Pandaram Athiram, Paul Jeyakumari, Wankhar Wankupar, Thakur Abhimanyu, Verma Sakshi, Vasudevan Karthick, Wankhar Dapkupar, Kammala Ananth Kumar, Sharma Priyanshu, Jaganathan Ravindran, Iyaswamy Ashok, Rajan Ravindran
Department of Physiology, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Chennai 600113, Tamil Nadu, India.
Faculty of Paramedical Sciences, Assam down town University, Guwahati 781026, Assam, India.
Biomedicines. 2024 Apr 12;12(4):855. doi: 10.3390/biomedicines12040855.
Aspartame, a widely used artificial sweetener, is present in many food products and beverages worldwide. It has been linked to potential neurotoxicity and developmental defects. However, its teratogenic effect on embryonic development and the underlying potential mechanisms need to be elucidated. We investigated the concentration- and time-dependent effects of aspartame on zebrafish development and teratogenicity. We focused on the role of sirtuin 1 (SIRT1) and Forkhead-box transcription factor (FOXO), two proteins that play key roles in neurodevelopment. It was found that aspartame exposure reduced the formation of larvae and the development of cartilage in zebrafish. It also delayed post-fertilization development by altering the head length and locomotor behavior of zebrafish. RNA-sequencing-based DEG analysis showed that SIRT1 and FOXO3a are involved in neurodevelopment. In silico and in vitro analyses showed that aspartame could target and reduce the expression of SIRT1 and FOXO3a proteins in neuron cells. Additionally, aspartame triggered the reduction of autophagy flux by inhibiting the nuclear translocation of SIRT1 in neuronal cells. The findings suggest that aspartame can cause developmental defects and teratogenicity in zebrafish embryos and reduce autophagy by impairing the SIRT1/FOXO3a axis in neuron cells.
阿斯巴甜是一种广泛使用的人工甜味剂，在全球许多食品和饮料中都有存在。它与潜在的神经毒性和发育缺陷有关。然而，其对胚胎发育的致畸作用及潜在机制仍有待阐明。我们研究了阿斯巴甜对斑马鱼发育和致畸性的浓度和时间依赖性影响。我们重点关注了沉默调节蛋白1（SIRT1）和叉头框转录因子（FOXO）这两种在神经发育中起关键作用的蛋白质的作用。研究发现，暴露于阿斯巴甜会减少斑马鱼幼虫的形成和软骨发育。它还通过改变斑马鱼的头部长度和运动行为延迟受精后的发育。基于RNA测序的差异表达基因分析表明，SIRT1和FOXO3a参与神经发育。计算机模拟和体外分析表明，阿斯巴甜可靶向并降低神经元细胞中SIRT1和FOXO3a蛋白的表达。此外，阿斯巴甜通过抑制神经元细胞中SIRT1的核转位引发自噬通量的降低。这些发现表明，阿斯巴甜可导致斑马鱼胚胎发育缺陷和致畸性，并通过损害神经元细胞中的SIRT1/FOXO3a轴减少自噬。
