Roundup disrupts male reproductive functions by triggering calcium-mediated cell death in rat testis and Sertoli cells

Free Radic Biol Med. 2013 Dec;65:335-346. doi: 10.1016/j.freeradbiomed.2013.06.043. Epub 2013 Jun 29.

Abstract

Glyphosate is the primary active constituent of the commercial pesticide Roundup. The present results show that acute Roundup exposure at low doses (36 ppm, 0.036 g/L) for 30 min induces oxidative stress and activates multiple stress-response pathways leading to Sertoli cell death in prepubertal rat testis. The pesticide increased intracellular Ca(2+) concentration by opening L-type voltage-dependent Ca(2+) channels as well as endoplasmic reticulum IP3 and ryanodine receptors, leading to Ca(2+) overload within the cells, which set off oxidative stress and necrotic cell death. Similarly, 30 min incubation of testis with glyphosate alone (36 ppm) also increased (45)Ca(2+) uptake. These events were prevented by the antioxidants Trolox and ascorbic acid. Activated protein kinase C, phosphatidylinositol 3-kinase, and the mitogen-activated protein kinases such as ERK1/2 and p38MAPK play a role in eliciting Ca(2+) influx and cell death. Roundup decreased the levels of reduced glutathione (GSH) and increased the amounts of thiobarbituric acid-reactive species (TBARS) and protein carbonyls. Also, exposure to glyphosate-Roundup stimulated the activity of glutathione peroxidase, glutathione reductase, glutathione S-transferase, γ-glutamyltransferase, catalase, superoxide dismutase, and glucose-6-phosphate dehydrogenase, supporting downregulated GSH levels. Glyphosate has been described as an endocrine disruptor affecting the male reproductive system; however, the molecular basis of its toxicity remains to be clarified. We propose that Roundup toxicity, implicated in Ca(2+) overload, cell signaling misregulation, stress response of the endoplasmic reticulum, and/or depleted antioxidant defenses, could contribute to Sertoli cell disruption in spermatogenesis that could have an impact on male fertility.

Keywords: Calcium homeostasis; Cell death; Cell signaling; Free radicals; Glyphosate; Oxidative stress; Roundup; Sertoli cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Calcium / metabolism
  • Glycine / analogs & derivatives*
  • Glycine / toxicity
  • Herbicides / toxicity*
  • Male
  • Necrosis / chemically induced
  • Oxidative Stress / physiology
  • Rats
  • Rats, Wistar
  • Sertoli Cells / drug effects*
  • Sertoli Cells / pathology
  • Testis / drug effects*
  • Testis / pathology

Substances

  • Herbicides
  • glyphosate
  • Calcium
  • Glycine