Prenatal Lead (Pb) Exposure and Peripheral Blood DNA Methylation (5mC) and Hydroxymethylation (5hmC) in Mexican Adolescents from the ELEMENT Birth Cohort,Environmental Health Perspectives

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Prenatal Lead (Pb) Exposure and Peripheral Blood DNA Methylation (5mC) and Hydroxymethylation (5hmC) in Mexican Adolescents from the ELEMENT Birth Cohort
Environmental Health Perspectives ( IF 10.4 ) Pub Date : 2021-6-21 , DOI: 10.1289/ehp8507
Christine A Rygiel ₁ , Jaclyn M Goodrich ₁ , Maritsa Solano-González ₂ , Adriana Mercado-García ₂ , Howard Hu ₃ , Martha M Téllez-Rojo ₂ , Karen E Peterson _{1,

4} , Dana C Dolinoy _{1,

4}

Affiliation

Abstract

Background:

Gestational lead (Pb) exposure can adversely affect offspring health through multiple mechanisms, including epigenomic alterations via DNA methylation (5mC) and hydroxymethylation (5hmC), an intermediate in oxidative demethylation. Most current methods do not distinguish between 5mC and 5hmC, limiting insights into their individual roles.

Objective:

Our study sought to identify the association of trimester-specific (T1, T2, T3) prenatal Pb exposure with 5mC and 5hmC levels at multiple cytosine-phosphate-guanine sites within gene regions previously associated with prenatal Pb (HCN2, NINJ2, RAB5A, TPPP) in whole blood leukocytes of children ages 11–18 years of age.

Methods:

Participants from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) birth cohorts were selected ( $lowercase italic n equals 144$ ) for pyrosequencing analysis following oxidative or standard sodium bisulfite treatment. This workflow directly quantifies total methylation ( $5-methylcytosine plus 5-hydroxymethylcytosine$ ) and 5mC only; 5hmC is estimated by subtraction.

Results:

Participants were 51% male, and mean maternal blood lead levels (BLL) were $6.43 \pm 5.16 μ g / dL$ in Trimester 1 (T1), $5.66 \pm 5.21 μ g / dL$ in Trimester 2 (T2), and $5.86 \pm 4.34 μ g / dL$ in Trimester 3 (T3). In addition, 5hmC levels were calculated for HCN2 ( $mean \pm standard deviation (SD)$ , $2.08 \pm 4.18 %$ ), NINJ2 (G/C: $2.01 \pm 5.95$ ; GG: $0.90 \pm 3.97$ ), RAB5A ( $0.66 \pm 0.80 %$ ), and TPPP ( $1.11 \pm 6.67 %$ ). Furthermore, 5mC levels were measured in HCN2 ( $81.3 \pm 9.63 %$ ), NINJ2 (heterozygotes: $38.6 \pm 7.39 %$ ; GG homozygotes: $67.3 \pm 9.83 %$ ), RAB5A ( $1.41 \pm 1.21 %$ ), and TPPP ( $92.5 \pm 8.03 %$ ). Several significant associations between BLLs and 5mC/5hmC were identified: T1 BLLs with 5mC in HCN2 ( $β = - 0.37$ , $lowercase italic p equals 0.03$ ) and 5hmC in NINJ2 ( $lowercase beta equals 0.49$ , $lowercase italic p equals 0.003$ ); T2 BLLs with 5mC in HCN2 ( $lowercase beta equals 0.37$ , $lowercase italic p equals 0.03$ ) and 5hmC in NINJ2 ( $lowercase beta equals 0.27$ , $lowercase italic p equals 0.008$ ); and T3 BLLs with 5mC in HCN2 ( $lowercase beta equals 0.50$ , $lowercase italic p equals 0.01$ ) and NINJ2 ( $β = - 0.35$ , $lowercase italic p equals 0.004$ ) and 5hmC in NINJ2 ( $lowercase beta equals 0.45$ , $lowercase italic p less than 0.001$ ). NINJ2 5mC was negatively correlated with gene expression (Pearson $r = - 0.5$ , $lowercase italic p equals 0.005$ ), whereas 5hmC was positively correlated ( $lowercase italic r equals 0.4$ , $lowercase italic p equals 0.04$ ).

Discussion:

These findings suggest there is variable 5hmC in human whole blood and that prenatal Pb exposure is associated with gene-specific 5mC and 5hmC levels at adolescence, providing evidence to consider 5hmC as a regulatory mechanism that is responsive to environmental exposures. https://doi.org/10.1289/EHP8507

中文翻译：

来自 ELEMENT 出生队列的墨西哥青少年的产前铅 (Pb) 暴露和外周血 DNA 甲基化 (5mC) 和羟甲基化 (5hmC)

摘要

背景：

妊娠期铅 (Pb) 暴露可通过多种机制对后代健康产生不利影响，包括通过 DNA 甲基化 (5mC) 和羟甲基化 (5hmC) 进行的表观基因组改变，羟甲基化是氧化去甲基化的中间体。大多数当前方法不区分 5mC 和 5hmC，限制了对其各自角色的了解。

客观的：

我们的研究试图确定妊娠期特异性（T1、T2、T3）产前铅暴露与先前与产前铅相关的基因区域内多个胞嘧啶-磷酸-鸟嘌呤位点的 5mC 和 5hmC 水平的关联（HCN2、NINJ2、RAB5A、TPPP )在 11-18 岁儿童的全血白细胞中。

方法：

选择了来自墨西哥早期生命接触环境毒物 (ELEMENT) 出生队列的参与者 ( $lowercase italic n equals 144$ ) 用于氧化或标准亚硫酸氢钠处理后的焦磷酸测序分析。此工作流程直接量化总甲基化 ( $5-methylcytosine plus 5-hydroxymethylcytosine$ ) 和 5mC 而已；5hmC 是通过减法估计的。

结果：

参与者为 51% 的男性，平均母体血铅水平 (BLL) 为 $6.43 \pm 5.16 μ G / 分升$ 在第 1 学期 (T1)， $5.66 \pm 5.21 μ G / 分升$ 在第 2 学期 (T2)，以及 $5.86 \pm 4.34 μ G / 分升$ 在第 3 学期 (T3)。此外，还计算了HCN2的 5hmC 水平（ $意思是 \pm 标准偏差 (标清)$ , $2.08 \pm 4.18 %$ ), NINJ2 (G/C: $2.01 \pm 5.95$ ; GG： $0.90 \pm 3.97$ ), RAB5A ( $0.66 \pm 0.80 %$ ), 和TPPP ( $1.11 \pm 6.67 %$ ). 此外，在HCN2中测量了 5mC 水平（ $81.3 \pm 9.63 %$ ), NINJ2 (杂合子: $38.6 \pm 7.39 %$ ; GG纯合子： $67.3 \pm 9.83 %$ ), RAB5A ( $1.41 \pm 1.21 %$ ), 和TPPP ( $92.5 \pm 8.03 %$ ). 确定了 BLL 和 5mC/5hmC 之间的几个重要关联：HCN2中具有 5mC 的 T1 BLL （ $β = - 0.37$ , $lowercase italic p equals 0.03$ ) 和NINJ2中的 5hmC ( $lowercase beta equals 0.49$ , $lowercase italic p equals 0.003$ ); 在HCN2中具有 5mC 的 T2 BLL ( $lowercase beta equals 0.37$ , $lowercase italic p equals 0.03$ ) 和NINJ2中的 5hmC ( $lowercase beta equals 0.27$ , $lowercase italic p equals 0.008$ ); 和在HCN2中具有 5mC 的 T3 BLL （ $lowercase beta equals 0.50$ , $lowercase italic p equals 0.01$ ) 和NINJ2 ( $β = - 0.35$ , $lowercase italic p equals 0.004$ ) 和NINJ2中的 5hmC ( $lowercase beta equals 0.45$ , $lowercase italic p less than 0.001$ ). NINJ2 5mC 与基因表达呈负相关 (Pearson $r = - 0.5$ , $lowercase italic p equals 0.005$ ), 而 5hmC 呈正相关 ( $lowercase italic r equals 0.4$ , $lowercase italic p equals 0.04$ ).