Behavioral Epigenetics of Developmental Methylmercury Exposure.

 描述（由申请方提供）：妊娠期甲基汞（MeHg）暴露可导致持续性反应、选择获得受损、冲动和皮质功能受损的其他标志物。这些影响出现在动物模型的成年期和衰老期，在这些动物模型中不存在明显的毒性，并且在环境相关的暴露下发生。此外，这些影响是可逆的经验和早期发育是一个特别敏感的窗口接触。总之，这些观察结果提出了一种可能性，即甲基汞的发育神经毒性是由大脑中的表观遗传变化介导的。青春期是一个对破坏大脑皮层发育的事件和具有表观遗传后果的事件敏感的生命阶段，但我们对这一潜在的脆弱发育期的甲基汞接触知之甚少。根据目标1，将在小鼠模型中研究妊娠期甲基汞暴露的行为和表观遗传后果。将对妊娠期间通过母体饮用水接触甲基汞的成年小鼠的前额皮质进行全基因组分析。分析将集中在RNA，甲基化和乙酰化，并将确定进一步研究的候选基因。其他小鼠将类似地暴露并暴露于设计用于研究甲基汞诱导的行为和表观遗传障碍的可逆性的三种干预之一：成对圈养（对照组）、环境富集和组蛋白脱乙酰化（HDAC）抑制剂丁酸钠给药。将在空间辨别抑制程序中检查成年小鼠，以确定这些拯救尝试的行为影响，之后将检查在整个表观基因组分析中鉴定的候选基因的表达。根据目标2，青少年接触甲基汞的情况将在与目标1相同的研究中进行调查。拟议中的研究将推进我们的理解发育甲基汞暴露的行为表观遗传的后果，两个重要的曝光窗口的相对脆弱性，以及通过富集或HDAC抑制救援的潜力。

 DESCRIPTION (provided by applicant): Methylmercury (MeHg) exposure during gestation causes perseverative responding, impaired acquisition of choice, impulsivity, and other markers of impaired cortical function. These effects appear in adulthood and aging in animal models in which no overt toxicity is present and occurs at environmentally relevant exposures. Moreover, the effects are reversible with experience and early developmental is an especially sensitive window of exposure. Together, these observations raise the possibility that MeHg's developmental neurotoxicity is mediated by epigenetic changes in the brain. Adolescence is a life stage that is sensitive to events that disrupt cortical development and those that also have epigenetic consequences, but we know very little about MeHg exposure during this potentially vulnerable developmental period. Under Aim 1, the behavioral and epigenetic consequences of gestational MeHg exposure will be examined in a mouse model. Whole genome analyses will be conducted from prefrontal cortex in adult mice exposed to MeHg during gestation via maternal drinking water. Analyses will focus on RNA, methylation, and acetylation and will identify candidate genes for further study. Additional mice will be exposed similarly and exposed to one of three interventions designed to investigate the reversibility of MeHg-induced behavioral and epigenetic disturbances: Paired- housing (Control group), environmental enrichment, and administration of a histone deacetylation (HDAC) inhibitor, Na-butyrate. The mice will be examined on a Spatial Discrimination Reversal procedure as adults to determine the behavioral impact of these rescue attempts, after which the expression of candidate genes identified in the whole epigenome analysis will be examined. Under Aim 2, adolescent MeHg exposure will be examined in studies that otherwise mirror those conducted under Aim 1. The proposed studies will advance our understanding of the behavioral epigenetic consequences of developmental MeHg exposure, the relative vulnerability of two important exposure windows, and the potential for rescue by enrichment or HDAC inhibition.