Triclosan Suppresses Testicular Steroidogenesis via the miR-6321/JNK/ Nur77 Cascade

Cellular Physiology and Biochemistry

Mei Ha¹ 

关键词: miR-6321;    Nur77;    JNK/c-Jun pathway;    Testicular steroidogenesis;    Triclosan;   

DOI  :  10.1159/000495049

学科分类：分子生物学，细胞生物学和基因

来源: S Karger AG

【 摘 要 】

Background/Aims Triclosan (TCS), a broad-spectrum antibacterial and antifungal compound and an endocrine disruptor, has anti-androgenic properties and could adversely affect male reproduction and fertility. Methods To elucidate the underlying roles of miRNAs and the MAPK pathway in TCS-mediated repression of testicular steroidogenesis, Sprague-Dawley male rats were dosed daily with TCS for 31 days, and TM3 cells were exposed to TCS for 24 h after the pretreatments with the activator of JNK, Nur77 siRNA, or recombinant lentivirus vector for Nur77. Tissues and/or cells were analyzed by several techniques including transmission electron microscopy, lentivirus production, overexpression, gene silencing, luciferase reporter assay, chromatin immunoprecipitation, western blot, and real-time PCR. Results TCS caused histopathologic alterations in the testis and reduced plasma LH and testicular testosterone. TCS induced miR-6321 expression, which in turn depressed its target gene, Map3k1. The inhibition of Map3k1 subsequently inactivated its downstream JNK/c-Jun pathway. ChIP and qPCR assays confirmed that c-Jun directly bound to the Nur77 DNA promoter regions to regulate Nur77 expression. The knockdown and overexpression of Nur77 demonstrated that the JNK/c-Jun-mediated decline in the transcription and translation of Nur77 resulted in the depression of steroidogenic proteins including SRB1, StAR, and 3β-HSD. Intriguingly, the protein expressions of 5α-Reductases (SRD5A1 and SRD5A2) were also downregulated after TCS exposure. Conclusion Taken together, the miR-6321/Map3k1-regulated JNK/c-Jun/ Nur77 cascade contributes to TCS-caused suppression of testicular steroidogenesis, and the decrease in 5α-Reductase expressions may be the compensatory mechanism.

【 授权许可】

CC BY-NC-ND