Chronic exposure to low doses of pharmaceuticals disturbs the hepatic expression of circadian genes in lean and obese mice

Toxicol Appl Pharmacol. 2014 Apr 1;276(1):63-72. doi: 10.1016/j.taap.2014.01.019. Epub 2014 Feb 11.

Abstract

Drinking water can be contaminated with pharmaceuticals. However, it is uncertain whether this contamination can be harmful for the liver, especially during obesity. Hence, the goal of our study was to determine whether chronic exposure to low doses of pharmaceuticals could have deleterious effects on livers of lean and obese mice. To this end, lean and ob/ob male mice were treated for 4 months with a mixture of 11 drugs provided in drinking water at concentrations ranging from 10 to 10⁶ ng/l. At the end of the treatment, some liver and plasma abnormalities were observed in ob/ob mice treated with the cocktail containing 10⁶ ng/l of each drug. For this dosage, a gene expression analysis by microarray showed altered expression of circadian genes (e.g. Bmal1, Dbp, Cry1) in lean and obese mice. RT-qPCR analyses carried out in all groups of animals confirmed that expression of 8 different circadian genes was modified in a dose-dependent manner. For some genes, a significant modification was observed for dosages as low as 10²-10³ ng/l. Drug mixture and obesity presented an additive effect on circadian gene expression. These data were validated in an independent study performed in female mice. Thus, our study showed that chronic exposure to trace pharmaceuticals disturbed hepatic expression of circadian genes, particularly in obese mice. Because some of the 11 drugs can be found in drinking water at such concentrations (e.g. acetaminophen, carbamazepine, ibuprofen) our data could be relevant in environmental toxicology, especially for obese individuals exposed to these contaminants.

Keywords: Circadian rhythm; Drug; Liver; Microarray; Mouse; Obesity.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / agonists
  • ARNTL Transcription Factors / antagonists & inhibitors
  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / metabolism
  • Animals
  • Cryptochromes / agonists
  • Cryptochromes / antagonists & inhibitors
  • Cryptochromes / genetics
  • Cryptochromes / metabolism
  • DNA-Binding Proteins / agonists
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Drug-Related Side Effects and Adverse Reactions*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects*
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Obesity / chemically induced
  • Obesity / metabolism*
  • Obesity / pathology
  • Oligonucleotide Array Sequence Analysis
  • Period Circadian Proteins / agonists
  • Period Circadian Proteins / antagonists & inhibitors
  • Period Circadian Proteins / genetics
  • Period Circadian Proteins / metabolism*
  • Pharmaceutical Preparations / administration & dosage*
  • Toxicity Tests, Chronic
  • Transcription Factors / agonists
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Water Pollutants, Chemical / administration & dosage*
  • Water Pollutants, Chemical / toxicity

Substances

  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • Cry1 protein, mouse
  • Cryptochromes
  • DNA-Binding Proteins
  • Dbp protein, mouse
  • Period Circadian Proteins
  • Pharmaceutical Preparations
  • Transcription Factors
  • Water Pollutants, Chemical