Microcystin-Leucine Arginine Causes Cytotoxic Effects in Sertoli Cells Resulting in Reproductive Dysfunction in Male Mice

Abstract

Microcystin-leucine arginine (MC-LR) is a potent toxin for Sertoli cells. However, the specific molecular mechanisms of MC-induced cytotoxicity still remain unclear. In this study, we performed a comprehensive analyses of changes of miRNAs and mRNAs in Sertoli cells treated with MC-LR. Through computational approaches, we showed the pivotal roles of differentially expressed miRNAs that were associated with cell metabolism, cellular growth and proliferation, cell-to-cell signaling and interaction and cellular movement. Ingenuity Pathway Analyses (IPA) revealed some differentially expressed miRNAs and mRNAs that may cause reproductive system diseases. Target gene analyses suggested that destruction in tight junctions (TJ) and adherens junctions (AJ) in testes may be mediated by miRNAs. Consistent with a significant enrichment of chemokine signaling pathways, we observed numerous macrophages in the testes of mice following treatment with MC-LR, which may cause testicular inflammation. Moreover, miR-98-5p and miR-758 were predicted to bind the 3′-UTR region of the mitogen-activated protein kinase 11 (MAPK11, p38 β isoform) gene which stimulates tumor necrosis factor-α (TNF-α) expression in Sertoli cells. TNF-α could interact with the tumor necrosis factor receptor 1 (TNFR1) on germ cells leading to induction of germ cell apoptosis. Collectively, our integrated miRNA/mRNA analyses provided a molecular paradigm, which was experimentally validated, for understanding MC-LR-induced cytotoxicity.

Resveratrol Ameliorates Microcystin-LR-Induced Testis Germ Cell Apoptosis in Rats via SIRT1 Signaling Pathway Activation

“…Accordingly, MC-LR has been shown to induce sperm abnormalities by downregulating miR-96 and altering deleted-in azoospermia-associated protein 2 (DAZAP2) expressions [ 12 ]. Chen et al found that MC-LR was cytotoxic to Sertoli cells by altering the expression of miRNAs and mRNAs [ 13 ]. In a previous study conducted by the investigators, it was demonstrated that Chinese hamster ovary (CHO) cell apoptosis after MC-LR treatment may be associated with the activation of endoplasmic reticulum stress (ERs) and autophagy [ 14 ].…”

Toxic metabolites, Sertoli cells and Y chromosome related genes are potentially linked to the reproductive toxicity induced by mequindox

“…Dysfunction of the BTB will lead to interference in spermatogenesis and infertility [ 21 , 22 ]. Tight junctions (TJs) that consist of Sertoli cells (SCs) are one of the most important components in the formation of the BTB and provide a microenvironment for spermatogonial stem cells [ 23 , 24 ]. Many studies have shown the critical role of SCs in the permeability of the BTB [ 25 ] and spermatogenesis [ 25 – 27 ].…”

Subcellular localization of microcystin in the liver and the gonads of medaka fish acutely exposed to microcystin-LR

“…Therefore, the high accumulation of MC-LR in the connective tissue and its subsequent toxic effect on gonadal somatic cells may indirectly disturb spermatogenesis process, affecting the reproductive process. Although Sertoli cell contributes to the formation of the blood-testis barrier (BTB) which hinders the diffusion of MCs into the spermatogenic microenvironment (Wan et al, 2013), a recent in vitro study reported that MC-LR can cause disruption of the tight junction between Sertoli cells, and destroy BTB (Chen et al, 2018(Chen et al, , 2016, implying that MC-LR could enter the spermatogenic microenvironment and subsequently induce apoptosis and degeneration in the spermatocyte. This could be one explanation for the accumulation of MC-LR in some degenerated spermatocyte-like structure observed here.…”