The effect of manganese exposure on GnRH secretion via Nrf2/mGluR5/COX-2/PGE2/signaling pathway

• Published in: Toxicology and industrial health 2019-03, Vol.35 (3), p.211-227
• Main Authors: Qi, Zhipeng, Mi, Chao, Wu, Fengdi, Yang, Xinxin, Sang, Yanqi, Liu, Yanan, Li, Jiashuo, Yang, Haibo, Xu, Bin, Liu, Wei, Xu, Zhaofa, Deng, Yu
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Astrocytes; Celecoxib; COX-2 inhibitors; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Cyclooxygenase-2; Dimethyl sulfoxide; Dinoprostone - genetics; Dinoprostone - metabolism; Disruption; Exposure; Gene expression; Genes; Glutamic acid receptors (metabotropic); Gonadotropin-releasing hormone; Gonadotropin-Releasing Hormone - genetics; Gonadotropin-Releasing Hormone - metabolism; Gonadotropins; Hypothalamus; Hypothalamus - drug effects; Manganese; Manganese - pharmacology; Mice; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Pituitary (anterior); Pretreatment; Prostaglandin E2; Proteins; Pyridines; Random Allocation; Receptor, Metabotropic Glutamate 5 - genetics; Receptor, Metabotropic Glutamate 5 - metabolism; RNA, Messenger - metabolism; Secretion; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Signaling; t-Butylhydroquinone
• ISSN: 0748-2337; 1477-0393
• DOI: 10.1177/0748233719825720

There are limited studies focused on the precise mechanism of gonadotropin-releasing hormone (GnRH) secretion dysfunction after overexposure to manganese (Mn). The objective of the present study was to explore the mechanism of Mn disruption of GnRH synthesis via nuclear factor erythroid-2-related factor-2 (Nrf2)/metabotropic glutamate receptor-5 (mGluR5)/cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) signaling pathway in vitro and in vivo. Primary astrocytes were cultured and treated with different doses of Mn, tert-butylhydroquinonet (tBHQ; Nrf2 agonists), 3-[(2-methyl-4-thaizolyl) ethynyl] pyridine (MTEP; mGluR5 inhibitor), and celecoxib (COX-2 inhibitor) to measure the levels of COX-2, mGluR5, Nrf2, and Nrf2 target genes. Mice were randomly divided into 11 groups, of which included the control group, 12.5-, 25-, and 50-mg/kg MnCl2 group, dimethyl sulfoxide (DMSO) group, tBHQ control group, tBHQ pretreatment group, MTEP control group, MTEP pretreatment group, celecoxib control group, and celecoxib pretreatment group. The injection was administered every day for 2 weeks. Then, levels of GnRH, PGE2, COX-2, mGluR5, Nrf2, Nrf2 target genes, and morphological changes in the hypothalamus of mice were measured. Mn reduced protein levels of Nrf2 and mRNA expression of Nrf2 target genes and increased mGluR5, COX-2, PGE2, and GnRH levels. Meanwhile, injury-related histomorphology changes in the hypothalamus of mice were significantly present. In conclusion, excessive exposure to Mn disrupts GnRH secretion through Nrf2/mGluR5/COX-2/PGE2 signaling pathway.