Pre-differentiation exposure to low-dose of atrazine results in persistent phenotypic changes in human neuronal cell lines
Pre-differentiation exposure to low-dose of atrazine results in persistent phenotypic changes in human neuronal cell lines
复制标题
分化前暴露于低剂量莠去津会导致人类神经细胞系持续表型变化
DOI：
10.1016/j.envpol.2020.116379
复制
发表时间：
2021
影响因子：
8.9
通讯作者：
Yuan, Chongli
中科院分区：
文献类型：
--
作者：
Xie, Junkai;Lin, Li;Sánchez, Oscar F.;Bryan, Chris;Freeman, Jennifer L.;Yuan, Chongli
暴露于有机农药，特别是在发育窗口期，与以后生活中的各种神经退行性疾病有关。阿特拉津（ATZ）是美国使用最多的杀虫剂之一，被怀疑与以后生活中神经退行性变增加有关，但很少有研究使用人类神经元细胞评估发育ATZ暴露的神经毒性。在此，我们将人SH-SY 5 Y细胞暴露于0.3、3和30 ppb的ATZ，然后在无ATZ的培养基中将其分化为多巴胺能样神经元，以模拟发育暴露。分化的神经元表现出改变的轴突生长和SNCA病理取决于ATZ治疗剂量。暴露后立即观察到表观基因组变化，如5 mC（仅0.3 ppb）、H3 K9 me 3和H3 K27 me 3降低。这些改变在分化的神经元中以补偿的方式持续存在。具体而言，我们观察到分化后ATZ暴露的细胞中5 mC和H3 K9 me 3的显著减少，以及H3 K27 me 3的增加，表明发育ATZ暴露后大量的染色质重排。相关表观遗传酶的转录变化也进行了定量，但发现只能部分解释观察到的表观基因组改变。因此，我们的研究结果共同表明，分化前暴露于低剂量ATZ可导致表观基因组的长期变化，并增加SNCA相关帕金森病的风险。
Exposures to organic pesticides, particularly during a developmental window, have been associated with various neurodegenerative diseases later in life. Atrazine (ATZ), one of the most used pesticides in the U.S., is suspected to be associated with increased neurodegeneration later in life but few studies assessed the neurotoxicity of developmental ATZ exposure using human neuronal cells. Here, we exposed human SH-SY5Y cells to 0.3, 3, and 30 ppb of ATZ prior to differentiating them into dopaminergic-like neurons in ATZ-free medium to mimic developmental exposure. The differentiated neurons exhibit altered neurite outgrowth and SNCA pathology depending on the ATZ treatment doses. Epigenome changes, such as decreases in 5mC (for 0.3 ppb only), H3K9me3, and H3K27me3 were observed immediately after exposure. These alterations persist in a compensatory manner in differentiated neurons. Specifically, we observed significant reductions in 5mC and H3K9me3, as well as, an increase in H3K27me3 in ATZ-exposed cells after differentiation, suggesting substantial chromatin rearrangements after developmental ATZ exposure. Transcriptional changes of relevant epigenetic enzymes were also quantified but found to only partially explain the observed epigenome alteration. Our results thus collectively suggest that exposure to low-dose of ATZ prior to differentiation can result in long-lasting changes in epigenome and increase risks of SNCA-related Parkinson’s Disease.