Home Blog of Signal Transduction Transmembrane Transporters CRM1 Heat stress upregulates aromatases expression through nuclear DAX-1 deficiency in R2C Leydig tumor cells

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Heat stress upregulates aromatases expression through nuclear DAX-1 deficiency in R2C Leydig tumor cells

An appropriate balance between testicular testosterone and estradiol is required for spermatogenesis. Excess estradiol is often identified in the semen and serum of infertile men; however, the mechanisms behind this observation remain unclear. This study indicates the relationship between heat stress and aromatase synthesis in Leydig cells. We used R2C rat Leydig tumor cells, which can synthesize both testosterone and estradiol. Aromatase transcription was regulated by the PⅡ promoter with or without heat stress. Heat stress at 40 °C increased aromatase expression and decreased testosterone to estradiol ratio and nuclear DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1), which is a suppressor of steroidogenic factor 1 (SF-1). Leptomycin B and KPT-185, a nuclear export inhibitor, prevented nuclear DAX-1 deficiency induced by heat stress and inhibited aromatase transcription. These results indicate that heat stress interferes with DAX-1-SF-1 interaction and induces SF-1-dependent aromatase transcription.

 

Comments:

The passage you provided describes a study investigating the relationship between heat stress and the synthesis of aromatase in Leydig cells, particularly in the context of testosterone and estradiol production. Here's a breakdown of the key points:

1. **Objective of the Study:**
   - The study aims to understand the mechanisms behind the observed increase in estradiol levels in the semen and serum of infertile men.

2. **Model Used:**
   - The researchers used R2C rat Leydig tumor cells in their study. These cells are capable of synthesizing both testosterone and estradiol.

3. **Effect of Heat Stress:**
   - Exposure to heat stress at 40 °C was found to increase the expression of aromatase.
   - Aromatase is an enzyme responsible for converting testosterone to estradiol.

4. **Hormonal Changes:**
   - Heat stress led to a decrease in the testosterone to estradiol ratio.
   - This hormonal imbalance could have implications for spermatogenesis and may contribute to infertility.

5. **Involvement of Nuclear DAX-1:**
   - Nuclear DAX-1, a suppressor of steroidogenic factor 1 (SF-1), was found to be decreased under heat stress conditions.
   - SF-1 is likely involved in the regulation of aromatase transcription.

6. **Prevention of Nuclear DAX-1 Deficiency:**
   - The study used substances called Leptomycin B and KPT-185, which are nuclear export inhibitors.
   - These substances prevented the deficiency of nuclear DAX-1 induced by heat stress.

7. **Mechanism of Action:**
   - The results suggest that heat stress interferes with the interaction between DAX-1 and SF-1.
   - This interference leads to SF-1-dependent aromatase transcription, potentially explaining the observed increase in estradiol levels.

In summary, the study suggests that heat stress can impact the balance between testosterone and estradiol by influencing the expression of aromatase in Leydig cells. The involvement of nuclear DAX-1 and SF-1 in this process highlights a potential mechanism by which heat stress affects hormonal regulation and may contribute to infertility in men.

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S7125 KPT-185 KPT-185 is a selective CRM1 inhibitor that induces growth inhibition and apoptosis in a panel of NHL cell lines with a median IC50 ~25 nM.

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CRM1