molecules, indicating that AOH might affect crucial signaling pathways in both physiological and pathophysiological processes in breast tissue.

Alternaria alternata Mycotoxins Activate the Aryl Hydrocarbon Receptor and Nrf2-ARE Pathway to Alter the Structure and Immune Response of Colon Epithelial Cells

“…Recently, AOH was reported to trigger both MMP-2 and MMP-9 mRNA transcription in mammary cells: however, this effect was biphasic and concentration-dependent; in fact, 10 μM AOH even slightly decreased MMP-9 mRNA relative transcription compared to solvent controls. 62 In the same study, zymography experiments revealed decreased enzyme activity for both MMPs, which was linked to reduced wound-healing capacity and changes in adhesion. Simultaneously, the relative expression of vimentin, a regulator of epithelial-to-mesenchymal transition was suppressed at a low concentration and enhanced at 10 μM.…”

“…In turn, while MMP-9 transcription was induced by IL-1β, single-toxin exposure slightly enhanced this, yet not in the binary mixture (Figure D). Recently, AOH was reported to trigger both MMP-2 and MMP-9 mRNA transcription in mammary cells: however, this effect was biphasic and concentration-dependent; in fact, 10 μM AOH even slightly decreased MMP-9 mRNA relative transcription compared to solvent controls . In the same study, zymography experiments revealed decreased enzyme activity for both MMPs, which was linked to reduced wound-healing capacity and changes in adhesion.…”

“…Mechanistically, these observations were connected to the toxins’ immunomodulatory and oxidative stress-inducing capacities. 62 Additionally, in relation to its potential to modify the membrane architecture in immune cells, AOH was recently reported to reduce LPS-induced Toll-like receptor 4 (TLR4) increase/recruitment in THP-1 -derived macrophages. 63 Also, ATX-II was previously described to modify membrane fluidity and cell structure in HCEC-1CT, particularly in relation to increased oxidative stress and modification of the Nrf2 translocation profile.…”

“…Simultaneously, the relative expression of vimentin, a regulator of epithelial-to-mesenchymal transition was suppressed at a low concentration and enhanced at 10 μM. Mechanistically, these observations were connected to the toxins’ immunomodulatory and oxidative stress-inducing capacities . Additionally, in relation to its potential to modify the membrane architecture in immune cells, AOH was recently reported to reduce LPS-induced Toll-like receptor 4 (TLR4) increase/recruitment in THP-1 -derived macrophages .…”

Alternariol alleviates breast carcinoma by inhibiting cellular proliferation correlated with increased apoptotic events in rats

“…Moreover, it also activates nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway and inhibits Akt/ERK pathway to regulate viability the mammary tissue on molecular level. 18 However, another study revealed that Alternaria toxin mixtures caused activation of aryl hydrocarbon receptor which induced Cytochrome P450 (CYP) 1A1/1A2/1B1 activity in phase I metabolism and activates the breast cancer cells. 19 Till now there is lack of documented evidences demonstrating the cytotoxic effect of AOH through the induction of apoptosis on the breast cancer model.…”