Role of Peroxisome Proliferator‐activated Receptor‐gamma in Type 2 Diabetes‐induced Testicular DNA Damage and Repair in Leptin Receptor‐deficient Obese Mice

Abstract

The DNA damage repair mechanisms under hyperglycemic conditions are a subject of intense research as unrepaired DNA damage may enhance the possibility of carcinogenicity in diabetic patients. In this study, we investigated the role of peroxisome proliferator‐activated receptor‐gamma (PPARγ) in diabetes‐induced alterations in testicular functions and DNA damage and repair. Leptin signaling intact lean (heterozygous; db+/db−) and leptin receptor‐mutant (db−/db−) obese male mice (7‐week‐old; n=10/group) received either pioglitazone (a PPARγ agonist) or 2‐chloro‐5‐nitro‐N‐phenylbenzamide (a PPARγ antagonist) for 84 days (12 weeks) to modulate the receptor activities. Semi‐quantification of 4‐hydroxynonenal and 8‐oxo‐dG levels meassured the oxidative stress, and the TUNEL assay measured apoptotic testicular cells. Western blotting technique quantified the levels of base‐excision repair (BER) pathway proteins‐8‐oxoguanine glycosylases 1&2, apurinic/apyrimidinic endonuclease, DNA polymerase δ, poly (ADP‐ribose) polymerase 1 and X‐ray repair cross‐complementing protein‐1. PPARγ activation increased the body weights and reduced the blood glucose levels, but inhibition of PPARγ activities did not significantly affect these parameters in obese diabetic mice. Inhibition of PPARγ activities improved testis and epididymis weights and sperm counts in obese diabetic mice. The obese diabetic mice showed seminiferous tubular degeneration, epithelial sloughing and tubular atrophy and, modulation of PPARγ activities did not significantly protect testicular structure and function. The lack of leptin signaling in obese diabetic mice increased oxidative stress and oxidative DNA damage, and stimulation of PPARγ activities reduced only lipid peroxidation, and inhibition of PPARγ activities inhibited both lipid peroxidation and oxidative DNA damage. The obese diabetic mice showed upregulated base excision repair proteins to repair the increased oxidative DNA damage. PPARγ stimulation inhibited the DNA damage repair indicating its detrimental effects, and the inhibition of PPARγ activities led to inhibition of DNA damage repair in conjunction with reduced oxidative DNA damage. However, regardless of these modulatory effects of PPARγ, the obese diabetic mice showed comparable levels of apoptosis in their testes. In conclusion, PPARγ activation although reduces blood glucose levels, in the absence of leptin signaling upregulates DNA damage and inhibits base excision repair mechanisms in the testis. The inhibited PPARγ activities in the absence of leptin signaling are beneficial to protect the testicular functions in obese diabetic mice.Support or Funding InformationSupported by Kuwait University grant # YM05/17 and CGS.