Triclosan Suppresses Testicular Steroidogenesis Via the miR6321/JNK/Nur77 Cascade

Abstract

Triclosan (TCS) has anti-androgenic properties and could adversely affect male reproduction and fertility. In vivo and in vitro studies were performed to elucidate the underlying roles of miRNAs and the MAPK pathway in TCS-mediated repression of testicular steroidogenesis. Results showed that TCS caused histopathologic alterations in testes and reduced the testicular steroid hormones including LH and testosterone. TCS induced miR-6321 expression, which in turn depressed its target gene, Map3k1. Inhibitions 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 Nur77 transcription and translation caused the depression of steroidogenic proteins including SRB1, StAR, and 3β-HSD. Intriguingly, protein expressions of 5α-Reductases (SRD5A1 and SRD5A2) were also downregulated. 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. Funding Statement: This work was funded by the Chongqing Population and Family Planning Science and Technology Research Institute (2016cstc-jbky-01701) and the Three Hundred Leading Talents in Scientific and Technological Innovation Program of Chongqing (CSTCCXLJRC201714). Declaration of Interests: The authors declare none. Ethics Approval Statement: Animal experiments were ratified by the Research Ethics Committee of Chongqing Population and Family Planning Science and Technology Research Institute.