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The dynamic changes of Nrf2 mediated oxidative stress, DNA damage and base excision repair in testis of rats during
Haixia Zhao1, Laixin Song2, Na Ma2
1College of Medical Science, China Three Gorges University, Yichang, Hubei 443002, PR China; Third-Grade Pharmacological Laboratory on Chinese Medicine Approved by State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, Hubei 443002, PR China.
Abstract:
Accumulation of oxidative stress, DNA damage and impaired DNA repair appear to play critical roles in the decline of testicular function with aging. However, when those factors begin to lose control in testis during aging has not yet been well understood. This study was designed to assess the changes of oxidative stress and DNA damage status, and DNA repair capacity in testis during aging. Thus, male Sprague-Dawley rats at 3, 9, 15 and 24 months of age were used to delineate the dynamic changes in testicular weight and index, testosterone concentration, testicular histology, Nrf2-mediated oxidative stress, DNA damage, DNA repair and apoptosis. Results showed that testicular weight and index, testosterone concentration and spermatid number progressively declined from 9 to 24 months of age. Similarly, seminiferous tubule diameters and seminiferous epithelium heights gradually diminished with aging. Nrf2-mediated antioxidant defense ability was significantly impaired in testis with increasing age including decreased the activity of SOD and the expression levels of Nrf2, HO-1 and NQO-1, and increased the contents of MDA. In addition, DNA damage including DNA single-strand breaks (SSBs) and DNA double-strand breaks (DSBs) also progressively increased accompanied by increased levels of 8-hydroxydeoxyguanosine (8-OHdG) and γ-H2AX, and activated ATM/Chk2 and ATR/Chk1 pathway. Consistent with the results of Nrf2 pathway, the expression levels of APE1, OGG1 and XRCC1 involved in base excision DNA repair (BER) pathway increased from 3 to 9 months of age, and then gradually decreased after 9 months of age. Finally, TUNEL and Western blot results further confirmed germ cell apoptosis progressively increased from 3 to 24 months of age as evidenced by decreased ratio of Bcl-2/Bax and levels of Bcl-2 expression, and increased Bax expression levels. Taken together, our results suggest that downregulation of antioxidant ability mediated by Nrf2 pathway and impairment of BER capacity might correlate with increased DNA damage, and then induce declining testicular function during aging after adult.
Insights
Aging impairs testicular function by reducing antioxidant defenses and DNA repair capacity, leading to increased DNA damage and germ cell apoptosis. These changes contribute to the decline in reproductive health over time.
Area of Science:
- Reproductive Biology
- Aging Research
- Molecular Toxicology
Background:
- Testicular function declines with age, linked to oxidative stress, DNA damage, and impaired repair.
- The precise timing of these failures in aging testes remains unclear.
Purpose of the Study:
- To assess age-related changes in oxidative stress, DNA damage, and DNA repair capacity in rat testes.
- To understand the dynamic interplay of these factors during testicular aging.
Main Methods:
- Male Sprague-Dawley rats (3, 9, 15, 24 months) were analyzed for testicular parameters.
- Evaluated testicular weight, testosterone, histology, Nrf2 pathway, DNA damage markers, DNA repair enzymes, and apoptosis.
Main Results:
- Testicular function, testosterone, and spermatid count declined from 9 months onwards.
- Antioxidant defense (Nrf2 pathway) weakened, while DNA damage (SSBs, DSBs, 8-OHdG, γ-H2AX) increased with age.
- Base excision repair (BER) capacity initially increased then decreased after 9 months, correlating with rising DNA damage.
Conclusions:
- Downregulation of Nrf2-mediated antioxidant defense and impaired BER capacity contribute to age-related testicular dysfunction.
- Increased DNA damage and germ cell apoptosis are key consequences of these molecular changes during aging.
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