Maternal smoking during gestation, differential DNA methylation, and changes in lung function at age 18 years

摘要

Background: DNA methylation (DNA-M) is considered to constitute an archive of past exposures, which may link gestational exposures with child and adult health outcomes. Aims: In a birth cohort followed into early adulthood, we explored whether epigenome-wide DNA-M in peripheral blood cells is related to intra-uterine exposure to maternal smoking 18 years earlier and whether differentially methylated cytosine-phosphate-guanine dinucleotide (CpG) sites are associated with lung function in adolescence. Methods: Genome-wide DNA-M was assessed using the Illumina Infinium HumanMethylation450 BeadChip, which interrogates ＞484,000 CpG sites. We focused on DNA-M in 245 female participants at age 18, who were randomly selected from the total cohort. A training-testing procedure was used to optimize the identification of methylated CpG sites. Forced expiratory volume (FEV1), forced vital capacity (FVC), and the FEV1/FVC ratio were measured in children of the Isle of Wight birth cohort at age 18. Current smoking and cotinine urine levels were ascertained at age 18 years. Results: In utero cigarette smoke exposure was associated with statistically significant differential methylation, particularly of CpG sites of the cytochrome P450 aryl hydrocarbon hydroxylase (CYP1A1), aryl hydrocarbon receptor repressor (AHRR),contactin-associated protein-like 2 (CNTNAP2), and myosin 1G (MYO1G) genes. For instance, the methylation of the CpG site cg17924476 of the AHRR gene was increased in relation to gestational smoke exposure. In turn, controlling for height and active smoking, differential methylation of cg17924476 of the AHRR gene was associated with a statistically reduced FEV1/FVC ratio (range 62-100%). The FEV1/FVC ratio was diminished by 2% per increase of DNA-M of 10%. Conclusions: In utero smoke exposure seems to establish long-term memory via DNA methylation leading to a higher susceptibility for diminished lung function at age 18 years of age.