Genome-wide alteration of histone methylation profiles associated with cognitive changes in response to developmental arsenic exposure in mice.
Genome-wide alteration of histone methylation profiles associated with cognitive changes in response to developmental arsenic exposure in mice.
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DOI：
10.1016/j.toxrep.2022.03.008
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发表时间：
2022
影响因子：
--
通讯作者：
Lefterov I
中科院分区：
文献类型：
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作者：
Fitz NF;Barchowsky A;Koldamova R;Lefterov I
无机砷是一种异生物质，主要通过受污染的饮用水和食物进入人体。有明确的机制描述了砷与癌症发病率增加的关系，但解释砷暴露和神经发育或衰老障碍的机制定义不清。近年来，砷对表观基因组的影响已成为一个特别的焦点。我们假设，人类相关的砷暴露在特定的发育窗口，或长期暴露在以后的生活中诱导病理生理神经变化，通过表观基因组的改变，特别是组蛋白甲基化谱，表现为认知能力下降。C57 BL/6野生型小鼠在交配前通过实验后代断奶持续暴露于饮用水中的亚砷酸钠（100 µg/L）。第二组老年APP/PS小鼠长期暴露于相同水平的砷。认知测试，大脑组织学检查和ChIP-seq后检查的H3 K4 me 3和H3 K27 me 3的全基因组甲基化水平被用来确定砷暴露的影响。发育期砷暴露导致野生型小鼠的认知能力显着下降。ChIP-seq数据分析和小鼠胚胎干细胞实验表明，砷暴露诱导的表观遗传变化转化为与神经元发育和神经系统疾病相关的基因表达改变。APP/PS小鼠海马淀粉样蛋白斑块水平的增加和认知能力的下降为砷暴露加重现有的阿尔茨海默病样表型提供了证据。我们发现发育期砷暴露显著影响大脑中的组蛋白修饰，这些修饰一直存在到成年期，并提供了一种发育期砷暴露影响认知功能的潜在机制。我们还表明，人类相关的慢性砷暴露对成年APP/PS小鼠有有害影响，并加剧现有的阿尔茨海默病样症状。研究结果表明，发育中的砷暴露如何影响大脑表观基因组，导致生命后期基因表达的改变。发育期砷暴露影响脑中具有生物学意义的组蛋白修饰。H3 K27的三甲基化减少与神经元命运和发育相关的过程相关。脑组织中组蛋白的改变是砷暴露影响认知功能的一个潜在机制。砷可加重AD模型小鼠的认知缺陷和神经炎症。
Inorganic arsenic is a xenobiotic entering the body primarily through contaminated drinking water and food. There are defined mechanisms that describe arsenic’s association with increased cancer incidence, however mechanisms explaining arsenic exposure and neurodevelopmental or aging disorders are poorly defined. In recent years, arsenic effects on epigenome have become a particular focus. We hypothesize that human relevant arsenic exposure during particular developmental windows, or long-term exposure later in life induce pathophysiological neural changes through epigenomic alterations, in particular histone methylation profile, manifesting as cognitive decline. C57BL/6 wild-type mice were continually exposed to sodium arsenite (100 µg/L) in drinking water prior to mating through weaning of the experimental progeny. A second cohort of aged APP/PS mice were chronically exposed to the same level of arsenic. Cognitive testing, histological examination of brains and genome-wide methylation levels of H3K4me3 and H3K27me3 examined after ChIP-seq were used to determine the effects of arsenic exposure. Developmental arsenic exposure caused significantly diminished cognition in wild-type mice. The analysis of ChIP-seq data and experiments with mouse embryonic stem cells demonstrated that epigenetic changes induced by arsenic exposure translated into gene expression alterations associated with neuronal development and neurological disease. Increased hippocampal amyloid plaques levels of APP/PS mice and cognitive decline provided evidence that arsenic exposure aggravated an existing Alzheimer’s disease-like phenotype. We show developmental arsenic exposure significantly impacts histone modifications in brain which remain present into adulthood and provide a potential mechanism by which developmental arsenic exposure influences cognitive functions. We also show that human relevant, chronic arsenic exposure has deleterious effects on adult APP/PS mice and exacerbates existing Alzheimer’s disease-like symptoms. The results demonstrate how developmental arsenic exposure impacts the brain epigenome, leading to altered gene expression later in life. Developmental arsenic exposure impacts biologically significant histone modifications in brain. Decreased trimethylation of H3K27 is associated with processes related to neuron fate and development. Histone modification in brain present a potential mechanism how developmental arsenic exposure impacts cognitive functions. Arsenic exacerbates cognitive deficits and neuroinflammation in AD model mice.