Key Laboratory of Environmental Medicine Engineering of Ministry of Education, Medical School, Southeast University, Nanjing, China.
Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China.
J Hazard Mater. 2024 Jun 5;471:134356. doi: 10.1016/j.jhazmat.2024.134356. Epub 2024 Apr 19.
Exposure to N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6-PPDQ) caused toxicity on Caenorhabditis elegans, including reproductive toxicity. However, the underlying mechanisms for this induced reproductive toxicity by 6-PPDQ remain largely unclear. We examined possible association of ferroptosis activation with reproductive toxicity of 6-PPDQ. In 1-100 μg/L 6-PPDQ exposed nematodes, Fe content was increased, which was accompanied with enhanced lipid peroxidation, increased malonydialdehyde (MDA) content, and decreased L-glutathione (GSH) content. Exposure to 1-100 μg/L 6-PPDQ decreased expressions of ftn-1 encoding ferritin, ads-1 encoding AGPS, and gpx-6 encoding GPX4 and increased expression of bli-3 encoding dual oxidase. After 6-PPDQ exposure, RNAi of ftn-1 decreased ads-1 and gpx-6 expressions and increased bli-3 expression. RNAi of ftn-1, ads-1, and gpx-6 strengthened alterations in ferroptosis related indicators, and RNAi of bli-3 suppressed changes of ferroptosis related indicators in 6-PPDQ exposed nematodes. Meanwhile, RNAi of ftn-1, ads-1, and gpx-6 induced susceptibility, and RNAi of bli-3 caused resistance to 6-PPDQ reproductive toxicity. Moreover, expressions of DNA damage checkpoint genes (clk-2, mrt-2, and hus-1) could be increased by RNAi of ftn-1, ads-1, and gpx-6 in 6-PPDQ exposed nematodes. Therefore, our results demonstrated activation of ferroptosis in nematodes exposed to 6-PPDQ at environmentally relevant concentrations, and this ferroptosis activation was related to reproductive toxicity of 6-PPDQ.
N-(1,3-二甲基丁基)-N'-苯基对苯二胺醌（6-PPDQ）暴露会导致秀丽隐杆线虫产生毒性，包括生殖毒性。然而，6-PPDQ 诱导生殖毒性的潜在机制在很大程度上仍不清楚。我们研究了铁死亡激活与 6-PPDQ 生殖毒性之间可能的关联。在 1-100μg/L 的 6-PPDQ 暴露线虫中，铁含量增加，伴随着脂质过氧化增强，丙二醛（MDA）含量增加，L-谷胱甘肽（GSH）含量减少。暴露于 1-100μg/L 的 6-PPDQ 会降低编码铁蛋白的 ftn-1、编码 AGPS 的 ads-1 和编码 GPX4 的 gpx-6 的表达，并增加编码双氧化酶的 bli-3 的表达。在 6-PPDQ 暴露后，ftn-1 的 RNAi 降低了 ads-1 和 gpx-6 的表达，并增加了 bli-3 的表达。ftn-1、ads-1 和 gpx-6 的 RNAi 增强了铁死亡相关指标的变化，而 bli-3 的 RNAi 抑制了 6-PPDQ 暴露线虫中铁死亡相关指标的变化。同时，ftn-1、ads-1 和 gpx-6 的 RNAi 诱导了对 6-PPDQ 生殖毒性的敏感性，而 bli-3 的 RNAi 导致了对 6-PPDQ 生殖毒性的抗性。此外，ftn-1、ads-1 和 gpx-6 的 RNAi 可在 6-PPDQ 暴露线虫中增加 DNA 损伤检查点基因（clk-2、mrt-2 和 hus-1）的表达。因此，我们的结果表明，在环境相关浓度的 6-PPDQ 暴露下，线虫中铁死亡的激活与 6-PPDQ 的生殖毒性有关。
