Key Laboratory of Environmental Medicine Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing, China.
Key Laboratory of Environmental Medicine Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing, China.
Chemosphere. 2024 Aug;361:142499. doi: 10.1016/j.chemosphere.2024.142499. Epub 2024 May 31.
CPPD quinone (CPPDQ) is a member of PPDQs, which was widely distributed in different environments. Using Caenorhabditis elegans as an animal model, we here examined neurotoxicity and accumulation of CPPDQ and the underlying mechanism. After exposure to 0.01-10 μg/L CPPDQ, obvious body accumulation of CPDDQ was detected. Meanwhile, exposure to CPPDQ (0.01-10 μg/L) decreased head thrash, body bend, and forward turn, and increased backward turn. Nevertheless, only exposure to 10 μg/L CPPDQ induced neurodegeneration in GABAergic system. Exposure to CPPDQ (0.01-10 μg/L) further decreased expressions of daf-7 encoding TGF-β ligand, jnk-1 encoding JNK MAPK, and mpk-1 encoding ERK MAPK. Additionally, among examined G protein-coupled receptor (GPCR) genes, exposure to CPPDQ (0.01-10 μg/L) decreased dcar-1 expression and increased npr-8 expression. RNAi of daf-7, jnk-1, mpk-1, and dcar-1 resulted in susceptibility, and nhr-8 RNAi caused resistance to CPPDQ neurotoxicity and accumulation. Moreover, in CPPDQ exposed nematodes, RNAi of dcar-1 decreased jnk-1 and mpk-1 expressions, and RNAi of npr-8 increased mpk-1 expression. Therefore, exposure to CPPDQ potentially resulted in neurotoxicity by inhibiting TGF-β, JNK MAPK, and ERK MAPK signals. The inhibition in JNK MAPK and ERK MAPKs signals in CPPDQ exposed nematodes was further related to alteration in GPCRs of DCAR-1 and NHR-8 in nematodes.
CPPD 醌（CPPDQ）是 PPDQ 的成员，广泛分布于不同的环境中。本研究以秀丽隐杆线虫为动物模型，考察 CPPDQ 的神经毒性、体内蓄积及其作用机制。结果发现，暴露于 0.01-10μg/L CPPDQ 后，线虫体内 CPPDQ 蓄积明显；暴露于 0.01-10μg/L CPPDQ 后，线虫头部摆动、身体弯曲和向前翻转次数减少，向后翻转次数增加；仅 10μg/L CPPDQ 诱导 GABA 能神经元发生神经退行性病变；暴露于 0.01-10μg/L CPPDQ 进一步降低了 TGF-β 配体 daf-7、JNK MAPK 编码基因 jnk-1 和 ERK MAPK 编码基因 mpk-1 的表达。此外，在所检测的 G 蛋白偶联受体（GPCR）基因中，暴露于 0.01-10μg/L CPPDQ 降低了 dcar-1 的表达，增加了 npr-8 的表达。daf-7、jnk-1、mpk-1 和 dcar-1 的 RNAi 增加了线虫对 CPPDQ 的敏感性，而 nhr-8 的 RNAi 降低了线虫对 CPPDQ 的敏感性。此外，在暴露于 CPPDQ 的线虫中，dcar-1 的 RNAi 降低了 jnk-1 和 mpk-1 的表达，而 npr-8 的 RNAi 增加了 mpk-1 的表达。因此，CPPDQ 可能通过抑制 TGF-β、JNK MAPK 和 ERK MAPK 信号导致神经毒性。CPPDQ 暴露线虫中 JNK MAPK 和 ERK MAPK 信号的抑制与线虫中 DCAR-1 和 NHR-8 两种 GPCR 的改变有关。
