Department of Ecology, Jinan University, Guangzhou, 510632, China.
Guangdong Laboratory Animals Monitoring Institute, Guangzhou, 510663, China.
Aquat Toxicol. 2022 Aug;249:106222. doi: 10.1016/j.aquatox.2022.106222. Epub 2022 Jun 15.
Paracetamol (APAP) is one of the most widely used non-steroidal anti-inflammatory drugs, which is frequently detected in various water bodies. Studies are limited about its toxic effects and mechanisms on non-target aquatic organisms. In this study, an estuarine bottom-dwelling fish named Mugilogobius chulae, distributed in southern China, was selected as experimental species and the changes of PXR signaling pathway, a key signaling pathway of detoxification metabolic system in liver, were investigated under APAP exposure (0.5 μg·L, 5 μg·L, 50 μg·L and 500 μg·L) for 24 h, 72 h and 168 h. Results showed that the key genes (e.g., P-gp, MRP1, CYP1A, CYP3A, GST and SULT) and the enzymatic activities of GST, EROD and ERND in PXR signaling pathway were induced to meet the requirements of detoxification metabolism. By up-regulating the expression of GCLC gene, the reductive small molecule GSH can be rapidly synthesized to counteract the attack of free radicals produced by APAP exposure. The expressions of SIRT1 and SIRT2 proteins decreased, while the expressions of most genes in PXR signaling pathway increased. It was speculated that the expression of PXR and its downstream target genes may be regulated epigenetically by SIRT1 and SIRT2. Studies showed that the exposure to environmental relevant concentrations of APAP can affect the detoxification metabolism of non-target organisms such as Mugilogobius chulae.
对乙酰氨基酚（APAP）是最广泛使用的非甾体抗炎药之一，经常在各种水体中被检测到。目前关于其对非靶标水生生物的毒性作用和机制的研究还很有限。在本研究中，选择了一种分布在中国南方的河口底层鱼类，即波纹唇鱼（ Mugilogobius chulae ）作为实验物种，研究了在对乙酰氨基酚（APAP）暴露（0.5μg·L、5μg·L、50μg·L 和 500μg·L）24h、72h 和 168h 后，肝脏解毒代谢系统的关键信号通路 PXR 信号通路的变化。结果表明，关键基因（如 P-gp、MRP1、CYP1A、CYP3A、GST 和 SULT）和 PXR 信号通路中的 GST、EROD 和 ERND 酶活性被诱导，以满足解毒代谢的要求。通过上调 GCLC 基因的表达，可以迅速合成还原性小分子 GSH，以抵抗 APAP 暴露产生的自由基的攻击。SIRT1 和 SIRT2 蛋白的表达减少，而 PXR 信号通路中的大多数基因的表达增加。据推测，SIRT1 和 SIRT2 可能通过表观遗传调控 PXR 及其下游靶基因的表达。研究表明，环境相关浓度的 APAP 暴露会影响非靶标生物如波纹唇鱼的解毒代谢。
