Fernández-Pomares Cynthia, Estrada-Pérez Alan Rubén, Mendoza-Figueroa Humberto L, García-Vázquez Juan Benjamín, Rosales-Hernández Martha C, Correa-Basurto José
Laboratorio de Diseño y Desarrollo de Nuevos Fármacos e Innovación Biotecnológica, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, 11340, Mexico City, Mexico.
Laboratorio de Biofísica y Biocatálisis, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico.
Sci Rep. 2025 May 28;15(1):18644. doi: 10.1038/s41598-025-03325-9.
The brine shrimp lethality test (Artemia spp.) is a classical model for assessing the toxicity of bioactive compounds. This study evaluated the toxicity and metabolomic changes induced by N-(2'- hydroxyphenyl)-2-propylpentanamide (HO-AAVPA), a derivative of valproic acid (VPA), in Artemia franciscana larvae using untargeted metabolomics through liquid chromatography-mass spectrometry (LC-MS/MS). The lethal concentration 50 (LC) was determined by acute toxicity tests at 24 and 48 h, and teratogenic effects were assessed by measuring the larvae body length. Larval metabolomic changes were examined following 24- and 48-hour exposures to sublethal concentrations of HO-AAVPA (LC = 0.04 mM, LC = 0.2 mM) and VPA (LC = 1.79 mM, LC = 8.95 mM). After 48 h, HO-AAVPA had an LC of 0.32 mM, while VPA had 18.7 mM. VPA induced teratogenic effects at 9.6 mM; in contrast, HO-AAVPA only significantly affected the body length at 0.56 mM. Metabolomic analysis revealed that sublethal concentrations of HO-AAVPA affected the sphingolipid and glycerophospholipid metabolism, while VPA impacted alanine, aspartate, and glutamate metabolism. These findings suggest HO-AAVPA has high toxicity, but lower teratogenicity compared to VPA. In conclusion, the present study indicates that alterations in lipid and amino acid metabolism could be critical points in the mode of action of these compounds in A. franciscana.
卤虫致死性试验（卤虫属）是评估生物活性化合物毒性的经典模型。本研究通过液相色谱 - 质谱联用（LC - MS/MS）的非靶向代谢组学方法，评估了丙戊酸（VPA）的衍生物N - （2'- 羟基苯基）-2 - 丙基戊酰胺（HO - AAVPA）对加州卤虫幼虫的毒性和代谢组学变化。通过24小时和48小时的急性毒性试验确定半数致死浓度（LC50），并通过测量幼虫体长评估致畸作用。在暴露于亚致死浓度的HO - AAVPA（LC = 0.04 mM，LC = 0.2 mM）和VPA（LC = 1.79 mM，LC = 8.95 mM）24小时和48小时后，检测幼虫的代谢组学变化。48小时后，HO - AAVPA的LC为0.32 mM，而VPA为18.7 mM。VPA在9.6 mM时诱导致畸作用；相比之下，HO - AAVPA仅在0.56 mM时显著影响体长。代谢组学分析表明，亚致死浓度的HO - AAVPA影响鞘脂和甘油磷脂代谢，而VPA影响丙氨酸、天冬氨酸和谷氨酸代谢。这些发现表明，HO - AAVPA具有高毒性，但与VPA相比致畸性较低。总之，本研究表明脂质和氨基酸代谢的改变可能是这些化合物对加州卤虫作用模式的关键点。
