Uppsala University, Department of Organismal Biology, 752 36 Uppsala, Sweden.
Karlstad University, Department of Health Sciences, 651 88 Karlstad, Sweden.
Environ Int. 2021 Nov;156:106617. doi: 10.1016/j.envint.2021.106617. Epub 2021 May 18.
Accumulating evidence suggests that prenatal chemical exposure triggers epigenetic modifications that could influence health outcomes later in life. In this study, we investigated whether DNA methylation (DNAm) levels at the glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B) gene underlies the association between prenatal exposure to an endocrine disrupting chemical (EDC), bisphenol F (BPF), and lower cognitive functions in 7-year-old children.
Data from 799 children participating in the Swedish Environmental Longitudinal Mother and child Asthma and allergy (SELMA) pregnancy cohort was analyzed. Prenatal BPF exposure was assessed by measuring BPF levels in maternal urine. At age 7, DNAm of three CpG sites in a regulatory region of the GRIN2B gene was analyzed from buccal swabs using bisulfite-Pyrosequencing. Cognitive functions, including full-scale IQ and four subscales, were evaluated using the Wechsler Intelligence Scale for Children (WISC-IV). Associations between prenatal BPF exposure and GRIN2B DNAm, as well as between GRIN2B DNAm and cognitive functions, were determined using regression models adjusted for potential confounders. Generalized structural equation models (gSEM) were used to evaluate if GRIN2B DNAm mediates the association between prenatal BPF exposure and cognitive functions at 7 years of age.
Prenatal BPF exposure was positively associated with GRIN2B DNAm levels at the third CpG site (CpG3), while CpG3 methylation was inversely associated with cognitive test scores. Mediation analyses showed that CpG3 methylation exerted 6-9% of the association between BPF exposure and full-scale IQ, as well as verbal comprehension and perceptual reasoning in boys, while not significant in girls.
This study is the first to identify locus-specific DNAm as a mediating factor underlying an epidemiological association between prenatal EDC exposure and cognitive functions in childhood. It also confirms previous findings, that GRIN2B DNAm is responsive to environmental exposures.
越来越多的证据表明，产前化学物质暴露会引发表观遗传修饰，从而影响生命后期的健康结果。在这项研究中，我们调查了谷氨酸离子型受体 NMDA 型亚基 2B（GRIN2B）基因的 DNA 甲基化（DNAm）水平是否是产前暴露于内分泌干扰化学物质（EDC）双酚 F（BPF）与 7 岁儿童认知功能下降之间关联的基础。
分析了参加瑞典环境纵向母婴哮喘和过敏（SELMA）妊娠队列的 799 名儿童的数据。通过测量母亲尿液中的 BPF 水平来评估产前 BPF 暴露。在 7 岁时，使用 bisulfite-Pyrosequencing 从口腔拭子中分析了 GRIN2B 基因调控区三个 CpG 位点的 DNAm。使用韦氏儿童智力量表（WISC-IV）评估认知功能，包括全量表智商和四个分量表。使用回归模型调整潜在混杂因素后，确定了产前 BPF 暴露与 GRIN2B DNAm 之间以及 GRIN2B DNAm 与认知功能之间的关联。使用广义结构方程模型（gSEM）评估 GRIN2B DNAm 是否介导了产前 BPF 暴露与 7 岁时认知功能之间的关联。
产前 BPF 暴露与 GRIN2B 基因第三个 CpG 位点（CpG3）的 DNAm 呈正相关，而 CpG3 甲基化与认知测试分数呈负相关。中介分析表明，CpG3 甲基化对 BPF 暴露与全量表智商以及男孩的言语理解和感知推理之间的关联有 6-9%的解释作用，但在女孩中没有显著意义。
本研究首次确定了特定基因座的 DNAm 作为产前 EDC 暴露与儿童认知功能之间的流行病学关联的中介因素。它还证实了先前的发现，即 GRIN2B DNAm 对环境暴露有反应。
