title: Associations between antibiotic exposure during pregnancy, birth weight and aberrant methylation at imprinted genes among offspring.
abstract: OBJECTIVE
  Low birth weight (LBW) has been associated with common adult-onset chronic diseases, including obesity, cardiovascular disease, type II diabetes and some cancers. The etiology of LBW is multi-factorial. However, recent evidence suggests exposure to antibiotics may also increase the risk of LBW. The mechanisms underlying this association are unknown, although epigenetic mechanisms are hypothesized. In this study, we evaluated the association between maternal antibiotic use and LBW and examined the potential role of altered DNA methylation that controls growth regulatory imprinted genes in these associations.
  
  
  METHODS
  Between 2009-2011, 397 pregnant women were enrolled and followed until delivery. Prenatal antibiotic use was ascertained through maternal self-report. Imprinted genes methylation levels were measured at differentially methylated regions (DMRs) using bisulfite pyrosequencing. Generalized linear models were used to examine associations among antibiotic use, birth weight and DMR methylation fractions.
  
  
  RESULTS
  After adjusting for infant gender, race/ethnicity, maternal body mass index, delivery route, gestational weight gain, gestational age at delivery, folic acid intake, physical activity, maternal smoking and parity, antibiotic use during pregnancy was associated with 138 g lower birth weight compared with non-antibiotic use (β-coefficient=-132.99, s.e.=50.70, P=0.008). These associations were strongest in newborns of women who reported antibiotic use other than penicillins (β-coefficient=-135.57, s.e.=57.38, P=0.02). Methylation at five DMRs, IGF2 (P=0.05), H19 (P=0.15), PLAGL1 (P=0.01), MEG3 (P=0.006) and PEG3 (P=0.08), was associated with maternal antibiotic use; among these, only methylation at the PLAGL1 DMR was also associated with birth weight.
  
  
  CONCLUSIONS
  We report an inverse association between in utero exposure to antibiotics and lower infant birth weight and provide the first empirical evidence supporting imprinted gene plasticity in these associations.
authors.affiliation: Division of Epidemiology, Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Vidal
authors.forename: S K
authors.initials: SK
authors.lastname: Murphy
authors.forename: A P
authors.initials: AP
authors.lastname: Murtha
authors.forename: J M
authors.initials: JM
authors.lastname: Schildkraut
authors.forename: A
authors.initials: A
authors.lastname: Soubry
authors.forename: Z
authors.initials: Z
authors.lastname: Huang
authors.forename: S E B
authors.initials: SE
authors.lastname: Neelon
authors.forename: B
authors.initials: B
authors.lastname: Fuemmeler
authors.forename: E
authors.initials: E
authors.lastname: Iversen
authors.forename: F
authors.initials: F
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Kurtzberg
authors.forename: R L
authors.initials: RL
authors.lastname: Jirtle
authors.forename: C
authors.initials: C
authors.lastname: Hoyo
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000009:adverse effects; D001724:Birth Weight; D002135:Calcium-Binding Proteins; D002318:Cardiovascular Diseases / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D047109:Fetal Development / Q000235:genetics*; D018392:Genomic Imprinting; D006801:Humans; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D009369:Neoplasms / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D009765:Obesity / Q000235:genetics; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000453:epidemiology / Q000235:genetics; D011446:Prospective Studies; D011506:Proteins / Q000235:genetics; D062085:RNA, Long Noncoding / Q000235:genetics; D049031:Sarcoglycans / Q000235:genetics; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D014481:United States / Q000453:epidemiology
chemical_list: D000900:Anti-Bacterial Agents; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; C512941:DLK1 protein, human; C094335:H19 long non-coding RNA; C035170:IGF2 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; C490237:NNAT protein, human; D009419:Nerve Tissue Proteins; C490820:PEG3 protein, human; C106464:PLAGL1 protein, human; D011506:Proteins; D062085:RNA, Long Noncoding; C526572:SGCE protein, human; D049031:Sarcoglycans; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C103637:mesoderm specific transcript protein; D007335:Insulin-Like Growth Factor II