Microcystin-leucine-arginine induces apical ectoplasmic specialization disassembly
Dihui Xu1, Jing Wang1, Yuhan Ma1
1Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China.
Abstract:
Microcystin-leucine-arginine (MC-LR) has been identified to be a hazardous material to cause hepatotoxicity. In this study, mice were exposed to MC-LR dissolved in drinking water at doses of 1, 10, 20 and 30 μg/L for 90 and 180 days, respectively. We validated MC-LR accelerated spermatid exfoliation and caused large vacuoles in testes, reducing sperm count and increasing percentage of morphologically abnormal sperm. Furthermore, we found MC-LR induced the apical ectoplasmic specialization (ES) disassembly by disrupting F-actin organization. Further studies identified that downregulation of Palladin, the actin crosslinking protein, might be associated with disassembly of the apical ES in mice testis following MC-LR exposure. We also confirmed that MC-LR disrupted the interaction between Palladin and other actin-related proteins and thus impeded the F-actin organization. Additionally, we found that autophagy initiated by AMPK/ULK1 signaling pathway mediated the degradation of Palladin in Sertoli cells challenged with MC-LR. Following exposure to MC-LR, reduced PP2A activity and upregulated expression of LKB1 and CAMKK2 could activate AMPK. In conclusion, these results revealed MC-LR induced the degradation of Palladin via AMPK/ULK1-mediated autophagy, which might result in the apical ES disorder and spermatid exfoliation from spermatogenic epithelium. Our work may provide a new perspective to understand MC-LR-induced male infertility.
Insights
Microcystin-leucine-arginine (MC-LR) exposure in mice caused male infertility by damaging sperm and disrupting testicular structure. MC-LR triggers Palladin degradation via autophagy, leading to spermatid exfoliation.
Area of Science:
- Toxicology
- Reproductive Biology
- Cell Biology
Background:
- Microcystin-leucine-arginine (MC-LR) is a known hepatotoxin.
- MC-LR's impact on male reproductive health requires further investigation.
Purpose of the Study:
- To investigate the effects of MC-LR exposure on male mouse reproductive system.
- To elucidate the underlying molecular mechanisms of MC-LR-induced testicular damage.
Main Methods:
- Mice were exposed to varying doses of MC-LR (1-30 μg/L) for 90 and 180 days.
- Evaluated sperm count, morphology, and testicular histology.
- Investigated F-actin organization, Palladin expression, and autophagy-related signaling pathways (AMPK/ULK1).
Main Results:
- MC-LR exposure reduced sperm count and increased abnormal sperm morphology.
- MC-LR induced apical ectoplasmic specialization (ES) disassembly and Palladin downregulation.
- MC-LR activated the AMPK/ULK1 pathway, leading to Palladin degradation via autophagy in Sertoli cells.
Conclusions:
- MC-LR induces male infertility through Palladin degradation and apical ES disruption.
- AMPK/ULK1-mediated autophagy plays a key role in MC-LR toxicity in testes.
- This study provides insights into MC-LR-induced male reproductive toxicity.
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