Zearalenone induces GnRH neurons activation related to central precocious puberty by triggering MKRN3 auto-ubiquitination and down-regulation.

Central precocious puberty (CPP) refers to gonadotropin-dependent sexual precocity that results from the early activation of the hypothalamic-pituitary-gonadal (HPG) axis. Zearalenone (ZEA), a non-steroidal mycotoxin, is one of the important triggering factors for the development of CPP; however, its regulatory mechanism remains unclear. In this study, the correlation between urinary zearalenone (ZEA) levels and the blood expression of MKRN3 (makorin RING-finger protein-3) in patients with central precocious puberty (CPP) was investigated. Subsequently, the regulatory mechanism of ZEA on MKRN3, as well as its association with gonadotropin-releasing hormone (GnRH) production, cell proliferation, and the expression and localization of the G protein-coupled estrogen receptor (GPER) were explored in the hypothalamic cell line GT1-7. Analysis of clinical samples revealed that urinary ZEA levels were negatively correlated with blood MKRN3 expression in CPP patients. The in vitro experiments revealed that ZEA treatment up-regulated cell proliferation as well as the expressions of GnRH and GPER and re-location of GPER in GT1-7 cells by triggering MKRN3 auto-ubiquitination and down-regulation. However, such effects were attenuated by GPER overexpression. In conclusion, this study reveals a novel mechanism by which ZEA influences CPP using clinical samples and an in vitro model. The findings suggest that MKRN3 may serve as a potential therapeutic target and a diagnostic biomarker for CPP.