Early microRNA indicators of PPARα pathway activation in the liver
| Autor: | Charles E. Wood, Brian N. Chorley, Virunya S. Bhat, Gleta Carswell, Gail M. Nelson |
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| Rok vydání: | 2020 |
| Předmět: |
microRNAs: Potential biomarkers of toxicity
BMD benchmark dose Nrf2 nuclear receptor erythroid 2-like 2 Hepatocellular carcinoma Health Toxicology and Mutagenesis AST aspartate aminotransferase 010501 environmental sciences Pharmacology Toxicology TMM trimmed mean of M-values 01 natural sciences DEmiRs differentially expressed miRNAs chemistry.chemical_compound AOP adverse outcome pathway 0302 clinical medicine tRNA transfer RNA Acox1 acyl-Coenzyme A oxidase 1 BMDA apical-based benchmark dose GEO Gene Expression Omnibus Benchmark dose (BMD) Receptor Regulation of gene expression Liver injury PXR pregnane X receptor Phthalate POD point-of-departure Peroxisome AIC Akaike Information Criterion mRNA messenger RNA rRNA ribosomal RNA mtDNA mitochondrial AhR aryl hydrocarbon receptor smallRNA-seq small RNA sequencing CAR constitutive androstane receptor BBP n-butyl benzyl phthalate PROD pentoxyresorufin O-depentylation Liver toxicity DEGs differentially expressed genes EPA U.S. Environmental Protection Agency BMDL BMD lower confidence interval Peroxisome proliferator-activated receptor alpha (PPARα) Biology BROD benzyloxyresorufin O-debenzylation 03 medical and health sciences lcsh:RA1190-1270 ALT alanine aminotransferase microRNA medicine miRNAs microRNAs Mode of action (MOA) Potency BMR benchmark response ddPCR droplet digital polymerase chain reaction lcsh:Toxicology. Poisons IPA Ingenuity Pathway Analysis 0105 earth and related environmental sciences DEHP di (2-thylhexyl) phthalate PPARα peroxisome proliferator-activated receptor alpha Activator (genetics) MOA mode of action Adverse outcome pathway (AOP) medicine.disease MicroRNAs HCA hepatocellular adenoma chemistry BMDT transcriptional-based benchmark dose EROD ethoxyresorufin O-dealkylation HCC hepatocellular carcinoma DNOP di-n-octyl phthalate SDH sorbitol dehydrogenase Biomarkers 030217 neurology & neurosurgery |
| Zdroj: | Toxicology Reports Toxicology Reports, Vol 7, Iss, Pp 805-815 (2020) |
| ISSN: | 2214-7500 |
| DOI: | 10.1016/j.toxrep.2020.06.006 |
| Popis: | MicroRNAs (miRNAs) are short non-coding RNA species that play key roles in post-transcriptional regulation of gene expression. MiRNAs also serve as a promising source of early biomarkers for different environmental exposures and health effects, although there is limited information linking miRNA changes to specific target pathways. In this study, we measured liver miRNAs in male B6C3F1 mice exposed to a known chemical activator of the peroxisome proliferator-activated receptor alpha (PPARα) pathway, di(2-ethylhexyl) phthalate (DEHP), for 7 and 28 days at concentrations of 0, 750, 1500, 3000, or 6000 ppm in feed. At the highest dose tested, DEHP altered 61 miRNAs after 7 days and 171 miRNAs after 28 days of exposure, with 48 overlapping miRNAs between timepoints. Analysis of these 48 common miRNAs indicated enrichment in PPARα–related targets and other pathways related to liver injury and cancer. Four of the 10 miRNAs exhibiting a clear dose trend were linked to the PPARα pathway: mmu-miRs-125a-5p, -182−5p, -20a−5p, and -378a−3p. mmu-miRs-182−5p and -378a−3p were subsequently measured using digital drop PCR across a dose range for DEHP and two related phthalates with weaker PPARα activity, di-n-octyl phthalate and n-butyl benzyl phthalate, following 7-day exposures. Analysis of mmu-miRs-182−5p and -378a−3p by transcriptional benchmark dose analysis correctly identified DEHP as having the greatest potency. However, benchmark dose estimates for DEHP based on these miRNAs (average 163; range 126−202 mg/kg-day) were higher on average than values for PPARα target genes (average 74; range 29−183 mg/kg-day). These findings identify putative miRNA biomarkers of PPARα pathway activity and suggest that early miRNA changes may be used to stratify chemical potency. |
| Databáze: | OpenAIRE |
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