title: Microcystin-LR causes sexual hormone disturbance in male rat by targeting gonadotropin-releasing hormone neurons.
abstract: Microcystin-LR (MC-LR), which generates strong reproductive toxicity, reduces serum testosterone level without directly damaging Leydig cells. The purpose of this study was to identify the target cells of MC-LR in the rat hypothalamic-pituitary axis and to investigate the underlying mechanisms. We found that the gonadotropin-releasing hormone (GnRH) neurons were the direct target of MC-LR. In vivo results showed that upon exposure to rats, cells around the third ventricle of hypothalamus underwent apoptosis. Gnrh1 expression was steadily decreased. The serum levels of GnRH, luteinizing hormone, follicle-stimulating hormone and testosterone showed a similar pattern of early-stage increase and late-stage decline. After treatment with MC-LR in immortalized hypothalamic (GT1-7) neurons, increase in cellular Ca2+and ATP resulted in downregulation of the transcriptional activators Oct-1, Otx-2, Pbx1a and Dlx2, and upregulation of the transcriptional repressor c-Jun, which may mechanistically account for the downregulation of GnRH synthesis. Ca2+and ATP could also stimulate the release of GnRH, contributing to its unique serum release pattern.
authors: Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China; Institute of Nautical Medicine, Nantong University, Nantong, Jiangsu 226019, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, China; State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, China.
authors: Xueting
authors: X
authors: Wang
authors: Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, China; State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, China.
authors: Jie
authors: J
authors: Ding
authors: Department of Microbiology and Immunology, Mucosal Immunobiology and Vaccine Research Center, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
authors: Zou
authors: Z
authors: Xiang
authors: Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China.
authors: Peipei
authors: P
authors: Jiang
authors: Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China.
authors: Jing
authors: J
authors: Du
authors: Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, China; State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, China. Electronic address: hanxd@nju.edu.cn.
authors: Xiaodong
authors: X
authors: Han
mesh_terms: D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D012739:Gonadal Steroid Hormones / Q000097:blood / Q000378:metabolism*; D007987:Gonadotropin-Releasing Hormone / Q000097:blood / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007928:Lethal Dose 50; D008297:Male; D008387:Marine Toxins; D052998:Microcystins / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects; D051381:Rats; D012098:Reproduction / Q000187:drug effects
chemical_list: D012739:Gonadal Steroid Hormones; D008387:Marine Toxins; D052998:Microcystins; D007987:Gonadotropin-Releasing Hormone; C057862:cyanoginosin LR; D002118:Calcium
keywords: GT1-7 cells; GnRH neuron; Hormones; Microcystin-LR