Wang Jia, Yin Jiechen, Peng Danhong, Zhang Xiaoqian, Shi Zhouhong, Li Weixi, Shi Yingchi, Sun Mingjun, Jiang Nan, Cheng Beijing, Meng Xingchen, Liu Ran
Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China.
Department of Obstetrics and Gynecology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China.
J Environ Sci (China). 2025 Jan;147:244-258. doi: 10.1016/j.jes.2023.09.032. Epub 2023 Oct 3.
4-Nitrophenol (4-NP), as a toxic and refractory pollutant, has generated significant concern due to its adverse effects. However, the potential toxic effects and mechanism remained unclear. In this study, the reproduction, development, locomotion and reactive oxygen species (ROS) production of Caenorhabditis elegans were investigated to evaluate the 4-NP toxicity. We used metabolomics to assess the potential damage mechanisms. The role of metabolites in mediating the relationship between 4-NP and phenotypes was examined by correlation and mediation analysis. 4-NP (8 ng/L and 8 µg/L) caused significant reduction of brood size, ovulation rate, total germ cells numbers, head thrashes and body bends, and an increase in ROS. However, the oosperm numbers in uterus, body length and body width were decreased in 8 µg/L. Moreover, 36 differential metabolites were enriched in the significant metabolic pathways, including lysine biosynthesis, β-alanine metabolism, tryptophan metabolism, pentose phosphate pathway, pentose and glucuronate interconversions, amino sugar and nucleotide sugar metabolism, starch and sucrose metabolism, galactose metabolism, propanoate metabolism, glycerolipid metabolism, and estrogen signaling pathway. The mechanism of 4-NP toxicity was that oxidative stress caused by the perturbation of amino acid, which had effects on energy metabolism through disturbing carbohydrate and lipid metabolism, and finally affected the estrogen signaling pathway to exert toxic effects. Moreover, correlation and mediation analysis showed glycerol-3P, glucosamine-6P, glucosamine-1P, UDP-galactose, L-aspartic acid, and uracil were potential markers for the reproduction and glucose-1,6P2 for developmental toxicity. The results provided insight into the pathways involved in the toxic effects caused by 4-NP and developed potential biomarkers to evaluate 4-NP toxicity.
4-硝基苯酚（4-NP）作为一种有毒且难降解的污染物，因其负面影响而备受关注。然而，其潜在的毒性效应和作用机制仍不清楚。在本研究中，通过对线虫的生殖、发育、运动以及活性氧（ROS）生成进行研究，以评估4-NP的毒性。我们采用代谢组学来评估潜在的损伤机制。通过相关性和中介分析，研究了代谢物在介导4-NP与表型之间关系中的作用。4-NP（8 ng/L和8 µg/L）导致产卵量、排卵率、总生殖细胞数量、头部摆动和身体弯曲显著减少，ROS增加。然而，8 µg/L组子宫内受精卵数量、体长和体宽减少。此外，36种差异代谢物在显著的代谢途径中富集，包括赖氨酸生物合成、β-丙氨酸代谢、色氨酸代谢、磷酸戊糖途径、戊糖与葡糖醛酸相互转化、氨基糖与核苷酸糖代谢、淀粉与蔗糖代谢、半乳糖代谢、丙酸代谢、甘油酯代谢以及雌激素信号通路。4-NP毒性的机制是氨基酸紊乱引起氧化应激，通过干扰碳水化合物和脂质代谢影响能量代谢，最终影响雌激素信号通路发挥毒性作用。此外，相关性和中介分析表明，甘油-3-磷酸、6-磷酸葡萄糖胺、1-磷酸葡萄糖胺、UDP-半乳糖、L-天冬氨酸和尿嘧啶是生殖毒性的潜在标志物，1,6-二磷酸葡萄糖是发育毒性的潜在标志物。这些结果为4-NP所致毒性效应的相关途径提供了见解，并开发了评估4-NP毒性的潜在生物标志物。
