Up-stream mechanisms for up-regulation of miR-125b from triclosan exposure to zebrafish (Danio rerio)

Abstract

A B S T R A C TTriclosan (TCS) exposure has widely adverse biological effects such as influencing biological reproduction and endocrine disorders. While some studies have addressed TCS-induced expression changes of miRNAs and their related down-stream target genes, no data are available concerning how TCS impairs miRNA expression leading us to study up-stream regulating mechanisms. Four miRNAs (miR-125b, miR-205, miR-142a and miR-203a) showed differential expression between TCS-exposure treatments and the control group; their functions mainly involved fatty acid synthesis and metabolism. TCS exposure led to the up-regulation of mature miR-125b that was concomitant with consistent changes in pri-mir-125b-1 and pri-mir-125b-3 among its 3 pri-mir-125bs. Upregulation of miR-125b originated from direct shear processes involving the two up-regulated precursors, but not pri-mir-125b2. Increased expression of pri-mir-125b-1 and pri-mir-125b-3 resulted from nfe2l2-and c/ebpα-integration with positive control elements of promoters for the two precursors. The overexpression of transcriptional factors, nfe2l2 and c/ebpα, initiated the promoter activity for the miR-125b precursor. CpG islands and Nfe2l2 were involved in constitutive expression of mir-125b-1 and mir-125b-3. The activities of two promoter regions, −487 to −1 bp for pri-mir-125b1 and −1327 to +14 bp for pri-mir-125b-3 having binding sites for NFE2 and Nfe2l2/MAF:NFE2, were higher than other regions, further demonstrating that the transcriptional factor Nfe2l2 was involved in the regulation of pri-mir-125b1 and pri-mir-125b-3. TCS's estrogen activity resulted from its effects on GPER, a novel membrane receptor, rather than the classical ERα and ERβ. These results explain, to some extent, the up-stream mechanism for miR-125b up-regulation, and also provide a guidance to future mechanistic study on TCS-exposure.

Lipid metabolism disorder induced by up-regulation of miR-125b and miR-144 following β-diketone antibiotic exposure to F0-zebrafish (Danio rerio)

“…These results from zebrafish are inconsistent with those in mice concerning changes in miR-125b and fat accumulation. Lin et al (2017) demonstrated that triclosan induced an estrogen effect that acted on the novel estrogen receptor GPER leading to over-expression of miR-125b and further hepatic steatosis, while not on the classical ERα and ERβ. It is assumed that miR-125b influences fat-metabolism disorders through estrogen effects; however, the receptors identified in various reports are different (Li et al, 2015;Lin et al, 2017).…”

“…Lin et al (2017) demonstrated that triclosan induced an estrogen effect that acted on the novel estrogen receptor GPER leading to over-expression of miR-125b and further hepatic steatosis, while not on the classical ERα and ERβ. It is assumed that miR-125b influences fat-metabolism disorders through estrogen effects; however, the receptors identified in various reports are different (Li et al, 2015;Lin et al, 2017). Currently, NAFLD is the most common chronic liver disease worldwide and is a major public health concern in modern society (De Alwis and Day, 2008;Liu et al, 2017).…”

Identification of receptors for eight endocrine disrupting chemicals and their underlying mechanisms using zebrafish as a model organism

“…In general, estrogens bind with two classes of receptors: nuclear hormone receptors (ERα and ERβ) that are ligand-dependent transcription factors, and the G protein-coupled estrogen receptor (GPER, also known as GPR30), an integral membrane protein. Lin et al (2017) reported that TCS acted on GPER, but not conventional receptors (ERα and ERβ). Additionally, high throughput RNA-seq identified differentially expressed genes induced by TCS or BPA exposure varied greatly because of their different estrogenic target molecules (Sun et al, 2020).…”

Lipid Metabolism Alteration by Endocrine Disruptors in Animal Models: An Overview

“…The expression of four miRNAs, miR-125b, miR-205, miR-142a, and miR-203a were significantly modulated by TCS in different experimental models both in vivo and in vitro ( 55 ), and resulted implicated in the downstream regulation of genes responsible for FA synthesis and metabolism. Moreover, in zebrafish, TCS was directly involved in the upstream regulation of miR-125b ( 68 ).…”