Chen Jian, Dai Xue-Yan, Malhi Kanwar K, Xu Xiang-Wen, Tang Yi-Xi, Li Xiao-Wei, Li Jin-Long
College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P.R. China.
Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, P.R. China.
Research (Wash D C). 2024 Dec 13;7:0547. doi: 10.34133/research.0547. eCollection 2024.
Atrazine (AT), a widely utilized chemical herbicide, causes widespread contamination of agricultural water bodies. Recently, exposure to AT has been linked to the development of age-related neurodegenerative diseases (NDs), suggesting its neurotoxicity potential. As an endocrine disruptor, AT targets the hypothalamus, a crucial part of the neuroendocrine system. However, the toxicological mechanism of AT exposure to the hypothalamus and its correlation with ND development remain unexplored. Our results indicated that AT exposure caused significant morphological and structural damage to the hypothalamus, leading to the loss of mature and intact neurons and microglial activation. Furthermore, hypothalamic neural stem cells (HtNSCs) were recruited to areas of neuronal damage caused by AT. Through in vivo and in vitro experiments, we clarified the outcomes of AT-induced HtNSC recruitment alongside the loss of mature/intact neurons. Mechanistically, AT induces senescence in these recruited HtNSCs by activating integrated stress response signaling. This consequently hinders the repair of damaged neurons by inhibiting HtNSC proliferation and differentiation. Overall, our findings underscore the pivotal role of the integrated stress response pathway in AT-induced HtNSC senescence and hypothalamic damage. Additionally, the present study offers novel perspectives to understand the mechanisms of AT-induced neurotoxicity and provides preliminary evidence linking AT contamination to the development of NDs.
莠去津（AT）是一种广泛使用的化学除草剂，导致农业水体受到广泛污染。最近，接触AT与年龄相关的神经退行性疾病（NDs）的发生有关，表明其具有神经毒性潜力。作为一种内分泌干扰物，AT作用于神经内分泌系统的关键部分——下丘脑。然而，AT暴露于下丘脑的毒理学机制及其与NDs发生的相关性仍未得到探索。我们的结果表明，AT暴露对下丘脑造成了显著的形态和结构损伤，导致成熟且完整的神经元丢失以及小胶质细胞激活。此外，下丘脑神经干细胞（HtNSCs）被募集到由AT引起的神经元损伤区域。通过体内和体外实验，我们阐明了AT诱导HtNSC募集以及成熟/完整神经元丢失的结果。从机制上讲，AT通过激活整合应激反应信号通路诱导这些被募集的HtNSCs衰老。这进而通过抑制HtNSC增殖和分化阻碍受损神经元的修复。总体而言，我们的研究结果强调了整合应激反应途径在AT诱导的HtNSC衰老和下丘脑损伤中的关键作用。此外，本研究为理解AT诱导神经毒性的机制提供了新的视角，并提供了将AT污染与NDs发生联系起来的初步证据。
