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

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

Author information

1
Departamento de Bioquímica and Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88040-970 Florianópolis, Santa Catarina, Brazil.
2
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
3
Departamento de Ecologia e Zoologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88040-970 Florianópolis, Santa Catarina, Brazil.
4
Departamento de Bioquímica and Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88040-970 Florianópolis, Santa Catarina, Brazil. Electronic address: ariane.zamoner@ufsc.br.

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

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