Fitz Nicholas F, Barchowsky Aaron, Koldamova Radosveta, Lefterov Iliya
Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, United States.
Toxicol Rep. 2022 Mar 4;9:393-403. doi: 10.1016/j.toxrep.2022.03.008. eCollection 2022.
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.
无机砷是一种外源性物质，主要通过受污染的饮用水和食物进入人体。虽然已有明确的机制描述砷与癌症发病率增加之间的关联，但解释砷暴露与神经发育或衰老障碍之间关系的机制尚不明确。近年来，砷对表观基因组的影响成为了一个特别的研究重点。我们推测，在特定发育阶段接触与人类相关的砷，或在生命后期长期接触砷，会通过表观基因组改变，特别是组蛋白甲基化谱的改变，诱发病理生理神经变化，表现为认知能力下降。在交配前直至实验后代断奶期间，C57BL/6野生型小鼠持续饮用含亚砷酸钠（100μg/L）的水。另一组老年APP/PS小鼠长期接触相同水平的砷。通过认知测试、大脑组织学检查以及ChIP-seq后检测H3K4me3和H3K27me3的全基因组甲基化水平，来确定砷暴露的影响。发育阶段的砷暴露导致野生型小鼠的认知能力显著下降。ChIP-seq数据分析以及对小鼠胚胎干细胞的实验表明，砷暴露诱导的表观遗传变化转化为与神经元发育和神经疾病相关的基因表达改变。APP/PS小鼠海马区淀粉样斑块水平增加以及认知能力下降，证明砷暴露加剧了现有的类似阿尔茨海默病的表型。我们发现发育阶段的砷暴露会显著影响大脑中的组蛋白修饰，这种影响会持续到成年期，并为发育阶段的砷暴露影响认知功能提供了一种潜在机制。我们还表明，与人类相关的慢性砷暴露对成年APP/PS小鼠有有害影响，并加剧了现有的类似阿尔茨海默病的症状。这些结果证明了发育阶段的砷暴露如何影响大脑表观基因组，并导致生命后期基因表达的改变。
