Behavioral Epigenetics of Developmental Methylmercury Exposure.

 描述(由申请人提供)：妊娠期间接触甲基汞(MeHg)会导致持续性反应、选择性获得受损、冲动和其他皮质功能受损的标志。这些影响出现在成年期和衰老的动物模型中，在这些动物模型中，没有明显的毒性，并且发生在与环境相关的暴露中。此外，这些影响在经验上是可逆的，早期发育是一个特别敏感的暴露窗口。综上所述，这些观察结果提出了这样一种可能性，即甲基汞的发育神经毒性是由大脑的表观遗传变化介导的。青春期是一个生命阶段，对扰乱皮质发育的事件和那些也具有表观遗传后果的事件很敏感，但我们对这一潜在脆弱的发育期的甲基汞暴露知之甚少。在目标1下，将在小鼠模型中检查妊娠甲基汞暴露的行为和表观遗传后果。全基因组分析将从怀孕期间通过母亲饮用水暴露于甲基汞的成年小鼠的前额叶皮质进行。分析将集中在RNA、甲基化和乙酰化，并将确定候选基因进行进一步研究。更多的小鼠将被类似地暴露，并暴露于三种干预措施之一，旨在研究甲基汞诱导的行为和表观遗传障碍的可逆性：配对住房(对照组)、环境浓缩和给药组蛋白去乙酰化(HDAC)抑制剂丁酸钠。这些小鼠将在成年后接受空间分辨逆转程序的检查，以确定这些救援尝试的行为影响，然后将检查在整个表观基因组分析中确定的候选基因的表达。在目标2下，青少年接触甲基汞的研究将与目标1下进行的研究相一致。拟议的研究将促进我们对发育中甲基汞暴露的行为表观遗传后果、两个重要暴露窗口的相对脆弱性以及通过富集或抑制HDAC进行拯救的可能性的理解。

 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.