Zeranol upregulates corticotropin releasing hormone expression in the placental cell line JEG-3

•Zeranol induced CRH mRNA expression in JEG-3 cells at sub-nM range.•ERK and PKCδ in the placental cells were activated.•CRE-binding activity in the CRH gene promoter was increased.

Corticotrophin-releasing hormone (CRH) plays a pivotal role in the control of parturition in human. Increased amount of plasma CRH is associated with pre-mature delivery. Zeranol or α-zearalanol is a mycotoxin produced by fungi in the Fusarium family. Unlike other mycotoxins, exposure to zeranol appears to have minimal health risk. In North America, it is used as a growth-promoting agent in livestock. Because of the health concern of zeranol residue in meat, this practice has not been adopted in Europe. In our study zeranol could induce CRH protein expression in JEG-3 cells as low as 0.1 nM. As electrophoretic mobility shift assay indicated an increase in the CRE binding activity in CRH promoter, the induction was likely triggered by transcriptional regulation. We further looked into the signal transduction pathway and PKCδ and ERK-1/2 were found to be activated. This study showed that zeranol could increase CRH expression in placental cells, and the findings might be a concern for pregnant women.