title: Prenatal exposure to tobacco smoke sex dependently influences methylation and mRNA levels of theIgfaxis in lungs of mouse offspring.
abstract: Prenatal smoke exposure is a risk factor for abnormal lung development and increased sex-dependent susceptibility for asthma and chronic obstructive pulmonary disease (COPD). Birth cohort studies show genome-wide DNA methylation changes in children from smoking mothers, but evidence for sex-dependent smoke-induced effects is limited. The insulin-like growth factor (IGF) system plays an important role in lung development. We hypothesized that prenatal exposure to smoke induces lasting changes in promoter methylation patterns ofIgf1andIgf1r, thus influencing transcriptional activity and contributing to abnormal lung development. We measured and compared mRNA levels along with promoter methylation ofIgf1andIgf1rand their protein concentrations in lung tissue of 30-day-old mice that had been prenatally exposed to cigarette smoke (PSE) or filtered air (control). Body weight at 30 days after birth was measured as global indicator of normal development. Female PSE mice showed lower mRNA levels ofIgf1and its receptor (Igf1:P= 0.05;Igf1r:P= 0.03). Furthermore, CpG-site-specific methylation changes were detected inIgf1rin a sex-dependent manner and the body weight of female offspring was reduced after prenatal exposure to smoke, while protein concentrations were unaffected. Prenatal exposure to smoke induces a CpG-site-specific loss ofIgf1rpromoter methylation, which can be associated with body weight. These findings highlight the sex-dependent and potentially detrimental effects of in utero smoke exposure on DNA methylation andIgf1andIgf1rmRNA levels. The observations support a role forIgf1andIgf1rin abnormal development.
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center, Groningen, The Netherlands.|GRIAC Research Institute, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: K F
authors.initials: KF
authors.lastname: Meyer
authors.affiliation: Priority Area Asthma and Allergy, Leibnitz Center for Medicine and Biosciences, Research Center Borstel and Christian Albrechts University Kiel, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Krauss-Etschmann
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center, Groningen, The Netherlands.|GRIAC Research Institute, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: Kooistra
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center, Groningen, The Netherlands.|GRIAC Research Institute, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Reinders-Luinge
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center, Groningen, The Netherlands.|GRIAC Research Institute, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: Timens
authors.affiliation: Molecular and Integrative Physiological Sciences Program, Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; and.
authors.forename: L
authors.initials: L
authors.lastname: Kobzik
authors.affiliation: Department of Obstetrics and Gynaecology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Plösch
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center, Groningen, The Netherlands; m.n.hylkema@umcg.nl.|GRIAC Research Institute, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: M N
authors.identifier: http://orcid.org/0000-0002-6732-8903
authors.initials: MN
authors.lastname: Hylkema
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D008297:Male; D008807:Mice, Inbred BALB C; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D012727:Sex Characteristics; D015398:Signal Transduction / Q000235:genetics; D012907:Smoking / Q000009:adverse effects*; D014026:Nicotiana
chemical_list: D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1
keywords: COPD; asthma; developmental origins of health and disease; epigenetics; fetal programming; pyrosequencing