Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK.
Department of Clinical Sciences, University of Bergen, Bergen, Norway.
Clin Epigenetics. 2023 Aug 31;15(1):131. doi: 10.1186/s13148-023-01540-7.
Experimental studies suggest that exposures may impact respiratory health across generations via epigenetic changes transmitted specifically through male germ cells. Studies in humans are, however, limited. We aim to identify epigenetic marks in offspring associated with father's preconception smoking.
We conducted epigenome-wide association studies (EWAS) in the RHINESSA cohort (7-50 years) on father's any preconception smoking (n = 875 offspring) and father's pubertal onset smoking < 15 years (n = 304), using Infinium MethylationEPIC Beadchip arrays, adjusting for offspring age, own smoking and maternal smoking. EWAS of maternal and offspring personal smoking were performed for comparison. Father's smoking-associated dmCpGs were checked in subpopulations of offspring who reported no personal smoking and no maternal smoking exposure.
Father's smoking commencing preconception was associated with methylation of blood DNA in offspring at two cytosine-phosphate-guanine sites (CpGs) (false discovery rate (FDR) < 0.05) in PRR5 and CENPP. Father's pubertal onset smoking was associated with 19 CpGs (FDR < 0.05) mapped to 14 genes (TLR9, DNTT, FAM53B, NCAPG2, PSTPIP2, MBIP, C2orf39, NTRK2, DNAJC14, CDO1, PRAP1, TPCN1, IRS1 and CSF1R). These differentially methylated sites were hypermethylated and associated with promoter regions capable of gene silencing. Some of these sites were associated with offspring outcomes in this cohort including ever-asthma (NTRK2), ever-wheezing (DNAJC14, TPCN1), weight (FAM53B, NTRK2) and BMI (FAM53B, NTRK2) (p < 0.05). Pathway analysis showed enrichment for gene ontology pathways including regulation of gene expression, inflammation and innate immune responses. Father's smoking-associated sites did not overlap with dmCpGs identified in EWAS of personal and maternal smoking (FDR < 0.05), and all sites remained significant (p < 0.05) in analyses of offspring with no personal smoking and no maternal smoking exposure.
Father's preconception smoking, particularly in puberty, is associated with offspring DNA methylation, providing evidence that epigenetic mechanisms may underlie epidemiological observations that pubertal paternal smoking increases risk of offspring asthma, low lung function and obesity.
实验研究表明，暴露可能会通过特定地通过雄性生殖细胞传递的表观遗传变化对跨代的呼吸健康产生影响。然而，人类研究有限。我们旨在确定与父亲受孕前吸烟相关的后代中的表观遗传标记。
我们在 RHINESSA 队列（7-50 岁）中进行了父亲任何受孕前吸烟（n=875 名后代）和父亲青春期开始吸烟<15 年（n=304）的全基因组关联研究（EWAS），使用 Infinium MethylationEPIC Beadchip 阵列，调整后代年龄、自身吸烟和母亲吸烟。进行了母亲和后代个人吸烟的 EWAS 比较。在报告无个人吸烟和无母亲吸烟暴露的后代亚群中检查了与父亲吸烟相关的 dmCpG。
父亲受孕前开始吸烟与两个胞嘧啶-磷酸-鸟嘌呤位点（CpG）（错误发现率（FDR）<0.05）的后代血液 DNA 甲基化有关（PRR5 和 CENPP）。父亲青春期开始吸烟与 19 个 CpG （FDR<0.05）有关，这些 CpG 映射到 14 个基因（TLR9、DNTT、FAM53B、NCAPG2、PSTPIP2、MBIP、C2orf39、NTRK2、DNAJC14、CDO1、PRAP1、TPCN1、IRS1 和 CSF1R）。这些差异甲基化位点呈超甲基化状态，与能够基因沉默的启动子区域相关。其中一些位点与该队列中的后代结局相关，包括既往哮喘（NTRK2）、既往喘息（DNAJC14、TPCN1）、体重（FAM53B、NTRK2）和 BMI（FAM53B、NTRK2）（p<0.05）。通路分析显示，基因表达调控、炎症和先天免疫反应等基因本体通路富集。父亲吸烟相关的位点与个人和母亲吸烟的 EWAS 中鉴定的 dmCpG 没有重叠（FDR<0.05），并且在分析无个人吸烟和无母亲吸烟暴露的后代时，所有位点仍然具有统计学意义（p<0.05）。
父亲受孕前吸烟，特别是在青春期，与后代 DNA 甲基化有关，这为表观遗传机制可能是青春期父亲吸烟增加后代哮喘、肺功能低下和肥胖风险的流行病学观察提供了证据。
