Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA.
PLoS One. 2013;8(2):e53478. doi: 10.1371/journal.pone.0053478. Epub 2013 Feb 6.
Chronic exposure to arsenic in drinking water, especially in utero or perinatal exposure, can initiate neurological and cognitive dysfunction, as well as memory impairment. Several epidemiological studies have demonstrated cognitive and learning deficits in children with early exposure to low to moderate levels of arsenic, but pathogenic mechanisms or etiology for these deficits are poorly understood. Since in vivo studies show a role for histone acetylation in cognitive performance and memory formation, we examined if prenatal exposure to arsenic causes changes in the epigenomic landscape. We exposed C57Bl6/J mice to 100 μg/L arsenic in the drinking water starting 1 week before conception till birth and applied chromatin immunoprecipitation followed by high-throughput massive parallel sequencing (ChIP-seq) to evaluate H3K9 acetylation pattern in the offspring of exposed and control mice. Arsenic exposure during embryonic life caused global hypo-acetylation at H3K9 and changes in functional annotation with highly significant representation of Krüppel associated box (KRAB) transcription factors in brain samples from exposed pups. We also found that arsenic exposure of adult mice impaired spatial and episodic memory, as well as fear conditioning performance. This is the first study to demonstrate: a) genome wide changes in H3K9 acetylation pattern in an offspring prenatally exposed to arsenic, and b) a connection between moderate arsenic exposure and cognitive impairment in adult mice. The results also emphasize the applicability of Next Generation Sequencing methodology in studies aiming to reveal the role of environmental factors, other than dietary restriction, in developmental reprogramming through histone modifications during embryonic development.
慢性暴露于饮用水中的砷，特别是在子宫内或围产期暴露，会引发神经和认知功能障碍，以及记忆损伤。几项流行病学研究表明，早期接触低至中等水平砷的儿童存在认知和学习缺陷，但这些缺陷的发病机制或病因尚不清楚。由于体内研究表明组蛋白乙酰化在认知表现和记忆形成中起作用，我们研究了产前暴露于砷是否会导致表观基因组景观发生变化。我们从受孕前一周开始让 C57Bl6/J 小鼠饮用 100μg/L 的砷水，直至出生，并应用染色质免疫沉淀技术结合高通量大规模平行测序（ChIP-seq），以评估暴露和对照小鼠后代中 H3K9 乙酰化模式。胚胎期暴露于砷会导致 H3K9 整体去乙酰化，以及功能注释发生变化，暴露幼鼠的大脑样本中 Krüppel 相关盒（KRAB）转录因子的代表性非常显著。我们还发现，成年小鼠暴露于砷会损害空间和情景记忆，以及恐惧条件反射表现。这是第一项研究表明：a）在产前接触砷的后代中，H3K9 乙酰化模式发生全基因组变化，b）中度砷暴露与成年小鼠认知障碍之间存在联系。研究结果还强调了下一代测序方法在研究中的适用性，这些研究旨在通过胚胎发育过程中的组蛋白修饰，揭示环境因素（除饮食限制外）在发育重编程中的作用。
