Reduction of excessive unfolded protein response by 4-phenylbutyric acid may mitigate procymidone-induced testicular damage in mice by changing the levels of circRNA Scar and circZc3h4

by Selleckchem | Feb 08 2024

Procymidone (PCM) exposure below the no-observed-effect level triggers changes in circRNA Scar and circZc3h4 and overactivation of the unfolded protein response (UPR) in mice, culminating in testicular injury. The 4-phenyl butyric acid (4-PBA) is known to stabilize proteins and reduce the UPR. This study employed an in vitro system in which mouse testes were cultured with 1 × 10-5 M PCM and varying concentrations (0, 20, 40, and 80 mM) of 4-PBA; 4-week-old male mice were subsequently treated with 100 mg/kg/d PCM (suspended in corn oil) and/or 100 mg/kg/d 4-PBA for 21 d, consecutively. The treatments were as follows: the negative control (NC) group was orally administered corn oil; the positive control (PC) group was orally administered PCM; the 4-PBA group was intraperitoneally injected with 4-PBA; the 4-PBA-I group was orally administered PCM and 4-PBA simultaneously; the 4-PBA-II group received daily administration of 4-PBA 24 h prior to PCM; and the 4-PBA-III group was intraperitoneally injected with 4-PBA for 7 d after 21 d of PCM administration. However, the 4-PBA intervention groups showed no considerable changes in the overall or testicular appearance of mice. In vitro, 4-PBA inhibited the PCM-induced testicular injury, with the most significant effect observed at 80 mM. In vivo, the 4-PBA-III group exhibited the best in vivo effects. Our findings indicate that 4-PBA conferred testicular protection by decreasing PCM-induced circRNA Scar, elevating circZc3h4, and suppressing UPR both in vitro and in vivo. It has been hypothesized that 4-PBA mitigates testicular damage by reducing excessive UPR levels.

Comments:

It sounds like this study investigated the effects of procymidone (PCM) exposure on testicular injury in mice and explored the potential protective effects of 4-phenyl butyric acid (4-PBA) against PCM-induced damage.

Here's a breakdown of the study:

1. **Experiments:**
- **In Vitro:** Mouse testes were cultured with PCM and different concentrations of 4-PBA.
- **In Vivo:** Four-week-old male mice were treated with PCM, 4-PBA, or both for 21 consecutive days.

2. **Groups in the Experiment:**
   - **Negative Control (NC):** Administered corn oil only.
   - **Positive Control (PC):** Administered PCM.
   - **4-PBA Group:** Received 4-PBA injections.
   - **4-PBA-I Group:** Simultaneously administered PCM and 4-PBA.
   - **4-PBA-II Group:** Received 4-PBA 24 hours before PCM.
   - **4-PBA-III Group:** Injected with 4-PBA after 21 days of PCM administration.

3. **Observations:**
- **In Vitro:** 4-PBA inhibited PCM-induced testicular injury, especially at higher concentrations (80 mM).
- **In Vivo:** The 4-PBA-III group showed the most significant protective effects against testicular injury induced by PCM.

4. **Conclusion:**
- 4-PBA protected the testes by reducing PCM-induced changes in specific circRNAs (Scar and Zc3h4) and suppressing the unfolded protein response (UPR), both in vitro and in vivo.
- The hypothesis suggests that 4-PBA mitigates testicular damage by reducing excessive UPR levels triggered by PCM exposure.

This study indicates that 4-PBA has potential as a protective agent against testicular injury induced by PCM, particularly when administered after PCM exposure. The findings suggest a mechanism involving the regulation of specific circRNAs and the UPR pathway.