Diabetes-induced DNA damage and apoptosis are associated with poly (ADP ribose) polymerase 1 inhibition in the rat testis.
Molecular mechanisms responsible for diabetes-induced testicular dysfunction are not well understood. This study investigated oxidative stress, stage-dependent DNA base modification and expression of poly (ADP ribose) polymerase 1 (PARP1) in the testes of streptozotocin-induced diabetic rats. Hyperglycemia led to testicular dysfunction characterized by impaired sperm parameters and testicular structure at the end of first (DM1) and third (DM3) month after the induction of diabetes. In the testis, total oxidant levels increased and total antioxidant levels decreased, which led to the induction of oxidative stress status. The oxidative stress up-regulated the levels of 8-oxo-7, 8-dihydro-2'-deoxyguanosine - an oxidized form of the DNA base, deoxyguanosine - in a stage-dependent manner. In DM1, stage VII-IX tubules showed more cytoplasmic expression of 8-oxo-7, 8-dihydro-2'-deoxyguanosine in all germ cell types and the Sertoli cells than did the other stage tubules, which suggested mitochondrial DNA damage. In DM3, mainly a stage-dependent nuclear expression of 8-oxo-7, 8-dihydro-2'-deoxyguanosine was observed in germ cells, but not in the Sertoli cells. Diabetes increased the cytoplasmic expression of 4-hydroxynonenal and concurrently inhibited the expression of both full length and 89kDa large cleaved-fragment of PARP1 in DM1 and DM3. The germ and Sertoli cells showed the nuclear expression of the protein in a stage-dependent manner, which decreased from DM1 to DM3. The increase in oxidative DNA damage and a decrease in PARP1 led to a stage-dependent induction of apoptosis of testicular cells. In conclusion, diabetes-induced oxidative stress, oxidative DNA damage and apoptosis occur in parallel with PARP1 inhibition in the testis.
Department of Anatomy, Faculty of Medicine, Health Science Center, Kuwait University, Kuwait. Electronic address: knarayana@hsc.edu.kw.
Narayana
N
Kilarkaje
Department of Anatomy, Faculty of Medicine, Health Science Center, Kuwait University, Kuwait.
Heba
H
Al-Hussaini
Department of Physiology, Faculty of Medicine, Health Science Center, Kuwait University, Kuwait.
Maie M
MM
Al-Bader
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D017209:Apoptosis; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D015971:Gene Expression Regulation, Enzymologic; D008297:Male; D009929:Organ Size; D018384:Oxidative Stress; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction; D012670:Seminiferous Epithelium / Q000473:pathology; D012708:Sertoli Cells / Q000473:pathology; D013076:Sperm Count; D013081:Sperm Motility; D013094:Spermatozoa / Q000473:pathology / Q000502:physiology; D013737:Testis / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology
D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000080242:8-Hydroxy-2'-Deoxyguanosine; D011065:Poly(ADP-ribose) Polymerases; D003849:Deoxyguanosine
DNA damage; DNA repair; Germ cell apoptosis; Hyperglycemia; Hypogonadism; Infertility