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Time and dose-dependent effects of phenobarbital on the rat liver miRNAome

Costas Koufaris1, Jayne Wright, Michael Osborne

  • 1Surgery and Cancer, Imperial College London, SW72AZ, UK; Department of Cytogenetics and Genomics, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.

Toxicology
|October 26, 2013
PubMed

Insights

Phenobarbital (PB) exposure in male Fischer rats showed limited liver microRNA (miRNA) effects acutely, but dose-dependent changes emerged with longer exposure, suggesting a role in maintaining liver homeostasis. Further research is needed for other chemicals.

Area of Science:

  • Toxicology
  • Molecular Biology
  • Hepatology

Background:

  • Previous studies demonstrated chemical-induced liver microRNA (miRNA) alterations in male Fischer rats.
  • Phenobarbital (PB) is a drug with known hepatic effects, making it a relevant model for toxicological studies.

Purpose of the Study:

  • To investigate the relationship between phenobarbital (PB) exposure duration and dose on liver miRNA in male Fischer rats.
  • To understand the temporal dynamics of miRNA responses to xenobiotic exposure.

Main Methods:

  • Male Fischer rats were treated with phenobarbital (PB) for varying durations (1-90 days) and doses.
  • Liver miRNA and mRNA expression levels were analyzed.
  • Liver phenotype, DNA methylation, and zeb1/zeb2 protein levels were assessed.

Main Results:

  • Acute PB treatment (1-7 days) caused significant liver mRNA changes and expected phenotypic effects but limited miRNA alterations.
  • Dose-dependent changes in liver miRNA were observed after 14 days of PB exposure.
  • Long-term PB exposure (up to 90 days) led to persistent induction of miR-200a/200b/429 and miR-96/182 clusters, and associations with DNA methylation and zeb1/zeb2 proteins were found for miR-29b and miR-200a/200b.

Conclusions:

  • MicroRNAs (miRNAs) are unlikely to be involved in the acute response of the adult rodent liver to PB.
  • The observed miRNA responses to sub-chronic and chronic PB exposure suggest a potential role in maintaining liver homeostasis against xenobiotic-induced perturbations.
  • Further studies across various chemicals are necessary to determine if these temporal and dose-dependent miRNA-toxicant interaction patterns are broadly applicable.
Keywords:
CARConstitutive Androstane ReceptorDosePBProliferationTemporalXenobioticmiRNAmicroRNAparts per millionperoxisome proliferator-activated receptorsphenobarbitalpparαppm

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