Estrogen Receptor β Participates in Alternariol-Induced Oxidative Stress in Normal Prostate Epithelial Cells

Abstract

Alternaria toxins are considered as emerging mycotoxins, however their toxicity has not been fully evaluated in humans. Alternariol (AOH), the most prevalent Alternaria mycotoxin, was previously reported to be genotoxic and to affect hormonal balance in cells; however, its direct molecular mechanism is not known. The imbalance in androgen/estrogen ratio as well as chronic inflammation are postulated as factors in prostate diseases. The environmental agents affecting the hormonal balance might participate in prostate carcinogenesis. Thus, this study evaluated the effect of two doses of AOH on prostate epithelial cells. We observed that AOH in a dose of 10 µM induces oxidative stress, DNA damage and cell cycle arrest and that this effect is partially mediated by estrogen receptor β (ERβ) whereas the lower tested dose of AOH (0.1 µM) induces only oxidative stress in cells. The modulation of nuclear erythroid-related factor 2 (Nrf2) was observed in response to the higher dose of AOH. The use of selective estrogen receptor β (ERβ) inhibitor PHTPP revealed that AOH-induced oxidative stress in both tested doses is partially dependent on activation of ERβ, but lack of its activation did not protect cells against AOH-induced ROS production or DNA-damaging effect in case of higher dose of AOH (10 µM). Taken together, this is the first study reporting that AOH might affect basic processes in normal prostate epithelial cells associated with benign and malignant changes in prostate tissue.

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

“…Here, using nontransformed intestinal cells, with the measurement of IL-8 secretion levels, we could demonstrate that both toxins can affect the proinflammatory response of IL-1β (5 h of incubation, Figure ). Even though the literature regarding ATX-II is limited, a recent study in hormone-sensitive prostate cells reported AOH to suppress IL-1β gene transcription . Furthermore, Kowalska and colleagues found AOH to induce IL-6 at transcript and protein levels, an effect that could be partially linked to the estrogen-like capacities of AOH toward the estrogen receptor β (ER-β) .…”

“…Besides, the toxin was found to suppress relative gene expression of the NF-κB subunit p65 (RelA), partly attributed to the endocrine capacity of AOH, in this particular in vitro model. 46 Supportive of the cross talk between AhR and Nrf2, CH-22, known as AhR antagonist, 33 showed the capability to suppress the Nrf2 nuclear/cytosol ratio for all substances tested ( Figure 5 ). On this note, it was recently reported for urolithin A (Uro A) that expression of both Nrf2 and AhR is crucial for the chemicals’ potential to increase mRNA levels of Nrf2 and heme oxygenase 1 (HO-1) in colon explants from mice.…”

“…Even though the literature regarding ATX-II is limited, a recent study in hormone-sensitive prostate cells reported AOH to suppress IL-1β gene transcription. 46 Furthermore, Kowalska and colleagues found AOH to induce IL-6 at transcript and protein levels, an effect that could be partially linked to the estrogen-like capacities of AOH toward the estrogen receptor β (ER-β). 46 The two cytokines IL-8 and TNF-α typically sustain the early phases of acute inflammation.…”

“… 46 Furthermore, Kowalska and colleagues found AOH to induce IL-6 at transcript and protein levels, an effect that could be partially linked to the estrogen-like capacities of AOH toward the estrogen receptor β (ER-β). 46 The two cytokines IL-8 and TNF-α typically sustain the early phases of acute inflammation. 47 Hence, we postulate that modulations by Alternaria toxins obtained even in short incubation times ( Figures 2 and 3 ) might impact on the cytokines’ downstream signaling and further influence subsequent processes within the immune response.…”

Combinatory Exposure to Urolithin A, Alternariol, and Deoxynivalenol Affects Colon Cancer Metabolism and Epithelial Barrier Integrity in vitro

“…Alternariol (AOH, Figure 1B), a small molecule produced by Alternaria alternata, is considered an "emerging mycotoxin", that requires toxicological risk assessment beyond its reported toxic effects (34,35). AOH was previously described to hold, amongst others, genotoxic, endocrine disruptive, pro-oxidative, and immunomodulatory potential (36)(37)(38)(39). Furthermore, AOH was suggested to impact cell membrane properties relevant for the innate immune response (40).…”