AOH induces oxidative stress and DNA damage in ovarian cancer cells via modulation of GPER1 and HIF1α/PI3K/CLDNs signaling pathway

Claudins (CLDNs) are small proteins that form tight junctions (TJs) in cells and play a key role in various biological processes in cells. Previous results have shown that CLDNs expression can be regulated by hormones and, therefore, can also be regulated by compounds that mimic their action. Such compounds belong to a large group called endocrine-disrupting chemicals (EDCs). Alternariol (AOH), an emerging mycotoxin, contaminates various food products. AOH is reported to be genotoxic and to induce oxidative stress. Previous results showed that AOH is also estrogenic and acts as an androgen receptor (AR) agonist, suggesting that it might act as one of the EDCs, however, its detailed molecular mechanism has not been fully elucidated yet. In this study, we decided to evaluate the interplay between AOH and G protein-coupled estrogen receptor 1 (GPER1) in hormone-dependent human ovarian cancer (OC) cells with a focus on the involvement of hypoxia-inducible factor 1-alpha/phosphoinositide 3-kinases/protein kinase B (HIF1α/PI3K/Akt) and claudins (CLDNs) signaling pathways in that effect. We observed that AOH induces oxidative stress and DNA damage in OC cells, and this effect is partially mediated by GPER1. We found that the GPER1 antagonist G15 partially mitigated AOH-induced ROS production and significantly reduced DNA damage, confirming the receptor's role in mediating these effects. Furthermore, we observed the involvement of HIF1α/PI3K/Akt and CLDNs pathways in AOH effect in OC cells. In conclusion, we postulate that AOH has pro-oxidative ability and that this effect is partially mediated by GPER1. Moreover, we postulated that HIF1α/PI3K/Akt and CLDNs participate in AOH action in OC cells, which in turn provides useful information for future toxicological research studies as a new molecular mechanism of AOH.