Medical Research Center, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350013, China; Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian 350001, China.
Medical Research Center, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350013, China; Department of Cardiac Surgery, Fujian Children's Hospital (Fujian Branch of Shanghai Children's Medical Center), College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350011, China; Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian 350001, China.
Ecotoxicol Environ Saf. 2024 Nov 1;286:117165. doi: 10.1016/j.ecoenv.2024.117165. Epub 2024 Oct 12.
Valproic acid (VPA) is predominantly prescribed for epilepsy, convulsions, and other psychiatric disorders. As an epigenetic regulator, it is also used to treat various forms of cancer. The clinical demand for the drug may pose an environmental hazard. Evidence indicates that VPA's significant therapeutic value comes at the cost of possible side toxic effects, as symptoms of birth defects have been confirmed in animal experiments using VPA. However, the effects of VPA during the development of the circulatory system remain unclear. In this study, zebrafish embryos were exposed to a series of concentrations of VPA between three hours post fertilization (hpf) and five days post fertilization (dpf). The results demonstrated time- and dose-dependent developmental delays in the zebrafish, including cardiovascular malformation and decreased movement and reaction time. Consistent with the in vivo results, exposure to VPA increased the levels of myocardial reactive oxygen species (ROS) and cell apoptosis through cardiac mitochondrial turnover disorders. The expression levels of genes related to cardiovascular development and antioxidant response were downregulated, while genes related to apoptosis pathways were upregulated. Overall, our toxicological studies of VPA exposure illustrate the damage to cardiovascular development, raising concerns about the hazard of VPA exposure in early pregnancy. Our study provides novel insights into the potential environmental risks of VPA.
丙戊酸（VPA）主要用于治疗癫痫、抽搐和其他精神疾病。作为一种表观遗传调节剂，它也被用于治疗各种形式的癌症。这种药物的临床需求可能会带来环境危害。有证据表明，VPA 的显著治疗价值是以可能的毒副作用为代价的，因为在使用 VPA 的动物实验中已经证实了出生缺陷的症状。然而，VPA 在循环系统发育过程中的作用尚不清楚。在这项研究中，斑马鱼胚胎在受精后 3 小时（hpf）至 5 天（dpf）期间暴露于一系列浓度的 VPA 中。结果表明，斑马鱼出现了时间和剂量依赖性的发育迟缓，包括心血管畸形以及运动和反应时间减少。与体内结果一致，通过心脏线粒体周转紊乱，暴露于 VPA 会增加心肌活性氧（ROS）水平和细胞凋亡。与心血管发育和抗氧化反应相关的基因表达水平下调，而与凋亡途径相关的基因上调。总之，我们对 VPA 暴露的毒理学研究说明了其对心血管发育的损害，这引发了对早孕时期 VPA 暴露危害的关注。我们的研究为 VPA 的潜在环境风险提供了新的见解。
