ABSTRACT: BACKGOUND: Drinking water can be contaminated with pharmaceuticals. However, it is uncertain whether this contamination can have harmful consequences for the liver, especially in the context of obesity. OBJECTIVES: To determine whether chronic, low dose exposure to pharmaceuticals could have deleterious effects in livers of lean and obese mice. METHODS: Lean and ob/ob male mice (5-week-old) were treated for 4 months with a mixture of 11 drugs (acetaminophen, caffeine, carbamazepine, cotinine, diclofenac, erythromycin, ibuprofen, phenazone, roxithromycin, salicylic acid and sulfamethoxazole) provided in drinking water at a concentration of 1 mg/L (for each drug). At the end of the treatment, investigations were performed in liver and plasma. RESULTS: Some liver and plasma abnormalities were observed in ob/ob mice treated with the cocktail containing 1 mg/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 indicated that expression of 8 different circadian genes was significantly modified in a dose-dependent manner. For some genes, a significant modification was observed for dosages as low as 100-1,000 ng/L. Drug mixture and obesity presented an additive effect on circadian gene expression. These data were confirmed in an independent study performed in female mice. CONCLUSIONS: Chronic, low dose exposure to pharmaceuticals disturbed hepatic expression of circadian genes, especially in obese mice. Because some of the 11 drugs can be found in the drinking water at such concentrations (e.g. acetaminophen, carbamazepine, ibuprofen) our data could be relevant in environmental toxicology, in particular for obese individuals exposed to these contaminants.
