Prenatal alcohol exposure alters steady-state and activated gene expression in the adult rat brain

Background: Prenatal alcohol exposure (PAE) is associated with alterations in numerous physiological systems, including the stress and immune systems. We have previously shown that PAE increases the course and severity of arthritis in an adjuvant-induced arthritis (AA) model. While the molecular mechanisms underlying these effects are not fully known, changes in neural gene expression are emerging as important factors in the etiology of PAE effects. As the prefrontal cortex (PFC) and hippocampus (HPC) play key roles in neuroimmune function, PAE-induced alterations to their transcriptome may underlie abnormal steady-state functions and responses to immune challenge. The current study examined brains from adult PAE and control females from our recent AA study to determine whether PAE causes long-term alterations in gene expression and whether these mediate the altered severity and course of arthritis in PAE females Methods: Adult females from PAE, pair-fed [PF], and ad libitum-fed control [C]) groups were injected with either saline or complete Freund’s adjuvant. Animals were terminated at the peak of inflammation or during resolution (days 16 and 39 post-injection, respectively); cohorts of saline-injected PAE, PF and C females were terminated in parallel. Gene expression was analyzed in the PFC and HPC using whole genome mRNA expression microarrays. Results: Significant changes in gene expression in both the PFC and HPC were found in PAE compared to controls in response to ethanol exposure alone (saline-injected females), including genes involved in neurodevelopment, apoptosis, and energy metabolism. Moreover, in response to inflammation (adjuvant-injected females), PAE animals showed unique expression patterns, while failing to exhibit the activation of genes and regulators involved in the immune response observed in control and pair-fed animals. Conclusions: These results support the hypothesis that PAE affects neuroimmune function at the level of gene expression, demonstrating long-term effects of PAE on the CNS response under steady-state conditions and following an inflammatory insult. Key words: prenatal alcohol exposure (PAE), ethanol, inflammation, arthritis, gene expression, rat.背景：产前酒精暴露（prenatal alcohol exposure, PAE）与包括应激系统与免疫系统在内的诸多生理系统异常密切相关。本团队此前的研究证实，在佐剂诱导性关节炎（adjuvant-induced arthritis, AA）模型中，PAE会加剧关节炎的病程与严重程度。尽管上述效应的分子机制尚未完全阐明，但神经基因表达的改变正逐渐被认为是PAE相关效应致病机制中的关键因素。由于前额叶皮层（prefrontal cortex, PFC）与海马体（hippocampus, HPC）在神经免疫功能中发挥核心作用，PAE诱导的二者转录组改变，可能是稳态功能异常以及免疫挑战应答异常的潜在基础。本研究对本团队近期一项AA研究中的成年PAE组与对照组雌性大鼠脑组织进行分析，旨在明确PAE是否会引发基因表达的长期改变，以及此类改变是否介导了PAE雌性大鼠关节炎严重程度与病程的异常变化。 方法：将成年雌性大鼠分为PAE组、配对喂养组（pair-fed, PF）与自由进食对照组（ad libitum-fed control, C），分别给予生理盐水或完全弗氏佐剂（Complete Freund’s Adjuvant）注射。分别于炎症峰值期与炎症消退期（即注射后第16天与第39天）处死动物；同时并行处死注射生理盐水的PAE组、PF组与C组雌性大鼠。采用全基因组mRNA表达微阵列技术，对前额叶皮层与海马体的基因表达水平进行分析。 结果：相较于对照组，仅暴露于乙醇的PAE组（即注射生理盐水的雌性大鼠）在前额叶皮层与海马体中均出现显著的基因表达改变，涉及神经发育、细胞凋亡与能量代谢相关基因。此外，在应对炎症刺激（即注射完全弗氏佐剂的雌性大鼠）时，PAE组大鼠呈现出独特的基因表达谱，且未出现对照组与配对喂养组中观察到的免疫应答相关基因及调控因子的激活现象。 结论：本研究结果支持"PAE可通过基因表达层面影响神经免疫功能"这一假说，证实了PAE对中枢神经系统在稳态条件下以及炎性损伤后的应答均存在长期效应。 关键词：产前酒精暴露（PAE）、乙醇、炎症、关节炎、基因表达、大鼠。