Pre-differentiation exposure of PFOA induced persistent changes in DNA methylation and mitochondrial morphology in human dopaminergic-like neurons
Pre-differentiation exposure of PFOA induced persistent changes in DNA methylation and mitochondrial morphology in human dopaminergic-like neurons
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PFOA 分化前暴露可诱导人类多巴胺能样神经元 DNA 甲基化和线粒体形态的持续变化
DOI：
10.1016/j.envpol.2022.119684
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发表时间：
2022
影响因子：
8.9
通讯作者：
Yuan, Chongli
中科院分区：
文献类型：
--
作者：
Zhao, Han;Xie, Junkai;Wu, Shichen;Sánchez, Oscar F;Zhang, Xinle;Freeman, Jennifer L.;Yuan, Chongli
全氟辛酸（PFOA）由于其在消费品和工业应用中的历史用途而在环境中大量存在。暴露于低剂量的PFOA与各种疾病风险有关，包括神经系统疾病。然而，对潜在的机制仍然知之甚少。在这项研究中，我们研究了0.4和4 μ g/L的低剂量PFOA暴露对多巴胺能（DA）样SH-SY5Y细胞的形态学、表观基因组、突触子和神经元标志物的影响。我们观察到，在暴露于0.4和4 μ g/L PFOA的SH-SY5Y细胞分化的DA样神经元中，细胞核中H3K4me3、H3K27me3和5 mC标记物持续减少，同时细胞核大小和染色质致密化百分比发生变化。在所选的表观遗传特征中，DNA甲基化模式可用于区分PFOA暴露人群和未暴露人群，表明表观遗传调控的参与。此外，DA样神经元与分化前PFOA暴露表现出改变网络连接，线粒体体积和TH的表达，这意味着损害DA神经元功能。总的来说，我们的研究结果揭示了发育中的PFOA暴露对DA样神经元适应性的长期影响，并确定了表观基因组和神经元作为承受长期变化的潜在靶点，这些变化有助于增加以后生活中神经系统疾病的风险。
Perfluorooctanoic acid (PFOA) is abundant in environment due to its historical uses in consumer products and industrial applications. Exposure to low doses of PFOA has been associated with various disease risks, including neurological disorders. The underlying mechanism, however, remains poorly understood. In this study, we examined the effects of low dose PFOA exposure at 0.4 and 4 μg/L on the morphology, epigenome, mitochondrion, and neuronal markers of dopaminergic (DA)-like SH-SY5Y cells. We observed persistent decreases in H3K4me3, H3K27me3 and 5 mC markers in nucleus along with alterations in nuclear size and chromatin compaction percentage in DA-like neurons differentiated from SH-SY5Y cells exposed to 0.4 and 4 μg/L PFOA. Among the selected epigenetic features, DNA methylation pattern can be used to distinguish between PFOA-exposed and naïve populations, suggesting the involvement of epigenetic regulation. Moreover, DA-like neurons with pre-differentiation PFOA exposure exhibit altered network connectivity, mitochondrial volume, and TH expression, implying impairment in DA neuron functionality. Collectively, our results revealed the prolonged effects of developmental PFOA exposure on the fitness of DA-like neurons and identified epigenome and mitochondrion as potential targets for bearing long-lasting changes contributing to increased risks of neurological diseases later in life.