Many studies have focused on environmental estrogen-related diseases. However, no consistent gene markers or signatures for estrogenicity have been discovered in mammals. This study investigated the estrogenic effects of 17β-estradiol on the prostate in immature male mice. Consistent U-shaped responses were seen in bodyweight, ventral prostate epithelial morphology, and miRNA expression levels. Specifically, most estradiol regulated miRNAs were downregulated at low doses of estradiol (0.2 and 2 mg·kg^–1), and whose expression returned to the control level at a larger dose (200 mg·kg^–1). The function of these regulated miRNAs is related to the prostate cancer and PI3K-Akt signaling pathways, which is consistent with the function of estradiol. Furthermore, the miRNA-processing machinery, Drosha, in the prostate was also regulated in a similar pattern, which could be a part of the U-shaped miRNA expression mechanism. All of these data indicate that the prostate is a reliable organ for evaluating estrogenic activity and that the typical nonmonotonic dose-response relationship could be used as a novel biomarker for estrogenicity.

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