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CPU86017-RS attenuate hypoxia-induced testicular dysfunction in mice by normalizing androgen biosynthesis genes and
Guo-lin Zhang1, Feng Yu, De-zai Dai
1Faculty of Pharmacy, China Pharmaceutical University, Nanjing, China.
Aim:
Downregulation of androgen biosynthesis genes StAR (steroidogenic acute regulatory) and 3β-HSD (3β-hydroxysteroid dehydrogenase) contributes to low testosterone levels in hypoxic mice and is possibly related to increased expression of pro-inflammatory cytokines in the testis. The aim of this study is to investigate the effects of CPU86017-RS that block Ca(2+) influx on hypoxia-induced testis insult in mice.
Methods:
Male ICR mice were divided into 5 groups: control group, hypoxia group, hypoxia group treated with nifedipine (10 mg/kg), hypoxia groups treated with CPU86017-RS (60 or 80 mg/kg). Hypoxia was induced by placing the mice in a chamber under 10%±0.5% O2 for 28 d (8 h per day). The mice were orally administered with drug in the last 14 d. At the end of experiment the testes of the mice were harvested. The mRNA and protein levels of StAR, 3β-HSD, connexin 43 (Cx43), matrix metalloprotease 9 (MMP9), endothelin receptor A (ET(A)R) and leptin receptor (OBRb) were analyzed using RT-PCR and Western blotting, respectively. The malondialdehyde (MDA), lactate dehydrogenase (LDH), succinate dehydrogenase (SDH) and acid phosphatase (ACP) levels were measured using biochemical kits. Serum testosterone concentration was measured with radioimmunoassay.
Results:
Hypoxia significantly increased the MDA level, and decreased the LDH, ACP and SDH activities in testes. Meanwhile, hypoxia induced significant downregulation of StAR and 3β-HSD in testes responsible for reduced testosterone biosynthesis. It decreased the expression of Cx43, and increased the expression of MMP9, ETAR and OBRb, leading to abnormal testis function and structure. These changes were effectively diminished by CPU86017-RS (80 mg/kg) or nifedipine (10 mg/kg).
Conclusion:
Low plasma testosterone level caused by hypoxia was due to downregulation of StAR and 3β-HSD genes, in association with an increased expression of pro-inflammatory cytokines. These changes can be alleviated by CPU86017-RS or nifedipine.
Insights
Hypoxia lowers testosterone by downregulating StAR and 3β-HSD genes. CPU86017-RS and nifedipine treatments effectively reversed these hypoxia-induced testicular changes in mice.
Area of Science:
- Reproductive biology and toxicology
- Endocrinology and molecular mechanisms of hypoxia
Background:
- Hypoxia-induced testicular insult is linked to downregulated androgen biosynthesis genes, steroidogenic acute regulatory (StAR) and 3β-hydroxysteroid dehydrogenase (3β-HSD), leading to low testosterone.
- Increased pro-inflammatory cytokines may exacerbate testicular dysfunction under hypoxic conditions.
Purpose of the Study:
- To investigate the protective effects of CPU86017-RS, a calcium channel blocker, against hypoxia-induced testicular damage in mice.
- To elucidate the molecular mechanisms underlying hypoxia-induced alterations in testicular gene and protein expression.
Main Methods:
- Male ICR mice were exposed to hypoxia (10% O2) for 28 days, with treatments including nifedipine and CPU86017-RS.
- Analysis of testicular mRNA and protein levels for StAR, 3β-HSD, Cx43, MMP9, ETAR, and OBRb via RT-PCR and Western blotting.
- Biochemical assays measured oxidative stress markers (MDA) and enzyme activities (LDH, SDH, ACP); serum testosterone was quantified.
Main Results:
- Hypoxia increased MDA levels and altered LDH, ACP, and SDH activities, while downregulating StAR and 3β-HSD, reducing testosterone biosynthesis.
- Hypoxia altered the expression of Cx43, MMP9, ETAR, and OBRb, contributing to testicular dysfunction and structural abnormalities.
- CPU86017-RS (80 mg/kg) and nifedipine (10 mg/kg) treatments significantly ameliorated these hypoxia-induced changes.
Conclusions:
- Hypoxia-induced low testosterone levels are associated with StAR and 3β-HSD gene downregulation and increased pro-inflammatory cytokines.
- CPU86017-RS and nifedipine demonstrate potential therapeutic efficacy in mitigating hypoxia-related testicular damage.
