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.
The Generation R Study Group, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands ; Department of Obstetrics and Gynecology, Erasmus MC, University Medical Centre, Ee-building Room 2271a, PO Box 1738, 3000 DR Rotterdam, The Netherlands.
Marieke I
MI
Bouwland-Both
The Generation R Study Group, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands ; Department of Obstetrics and Gynecology, Erasmus MC, University Medical Centre, Ee-building Room 2271a, PO Box 1738, 3000 DR Rotterdam, The Netherlands ; Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.
Nina H
NH
van Mil
The Generation R Study Group, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands ; Department of Obstetrics and Gynecology, Erasmus MC, University Medical Centre, Ee-building Room 2271a, PO Box 1738, 3000 DR Rotterdam, The Netherlands.
Catharina P
CP
Tolhoek
Department of Internal Medicine, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.
Lisette
L
Stolk
Department of Biostatistics, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.
Paul H C
PH
Eilers
Department of Internal Medicine, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.
Michael M P J
MM
Verbiest
Department of Molecular Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands.
Bastiaan T
BT
Heijmans
Department of Internal Medicine, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands ; Department of Epidemiology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.
André G
AG
Uitterlinden
Department of Epidemiology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.
Albert
A
Hofman
School for Pedagogical and Educational Sciences, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.
Marinus H
MH
van Ijzendoorn
Department of Epidemiology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands ; Department of Pediatrics, Erasmus Medical Center, Rotterdam, The Netherlands.
Liesbeth
L
Duijts
Department of Pediatrics, Erasmus Medical Center, Rotterdam, The Netherlands.
Johan C
JC
de Jongste
Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands ; Department of Epidemiology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.
Henning
H
Tiemeier
Department of Obstetrics and Gynecology, Erasmus MC, University Medical Centre, Ee-building Room 2271a, PO Box 1738, 3000 DR Rotterdam, The Netherlands.
Eric A P
EA
Steegers
The Generation R Study Group, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands ; Department of Epidemiology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.
Vincent W V
VW
Jaddoe
Department of Obstetrics and Gynecology, Erasmus MC, University Medical Centre, Ee-building Room 2271a, PO Box 1738, 3000 DR Rotterdam, The Netherlands.
Régine P M
RP
Steegers-Theunissen
Cigarettes; Cord blood; DNA methylation; Epigenetic epidemiology; H19; IGF2DMR; Maternal tobacco smoking; Paternal tobacco smoking