Early Life Environment Modifies Behavioral, Epigenetic, and Transcriptional Outcomes from Developmental Lead Exposure

各种环境/行为因素可以影响大脑发育以及随后的认知和行为。 行为功能。在促进最佳神经发育的因素中，出生后的丰富 环境和照料质量，这两者都已被证明影响大脑、行为和社交发展- 子孙后代的繁殖。然而，环境暴露有能力破坏神经和认知/行为- 道德发展，带来终生的负面后果。发育中的铅暴露(铅)是一种重要的 公共卫生问题，可以影响所有人口，然而，低社会经济地位的成员- 社区接触铅的风险更高，血铅水平最高，并会产生不良后果 可能会更加严重。低SES对认知和行为发育的影响是多因素的 但父母照顾和家庭环境质量的差异似乎起到了重要作用。这些是如何 各种因素单独作用并相互作用，调节大脑对铅的表观遗传和转录反应。 对认知/行为结果的定位和影响还没有研究过。我们实验室以前的研究和 新的初步数据显示，海马区(HIPP)和额叶皮质(Fc)的DNA甲基化和反式 HIPP的残疾特征受出生后环境质量和铅暴露、砷的影响 是联想学习、记忆和执行功能。然而，母婴质量的影响 在铅神经毒性的实验研究中，CARE尚未被作为效应调节剂进行检验，也没有 研究了产妇护理和断奶后社会环境质量的联合影响。 初步数据首次显示，产妇护理质量是有毒物质的重要影响修饰物 铅暴露的影响。数据表明，不同的早期生活经历可能会改变COG的表达- 由发育性铅暴露所产生的行为和行为缺陷，并可能通过进一步的改变- 铅暴露对甲基化和转录谱的影响。拟议的研究将 通过以下具体目标调查这一点：目标1：检查社会环境变化的程度 产妇护理的环境和质量独立或联合改变男性的认知/行为结果 和有发育性铅暴露的女性；目标2：确定HIPP关键基因水平的甲基化变化， FC和AMYG(使用甲基化依赖的免疫沉淀测序(MeDIP-seq)和甲基化- 敏感的限制性内切酶序列分析(MRE-SEQ)与转录/功能网络的变化 (使用RNA-seq)受发育期铅暴露的影响，以及改变的剖面可能的程度 受产妇护理质量和/或环境丰富的影响。这些研究将提供新的- 环境/行为因素如何相互作用影响神经发育脆弱性的形成 和铅暴露后的恢复能力，并提供相关信息，以了解 社会/行为干预对改善铅暴露的结果具有翻译意义。

Various environmental/behavioral factors can influence brain development and subsequent cognitive and be- havioral functioning. Among factors contributing to optimal neurodevelopment are the richness of the postnatal environment and caregiving quality, both of which have been shown to affect brain, behavior, and social devel- opment of offspring. Environmental exposures however, have the ability to derail neural and cognitive/behav- ioral development, with lifelong negative consequences. Developmental exposure to lead (Pb), an important public health problem, can affect all populations, however, members of low socioeconomic status (SES) com- munities are at higher risk of exposure, sustain the highest blood Pb levels, and have adverse outcomes that are potentially more severe. The effects of low SES on cognitive and behavioral development are multifactorial but variations in parental care and quality of the home environment appear to play important roles. How these factors act individually and interact to modulate the brain’s epigenetic and transcriptional responses to Pb ex- posure and affect cognitive/behavioral outcomes has not been examined. Previous studies from our lab and new preliminary data show that DNA methylation in the hippocampus (HIPP) and frontal cortex (FC) and trans- criptional profiles in HIPP are modulated by the quality of the postnatal environment and by Pb exposure, as are associative learning and memory and executive functioning. However, the impact of quality of maternal care has not been examined as an effect modifier in experimental studies of Pb neurotoxicity nor have the combined influences of maternal care and the quality of the post-weaning social environment been studied. Preliminary data show for the first time that quality of maternal care is an important effect modifier of the toxic influences of Pb exposure. Data suggest that different early life experiences may modify the expression of cog- nitive and behavioral deficits produced by developmental Pb exposure and may do so through further altera- tions of methylation and transcriptional profiles initially modified by Pb exposure. The proposed studies will investigate this through the following specific aims: Aim 1: Examine the extent to which variations in social en- vironment and quality of maternal care independently or jointly modify cognitive/behavioral outcomes in males and females with developmental Pb exposure; Aim 2: Identify critical gene-level methylation changes in HIPP, FC, and AMYG (using Methylation Dependent ImmunoPrecipitation sequencing (MeDIP-seq) and Methylation- sensitive Restriction Enzyme digestion sequencing (MRE-seq)) and transcriptional/functional network changes (using RNA-seq) that are affected by developmental Pb exposure and the extent to which altered profiles can be modulated by quality of maternal care and/or environmental enrichment. These studies will provide new in- formation on how environmental/behavioral factors may interact to influence neurodevelopmental vulnerability and resiliency following Pb exposure and provide information relevant to understanding the biological bases of social/behavioral interventions that are translationally relevant for improving outcomes from Pb exposure.