INSERM, U991, Université de Rennes 1, 35000 Rennes, France.
Pathology Department, Saint-Joseph University, Beirut, Lebanon.
Toxicol Appl Pharmacol. 2014 Apr 1;276(1):63-72. doi: 10.1016/j.taap.2014.01.019. Epub 2014 Feb 11.
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.
饮用水可能会受到药物的污染。然而，尚不清楚这种污染是否会对肝脏造成危害，尤其是在肥胖的情况下。因此，我们的研究目的是确定慢性暴露于低剂量药物是否会对瘦鼠和肥胖鼠的肝脏造成有害影响。为此，我们用饮用水中浓度范围为 10 到 10⁶ ng/L 的 11 种药物混合物对 lean 和 ob/ob 雄性小鼠进行了 4 个月的治疗。在治疗结束时，在接受含有每种药物 10⁶ ng/L 的鸡尾酒治疗的 ob/ob 小鼠中观察到一些肝脏和血浆异常。对于该剂量，通过微阵列进行的基因表达分析显示，瘦鼠和肥胖鼠的昼夜节律基因（如 Bmal1、Dbp、Cry1）表达发生改变。在所有动物组中进行的 RT-qPCR 分析证实，8 种不同的昼夜节律基因的表达以剂量依赖的方式发生改变。对于一些基因，在低至 10²-10³ ng/L 的剂量下就观察到了显著的修饰。药物混合物和肥胖对昼夜节律基因表达有相加作用。这些数据在对雌性小鼠进行的独立研究中得到了验证。因此，我们的研究表明，慢性暴露于痕量药物会扰乱肝脏中昼夜节律基因的表达，尤其是在肥胖的小鼠中。由于在饮用水中可以发现 11 种药物中的一些药物，浓度达到如此水平（例如对乙酰氨基酚、卡马西平、布洛芬），我们的数据在环境毒理学中可能是相关的，特别是对于接触这些污染物的肥胖个体。
