Microcystin-LR reduces the synthesis of gonadotropin-releasing hormone by activating multiple signaling pathways resulting in decrease of testosterone in mice

Abstract

We previously reported Microcystin-LR (MC-LR) could enter the hypothalamus, reduce the expression of gonadotropin-releasing hormone (GnRH), and induce male reproductive barriers. However, the molecular mechanisms underlying in the hypothalamus have not been elucidated in detail. In this study, we further showed that MC-LR inhibited the synthesis of GnRH in GnRH neurons via activating protein kinase a (PKA), cAMP-response element binding protein (Creb), protein kinase c (PKC), nuclear factor kappa B (NF-κB), extracellular regulated protein kinases (Erk) and P38 protein, and thus resulted in the change of activity of transcriptional enhancers or suppressors such as Oct-1, Otx-2, Pbx1a, Dlx-2, c-Jun and c-Fos. Following exposure, MC-LR-treated mice exhibited decreased GnRH level. Our data demonstrated that MC-LR can stimulate intracellular Ca²⁺ and cAMP to activate PKC, PKA and MAPK signaling pathways in GnRH neurons, and then inhibit Pbx1a, Oct-1, Dlx-2, Otx-2 and upregulate c-Jun and c-Fos to initiate the transcription of GnRH, which provides novel insights to explore the mechanism associated with MC-LR-induced male reproductive barriers.

Keywords: GnRH; GnRH neurons; Microcystin-LR; PKC/PKA/MAPK signaling pathway; Transcriptional factors.