Behavioral Epigenetics of Developmental Methylmercury Exposure.

发育甲基汞暴露的行为表观遗传学。

• 批准号: 9111904
• 负责人: Marshall CHRISTOPHER NEWLAND
• 金额: $ 14.65万
• 依托单位: AUBURN UNIVERSITY AT AUBURN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9111904
• 关键词: Acceleration; Acetylation; Address; Adolescence; Adolescent; Adult; Affect; Aging; Agonist; Amphetamines; Animal Model; Animals; Behavior; Behavioral; Brain; Butyrates; Candidate Disease Gene; Childhood; Cocaine; Cognitive; Collection; Communities; Control Groups; Coupled; DNA Methylation; Data; Decision Making; Development; Disease; Dopamine; Epigenetic Process; Event; Experimental Models; Exposure to; Fishes; Functional disorder; Gene Expression; Genes; Goals; Health; Histone Acetylation; Histone Deacetylation; Housing; Human; Impairment; Impulsivity; Intervention; Life; Link; Mediating; Mercury; Methylmercury Compounds; Mining; Modification; Monkeys; Motor; Mus; Neurophysiology - biologic function; Neurotransmitters; Outcome; Pattern; Pentobarbital; Perinatal Exposure; Prefrontal Cortex; Pregnancy; Procedures; Process; RNA methylation; Rattus; Regulator Genes; Research; Resources; Risk; Rodent; Sensory; Sensory Process; Site; Space Perception; Staging; Testing; Therapeutic; Toxic effect; age related; base; behavioral impairment; developmental neurotoxicity; drinking water; drug of abuse; early experience; environmental enrichment for laboratory animals; epigenetic marker; epigenome; executive function; experience; exposed human population; fetal; frontal lobe; genome sequencing; histone modification; inhibitor/antagonist; methylmercury exposure; mouse model; nervous system development; neurotoxicity; reinforcer; reward processing; stressor; therapy design; toxic metal; uptake; whole genome

 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.

 描述（由应用程序提供）：妊娠期间的甲基汞（MEHG）暴露会导致持续的反应，选择，冲动性和其他皮质功能受损的标记受损。这些作用出现在成年和衰老中，在没有明显毒性的动物模型中发生，并且发生在环境相关的暴露范围内。此外，效果在经验方面是可逆的，而早期发育是一个特别敏感的暴露窗口。总之，这些观察结果提出了MEHG发育神经毒性的可能性，这是由大脑的表观遗传变化介导的。青少年是一个生命阶段，对破坏皮质发育的事件和也具有表观遗传学后果的事件敏感，但是在这个潜在脆弱的发育时期，我们对MEHG暴露很少了解。在AIM 1下，将在小鼠模型中检查妊娠MEHG暴露的行为和表观遗传后果。整个基因组分析将从妊娠在通过材料饮用水妊娠期间暴露于MEHG的成年小鼠的前额叶皮层进行。分析将侧重于RNA，甲基化和乙酰化，并将鉴定候选基因进行进一步研究。额外的小鼠将被相似地暴露，并暴露于旨在研究MEHG诱导的行为和表观遗传障碍的可逆性的三种干预措施之一：配对组（对照组），环境富集以及组蛋白脱乙酰基化（HDAC）抑制剂Na-Butrate，NA-Butrate。将对小鼠作为成年人的空间歧视逆转程序进行检查，以确定这些救援尝试的行为影响，此后将检查整个表观基因组分析中鉴定的候选基因的表达。在AIM 2下，将在AIM 1中检查青少年MEHG暴露于AIM 1的研究。拟议的研究将提高我们对发育MEHG暴露的行为表观遗传学后果的理解，两个重要的暴露窗口的相对脆弱性以及通过富集或HDAC抑制进行营救的潜力。

项目成果

Methylmercury, attention, and memory: baseline-dependent effects of adult d-amphetamine and marginal effects of adolescent methylmercury.

• DOI: 10.1016/j.neuro.2020.07.009
• 发表时间: 2020-09
• 期刊: NEUROTOXICOLOGY
• 影响因子: 3.4
• 作者: Kendricks, Dalisa R.;Boomhower, Steven R.;Newland, M. Christopher
• 通讯作者: Newland, M. Christopher

A bout analysis reveals age-related methylmercury neurotoxicity and nimodipine neuroprotection.

一项分析揭示了与年龄相关的甲基汞神经毒性和尼莫地平神经保护作用。

• DOI: 10.1016/j.bbr.2016.05.032
• 发表时间: 2016
• 期刊: Behavioural brain research
• 影响因子: 2.7
• 作者: Shen,AndrewNathanael;Cummings,Craig;Pope,Derek;Hoffman,Daniel;Newland,MChristopher
• 通讯作者: Newland,MChristopher

Adolescent methylmercury exposure alters short-term remembering, but not sustained attention, in male Long-Evans rats.

• DOI: 10.1016/j.neuro.2020.03.009
• 发表时间: 2020-03
• 期刊: Neurotoxicology
• 影响因子: 3.4
• 作者: Dalisa R. Kendricks;Steven R. Boomhower;M. Arnold;Douglas J. Glenn;-M.;Christopher M. Newland

Adolescent methylmercury exposure: Behavioral mechanisms and effects of sodium butyrate in mice.

• DOI: 10.1016/j.neuro.2018.10.011
• 发表时间: 2019-01
• 期刊: Neurotoxicology
• 影响因子: 3.4
• 作者: Boomhower SR;Newland MC
• 通讯作者: Newland MC