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Diabetes-Induced Oxidative DNA Damage Alters p53-p21CIP1/Waf1 Signaling in the Rat Testis

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Abstract

Diabetes is increasingly becoming a major cause of large-scale morbidity and mortality. Diabetes-induced oxidative stress alters numerous intracellular signaling pathways. Although testicular dysfunction is a major concern in diabetic men, the mechanistic alterations in the testes that lead to hypogonadism are not yet clear. Oxidative mitochondrial DNA damage, as indicated by 7,8-dihydro-8-oxo-2′-deoxyguanosine, and phosphorylation of p53 at ser315 residue (p-p53ser315) increased in a stage- and cell-specific manner in the testes of rats that were diabetic for 1 month (DM1). Prolongation of diabetes for 3 months (DM3) led to an increase in nuclear oxidative DNA damage in conjunction with a decrease in the expression of p-p53ser315. The nuclei of pachytene and preleptotene spermatocytes, steps 1, 11, and 12 spermatids, secondary spermatocytes and the Sertoli cells, and the meiotic figures showed an increase in the expression of p-p53ser315. An increase in the expression of a downstream target of p53 and protein 21cyclin-dependent kinase interacting protein 1/wild-type p53-activated factor 1 (p21CIP1/Waf1) in both diabetic groups did not show any time-dependent effects but occurred concurrent with an upregulation of p-p53ser315 in DM1 and a downregulation of the protein in DM3. In diabetic groups, the expression of p21CIP1/Waf1 was mainly cytoplasmic but also perinuclear in pachytene spermatocytes and round spermatids. The cytoplasmic localization of p21CIP1/Waf1 may be suggestive of an antiapoptotic role for the protein. The perinuclear localization is probably related to the cell cycle arrest meant for DNA damage repair. Diabetes upregulates p21CIP1/Waf1 signaling in testicular germ cells in association with alteration in p-p53ser315 expression, probably to counteract DNA damage-induced cell death.

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Authors and Affiliations

  1. Department of Anatomy, Faculty of Medicine, Health Science Center, Kuwait University, PO Box 24923, 13110, Safat, Kuwait

    Narayana Kilarkaje PhD

  2. Department of Physiology, Faculty of Medicine, Health Science Center, Kuwait University, Kuwait

    Maie M. Al-Bader PhD

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Correspondence to Narayana Kilarkaje PhD.

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Kilarkaje, N., Al-Bader, M.M. Diabetes-Induced Oxidative DNA Damage Alters p53-p21CIP1/Waf1 Signaling in the Rat Testis. Reprod. Sci. 22, 102–112 (2015). https://doi.org/10.1177/1933719114533729

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