Environmental Health Perspectives ( IF 10.1 ) Pub Date : 2021-1-15 , DOI: 10.1289/ehp7699 Catherine G Burke 1, 2 , Jason R Myers 3 , Christina M Post 2 , Lisbeth A Boulé 1, 2 , B Paige Lawrence 1, 2, 3
Abstract
Background:
Early life environmental exposures can have lasting effects on the function of the immune system and contribute to disease later in life. Epidemiological studies have linked early life exposure to xenobiotics that bind the aryl hydrocarbon receptor (AhR) with dysregulated immune responses later in life. Among the immune cells influenced by developmental activation of the AhR are T cells. Yet, the underlying affected cellular pathways via which activating the AhR early in life causes the responses of T cells to remain affected into adulthood remain unclear.
Objective:
Our goal was to identify cellular mechanisms that drive impaired T-cell responses later in life following maternal exposure to an exogenous AhR ligand.
Methods:
C57BL/6 mice were vertically exposed to the prototype AhR ligand, 2,3,7,8-tetrachlorodibenzo--dioxin (TCDD), throughout gestation and early postnatal life. The transcriptome and DNA methylation patterns were evaluated in T cells isolated from naïve and influenza A virus (IAV)-infected adult mice that were developmentally exposed to TCDD or vehicle control. We then assessed the influence of DNA methylation-altering drug therapies on the response of T cells from developmentally exposed mice to infection.
Results:
Gene and protein expression showed that developmental AhR activation reduced T-cell expansion and effector functions during IAV infection later in life. Furthermore, whole-genome bisulfite sequencing analyses revealed that developmental AhR activation durably programed DNA methylation patterns across the T-cell genome. Treatment of developmentally exposed offspring with DNA methylation-altering drugs alleviated some, but not all, of the impaired T-cell responses.
Discussion:
Taken together, these results indicate that skewed DNA methylation is one of the mechanisms by which early life exposures can durably change the function of T cells in mice. Furthermore, treatment with DNA methylation-altering drugs after the exposure restored some aspects of T-cell functional responsiveness. https://doi.org/10.1289/EHP7699
中文翻译：
发育暴露于芳基烃受体配体的幼稚小鼠和甲型流感病毒感染小鼠 CD4+ T 细胞中的 DNA 甲基化模式
抽象的
背景：
生命早期的环境暴露会对免疫系统的功能产生持久影响，并导致生命后期的疾病。流行病学研究表明，早年接触与芳烃受体（AhR）结合的异生素与晚年免疫反应失调有关。受 AhR 发育激活影响的免疫细胞包括 T 细胞。然而，生命早期激活 AhR 的潜在受影响细胞途径会导致以下反应： T 细胞在成年后是否仍受到影响仍不清楚。
客观的：
我们的目标是确定驱动受损的细胞机制母体暴露于外源性 AhR 配体后，T 细胞在生命后期发生反应。
方法：
C57BL/6小鼠垂直分离 与原型 AhR 配体 2,3,7,8-四氯二苯并- -二恶英（TCDD），贯穿整个妊娠期和产后早期。转录组和 DNA 甲基化模式的评估从幼稚小鼠和感染甲型流感病毒 (IAV) 的成年小鼠中分离出 T 细胞，这些小鼠在发育过程中暴露于 TCDD 或媒介物对照。然后我们评估了 DNA 甲基化改变药物疗法对以下反应的影响：来自发育中暴露于感染的小鼠的 T 细胞。
结果：
基因和蛋白质表达表明发育 AhR 激活减少晚年 IAV 感染期间 T 细胞扩增和效应器功能。此外，全基因组亚硫酸氢盐测序分析表明，发育过程中的 AhR 激活持久地编程了整个基因组的 DNA 甲基化模式。 T 细胞基因组。用 DNA 甲基化改变药物治疗发育暴露的后代可缓解部分（但不是全部）受损的症状 T 细胞反应。
讨论：
总而言之，这些结果表明，DNA 甲基化偏态是生命早期暴露可持久改变小鼠 T 细胞功能的机制之一。此外，在暴露后使用 DNA 甲基化改变药物进行治疗可以恢复某些方面的功能。 T 细胞功能反应。 https://doi.org/10.1289/EHP7699
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