Cargando…
Early microRNA indicators of PPARα pathway activation in the liver
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 cha...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334544/ https://www.ncbi.nlm.nih.gov/pubmed/32642447 http://dx.doi.org/10.1016/j.toxrep.2020.06.006 |
_version_ | 1783553948812050432 |
---|---|
author | Chorley, Brian N. Carswell, Gleta K. Nelson, Gail Bhat, Virunya S. Wood, Charles E. |
author_facet | Chorley, Brian N. Carswell, Gleta K. Nelson, Gail Bhat, Virunya S. Wood, Charles E. |
author_sort | Chorley, Brian N. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7334544 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-73345442020-07-07 Early microRNA indicators of PPARα pathway activation in the liver Chorley, Brian N. Carswell, Gleta K. Nelson, Gail Bhat, Virunya S. Wood, Charles E. Toxicol Rep microRNAs: Potential biomarkers of toxicity 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. Elsevier 2020-06-23 /pmc/articles/PMC7334544/ /pubmed/32642447 http://dx.doi.org/10.1016/j.toxrep.2020.06.006 Text en http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | microRNAs: Potential biomarkers of toxicity Chorley, Brian N. Carswell, Gleta K. Nelson, Gail Bhat, Virunya S. Wood, Charles E. Early microRNA indicators of PPARα pathway activation in the liver |
title | Early microRNA indicators of PPARα pathway activation in the liver |
title_full | Early microRNA indicators of PPARα pathway activation in the liver |
title_fullStr | Early microRNA indicators of PPARα pathway activation in the liver |
title_full_unstemmed | Early microRNA indicators of PPARα pathway activation in the liver |
title_short | Early microRNA indicators of PPARα pathway activation in the liver |
title_sort | early microrna indicators of pparα pathway activation in the liver |
topic | microRNAs: Potential biomarkers of toxicity |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334544/ https://www.ncbi.nlm.nih.gov/pubmed/32642447 http://dx.doi.org/10.1016/j.toxrep.2020.06.006 |
work_keys_str_mv | AT chorleybriann earlymicrornaindicatorsofpparapathwayactivationintheliver AT carswellgletak earlymicrornaindicatorsofpparapathwayactivationintheliver AT nelsongail earlymicrornaindicatorsofpparapathwayactivationintheliver AT bhatvirunyas earlymicrornaindicatorsofpparapathwayactivationintheliver AT woodcharlese earlymicrornaindicatorsofpparapathwayactivationintheliver |