Prenatal parental tobacco smoking, gene specific DNA methylation, and newborns size: the Generation R study.

Background: Deleterious effects of prenatal tobacco smoking on fetal growth and newborn weight are well-established. One of the proposed mechanisms underlying this relationship is alterations in epigenetic programming. We selected 506 newborns from a population-based prospective birth cohort in the Netherlands. Prenatal parental tobacco smoking was assessed using self-reporting questionnaires. Information on birth outcomes was obtained from medical records. The deoxyribonucleic acid (DNA) methylation of the growth genes IGF2DMR and H19 was measured in newborn umbilical cord white blood cells. Associations were assessed between parental tobacco smoking and DNA methylation using linear mixed models and adjusted for potential confounders.

Results: The DNA methylation levels of IGF2DMR and H19 in the non-smoking group were median (90 % range), 54.0 % (44.6-62.0), and 30.0 % (25.5-34.0), in the first trimester only smoking group 52.2 % (44.5-61.1) and 30.8 % (27.1-34.1), and in the continued smoking group 51.6 % (43.9-61.3) and 30.2 % (23.7-34.8), respectively. Continued prenatal maternal smoking was inversely associated with IGF2DMR methylation (β = -1.03, 95 % CI -1.76; -0.30) in a dose-dependent manner (P-trend = 0.030). This association seemed to be slightly more profound among newborn girls (β = -1.38, 95 % CI -2.63; -0.14) than boys (β = -0.72, 95 % CI -1.68; 0.24). H19 methylation was also inversely associated continued smoking <5 cigarettes/day (β = -0.96, 95 % CI -1.78; -0.14). Moreover, the association between maternal smoking and newborns small for gestational age seems to be partially explained by IGF2DMR methylation (β = -0.095, 95 % CI -0.249; -0.018). Among non-smoking mothers, paternal tobacco smoking was not associated with IGF2DMR or H19 methylation.

Conclusions: Maternal smoking is inversely associated with IGF2DMR methylation in newborns, which can be one of the underlying mechanisms through which smoking affects fetal growth.