Department of Epidemiology, Rollins School of Public Health, Emory University, 1518 Clifton Road, Atlanta, GA, 30322, USA.
Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
Clin Epigenetics. 2023 May 13;15(1):84. doi: 10.1186/s13148-023-01503-y.
Higher exposure to traffic-related air pollution (TRAP) is related to lower fertility, with specific adverse effects on the ovary. Folic acid may attenuate these effects. Our goal was to explore the relation of TRAP exposure and supplemental folic acid intake with epigenetic aging and CpG-specific DNA methylation (DNAm) in granulosa cells (GC). Our study included 61 women undergoing ovarian stimulation at a fertility center (2005-2015). DNAm levels were profiled in GC using the Infinium MethylationEPIC BeadChip. TRAP was defined using a spatiotemporal model to estimate residence-based nitrogen dioxide (NO) exposure. Supplemental folic acid intake was measured with a validated food frequency questionnaire. We used linear regression to evaluate whether NO or supplemental folic acid was associated with epigenetic age acceleration according to the Pan-tissue, mural GC, and GrimAge clocks or DNAm across the genome adjusting for potential confounders and accounting for multiple testing with a false discovery rate < 0.1.
There were no associations between NO or supplemental folic acid intake and epigenetic age acceleration of GC. NO and supplemental folic acid were associated with 9 and 11 differentially methylated CpG sites. Among these CpGs, only cg07287107 exhibited a significant interaction (p-value = 0.037). In women with low supplemental folic acid, high NO exposure was associated with 1.7% higher DNAm. There was no association between NO and DNAm in women with high supplemental folic acid. The genes annotated to the top 250 NO-associated CpGs were enriched for carbohydrate and protein metabolism, postsynaptic potential and dendrite development, and membrane components and exocytosis. The genes annotated to the top 250 supplemental folic acid-associated CpGs were enriched for estrous cycle, learning, cognition, synaptic organization and transmission, and size and composition of neuronal cell bodies.
We found no associations between NO, supplemental folic acid, and DNAm age acceleration of GC. However, there were 20 differentially methylated CpGs and multiple enriched GO terms associated with both exposures suggesting that differences in GC DNAm could be a plausible mechanism underlying the effects of TRAP and supplemental folic acid on ovarian function.
较高的交通相关空气污染（TRAP）暴露与较低的生育能力有关，对卵巢有特定的不利影响。叶酸可能会减轻这些影响。我们的目标是探索 TRAP 暴露和补充叶酸摄入与颗粒细胞（GC）中的表观遗传衰老和特定 CpG 的 DNA 甲基化（DNAm）之间的关系。我们的研究包括 61 名在生育中心接受卵巢刺激的女性（2005-2015 年）。使用 Infinium MethylationEPIC BeadChip 对 GC 中的 DNAm 水平进行了分析。TRAP 是使用时空模型来估计基于居住地的二氧化氮（NO）暴露来定义的。补充叶酸的摄入量是通过经过验证的食物频率问卷来测量的。我们使用线性回归来评估 NO 或补充叶酸是否与根据 Pan-tissue、壁 GC 和 GrimAge 时钟的 GC 表观遗传年龄加速或整个基因组的 DNAm 相关，同时考虑到潜在的混杂因素，并通过错误发现率<0.1 进行了多次测试。
NO 或补充叶酸摄入与 GC 的表观遗传年龄加速之间没有关联。NO 和补充叶酸与 9 个和 11 个差异甲基化 CpG 位点相关。在这些 CpG 中，只有 cg07287107 表现出显著的相互作用（p 值=0.037）。在补充叶酸水平较低的女性中，高 NO 暴露与 DNAm 增加 1.7%相关。在补充叶酸水平较高的女性中，NO 与 DNAm 之间没有关联。注释到前 250 个与 NO 相关的 CpG 的基因富含碳水化合物和蛋白质代谢、突触后电位和树突发育以及膜成分和胞吐作用。注释到前 250 个与补充叶酸相关的 CpG 的基因富含动情周期、学习、认知、突触组织和传递以及神经元细胞体的大小和组成。
我们没有发现 NO、补充叶酸与 GC 的 DNAm 年龄加速之间的关联。然而，有 20 个差异甲基化 CpG 和多个富集的 GO 术语与这两种暴露都相关，这表明 GC DNAm 的差异可能是 TRAP 和补充叶酸对卵巢功能影响的一个合理机制。
