1. Early microRNA indicators of PPARα pathway activation in the liver
- Author
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Charles E. Wood, Brian N. Chorley, Virunya S. Bhat, Gleta Carswell, and Gail M. Nelson
- Subjects
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 - Abstract
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.
- Published
- 2020
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