Microcystin-LR causes sexual hormone disturbance in male rat by targeting gonadotropin-releasing hormone neurons

Toxicon. 2016 Dec 1:123:45-55. doi: 10.1016/j.toxicon.2016.10.011. Epub 2016 Oct 20.

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.

Keywords: GT1-7 cells; GnRH neuron; Hormones; Microcystin-LR.

MeSH terms

  • Animals
  • Apoptosis
  • Calcium / metabolism
  • Cell Line
  • Gonadal Steroid Hormones / blood
  • Gonadal Steroid Hormones / metabolism*
  • Gonadotropin-Releasing Hormone / blood
  • Gonadotropin-Releasing Hormone / metabolism*
  • Hypothalamo-Hypophyseal System / drug effects
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Lethal Dose 50
  • Male
  • Marine Toxins
  • Microcystins / toxicity*
  • Neurons / drug effects*
  • Neurons / metabolism
  • Pituitary-Adrenal System / drug effects
  • Rats
  • Reproduction / drug effects

Substances

  • Gonadal Steroid Hormones
  • Marine Toxins
  • Microcystins
  • Gonadotropin-Releasing Hormone
  • cyanoginosin LR
  • Calcium