Deoxynivalenol enhances estrogen receptor alpha-induced signaling by ligand-independent transactivation

• Published in: Food and chemical toxicology Vol. 165; p. 113127
• Main Authors: Drouault, M., Delalande, C., Bouraïma-Lelong, H., Seguin, V., Garon, D., Hanoux, V.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.07.2022; Elsevier
• Subjects: Deoxynivalenol; Endocrine disruptors; Estrogen receptors; In vitro; Life Sciences; Microbiology and Parasitology; Mycology; Mycotoxins; Reproductive Biology; Zearalenone; Endocrine disruptors; PR; RT; ERα p-Ser167; JNK; Estrogen receptors; Zearalenone; mRNA; E2; TFF1/PS2; CTGF; p38; PI3K; 4-OH-TAM; TGF-β; PPARγ2; RT-qPCR; p90-RSK2; DON; ERβ; EGF; ERα; rRNA; siRNA; Deoxynivalenol; Akt; MAPK; In vitro; ESR1; ESR2; ERK1/2; PKR; Mycotoxins; GPER; ZEA; ERE; GAPDH
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2022.113127

Deoxynivalenol (DON), which is one of the prevalent mycotoxins in food and feeds, exerts adverse effects on animal and human health. These effects are mainly associated with its ribotoxic properties, although few studies suggest the involvement of other mechanisms of action. To assess the ability of DON to disrupt estrogen signaling, we conducted an in vitro study using MCF-7 and MDA-MB-231 cells. After 72h, DON reduced cell viability in both cell lines, thus highlighting its well-known cytotoxic effect. However, after 6h, DON increased the expression of estrogen-responsive genes, hence demonstrating the stimulation of estrogen signaling by this mycotoxin after a short-term exposure. This effect was partially reversed by siRNA-mediated silencing of ERα expression and by 4-hydroxytamoxifen (ERα antagonist), but neither by G36 (GPER antagonist) nor by the siRNA-mediated silencing of PPARγ2 expression. Moreover, DON exposure induced an increase in the level of ERα phosphorylation at serine 167. Furthermore, when combined with zearalenone (a naturally co-occurring mycotoxin recognized as an endocrine disruptor), DON increased the expression of estrogen-responsive genes to a greater extent than each individual compound taken separately. Taken together, our results suggest, for the first time, that DON can disrupt estrogen signaling through the ligand-independent activation of ERα. •DON induces the disruption of estrogen signaling pathway in vitro.•DON induces ERα phosphorylation at serine 167 site.•The effect of DON is mediated by the ligand-independent activation of ERα.•The effect of DON does not involve GPER nor PPARγ2.•DON enhances the estrogen signaling pathway induced by E2 or ZEA.