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Updated: Jun 1, 2026
Lung microRNA Profiling Across the Estrous Cycle in Ozone-exposed Mice
Published on: January 7, 2019
Involvement of microRNAs in dioxin-induced liver damage in the mouse
Wataru Yoshioka1, Wataru Higashiyama, Chiharu Tohyama
1Laboratory of Environmental Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
Abstract:
MicroRNA (miRNA) is a class of small RNA that functions as a negative regulator of gene expression. Human and mouse genomes encode over 1400 and 700 miRNAs, respectively, and most of the cellular pathways are considered to be modulated by miRNAs. However, the pathophysiological role of miRNAs is still largely unknown. Thus, we investigated the possible involvement of miRNAs in the toxic responses to xenobiotic chemicals. Here, we searched for miRNAs responsible for inducing liver damage in mice exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and found that miR-101a and miR-122 are differentially downregulated by TCDD in a time-dependent manner. Because miRNA exerts multiple actions by repressing its target genes, we quantified the target genes of miR-101a, such as cyclooxygenase-2 (COX-2), enhancer of zeste homolog 2, and cFos, and found the upregulation of these genes, which suggests that miR-101a downregulates the expressions of these genes in the mouse liver. A COX-2 selective inhibitor, NS-398, suppressed the onset of TCDD-induced liver damage. In conclusion, this study demonstrated that TCDD dysregulates the expression of miR101a and miR122 and that COX-2, a target gene of miR101a, plays a significant role in liver damage in mice exposed to TCDD.
Insights
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure downregulates microRNA-101a (miR-101a) and microRNA-122 (miR-122) in mice. Upregulated cyclooxygenase-2 (COX-2), a miR-101a target, contributes to TCDD-induced liver damage.
Area of Science:
- Toxicology
- Molecular Biology
- Gene Regulation
Background:
- MicroRNAs (miRNAs) are small RNAs regulating gene expression, with largely unknown roles in disease.
- Xenobiotic chemicals can disrupt cellular pathways, but their impact on miRNA expression and toxicity is under-investigated.
- 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent environmental toxicant known to cause various adverse effects.
Purpose of the Study:
- To investigate the role of miRNAs in the toxic responses to xenobiotic chemicals, specifically TCDD.
- To identify specific miRNAs and their target genes involved in TCDD-induced liver damage in mice.
- To elucidate the mechanism by which TCDD-induced miRNA dysregulation contributes to hepatotoxicity.
Main Methods:
- Mice were exposed to TCDD, and miRNA expression levels (miR-101a, miR-122) were quantified over time.
- Target genes of downregulated miRNAs, including cyclooxygenase-2 (COX-2), were identified and their expression levels measured.
- The effect of a COX-2 selective inhibitor (NS-398) on TCDD-induced liver damage was assessed.
Main Results:
- TCDD exposure led to a time-dependent downregulation of miR-101a and miR-122 in mouse liver.
- Target genes of miR-101a, such as COX-2, were significantly upregulated, indicating miRNA-mediated repression.
- Inhibition of COX-2 activity with NS-398 ameliorated TCDD-induced liver damage, implicating COX-2 in the toxic pathway.
Conclusions:
- TCDD dysregulates the expression of specific miRNAs, including miR-101a and miR-122, in the mouse liver.
- The upregulation of COX-2, a target gene of miR-101a, is a key mechanism contributing to TCDD-induced hepatotoxicity.
- Targeting miR-101a-regulated pathways, such as COX-2, may offer therapeutic strategies for TCDD toxicity.
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