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Volume 20, Issue 6 (November 2018) 20, 600–607; 10.4103/aja.aja_29_18

Nitrosative stress in human spermatozoa causes cell death characterized by induction of mitochondrial permeability transition-driven necrosis

Pamela Uribe1,2,3, María E Cabrillana4,5, Miguel W Fornés4,5, Favián Treulen1, Rodrigo Boguen1, Vladimir Isachenko6, Evgenia Isachenko6, Raúl Sánchez2,7, Juana V Villegas1,3

1 Center of Reproductive Biotechnology - Scientific and Technological Bioresource Nucleus (CEBIOR - BIOREN), University of La Frontera, Temuco 4811230, Chile
2 Center of Excellence in Translational Medicine, University of La Frontera, Temuco 4810296, Chile
3 Department of Internal Medicine, Faculty of Medicine, University of La Frontera, Temuco 4781218, Chile
4 Laboratory of Andrology Research of Mendoza (LIAM) Institute of Histology and Embriology of Mendoza (IHEM) Histology and Embryology Area, Department of Morphology and Physiology, School of Medicine, National University of Cuyo and CCT-Mendoza, CONICET, Mendoza 5500, Argentina
5 Research Institute (CIUDA), Medicine Faculty, Aconcagua University, Mendoza 5500, Argentina
6 Research Group for Reproductive Medicine, Cologne University Cologne 50937, Germany
7 Department of Preclinical Sciences, Faculty of Medicine, University of La Frontera, Temuco 4781218, Chile

Correspondence: Dr. JV Villegas (juana.villegas@ufrontera.cl)

Date of Submission 07-Sep-2017 Date of Acceptance 26-Mar-2018 Date of Web Publication 22-Jun-2018


Peroxynitrite is a highly reactive nitrogen species and a potent inducer of apoptosis and necrosis in somatic cells. Peroxynitrite-induced nitrosative stress has emerged as a major cause of impaired sperm function; however, its ability to trigger cell death has not been described in human spermatozoa. The objective here was to characterize biochemical and morphological features of cell death induced by peroxynitrite-mediated nitrosative stress in human spermatozoa. For this, spermatozoa were incubated with and without (untreated control) 3-morpholinosydnonimine (SIN-1), in order to generate peroxynitrite. Sperm viability, mitochondrial permeability transition (MPT), externalization of phosphatidylserine, DNA oxidation and fragmentation, caspase activation, tyrosine nitration, and sperm ultrastructure were analyzed. The results showed that at 24 h of incubation with SIN-1, the sperm viability was significantly reduced compared to untreated control (P < 0.001). Furthermore, the MPT was induced (P < 0.01) and increment in DNA oxidation (P < 0.01), DNA fragmentation (P < 0.01), tyrosine nitration (P < 0.0001) and ultrastructural damage were observed when compared to untreated control. Caspase activation was not evidenced, and although phosphatidylserine externalization increased compared to untreated control (P < 0.001), this process was observed in <10% of the cells and the gradual loss of viability was not characterized by an important increase in this parameter. In conclusion, peroxynitrite-mediated nitrosative stress induces the regulated variant of cell death known as MPT-driven necrosis in human spermatozoa. This study provides a new insight into the pathophysiology of nitrosative stress in human spermatozoa and opens up a new focus for developing specific therapeutic strategies to better preserve sperm viability or to avoid cell death.

Keywords: necrosis; nitrosative stress; oxidative stress; peroxynitrite; sperm cell death

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