title: In utero tobacco exposure epigenetically modifies placental CYP1A1 expression.
abstract: The metabolic pathways used by higher-eukaryotic organisms to deal with potentially carcinogenic xenobiotic compounds from tobacco smoke have been well characterized. Carcinogenic compounds such as polycyclic aromatic hydrocarbons are metabolized sequentially in 2 phases: in phase I, CYP1A1 catalyzes conversion into harmful hydrophilic DNA adducts, whereas in phase II, GSTT1 enables excretion via conjugation into polar electrophiles. In an effort to understand susceptibility to in utero tobacco exposure, we previously characterized known metabolic functional polymorphisms and demonstrated that although deletion of fetal GSTT1 significantly modified birth weight in smokers, no polymorphism fully accounted for fetal growth restriction. Because smoking up-regulates CYP1A1 expression, we hypothesized that nonallelic (epigenetic) dysregulation of placental CYP1A1 expression via alterations in DNA methylation (meCpG) may further modify fetal growth. In the present article, we compared placental expression of multiple CYP family members among gravidae and observed significantly increased CYP1A1 expression among smokers relative to controls (4.4-fold, P < .05). To fully characterize CYP1A1 meCpG status, bisulfite modification and sequencing of the entire proximal 1-kilobase promoter (containing 59 CpG sites) were performed. CpG sites immediately proximal to the 5′-xenobiotic response element transcription factor binding element were significantly hypomethylated among smokers (55.6% vs 45.9% meCpG, P = .027), a finding that uniquely correlated with placental gene expression (r = 0.737, P = .007). Thus, in utero tobacco exposure significantly increases placental CYP1A1 expression in association with differential methylation at a critical xenobiotic response element.
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Suter
authors.forename: Adi
authors.initials: A
authors.lastname: Abramovici
authors.forename: Lori
authors.initials: L
authors.lastname: Showalter
authors.forename: Min
authors.initials: M
authors.lastname: Hu
authors.forename: Cynthia Do
authors.initials: CD
authors.lastname: Shope
authors.forename: Michael
authors.initials: M
authors.lastname: Varner
authors.forename: Kjersti
authors.initials: K
authors.lastname: Aagaard-Tillery
mesh_terms: D000328:Adult; D001724:Birth Weight / Q000187:drug effects / Q000502:physiology; D016022:Case-Control Studies; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007231:Infant, Newborn; D018811:Maternal Exposure / Q000009:adverse effects; D008431:Maternal-Fetal Exchange / Q000235:genetics*; D010920:Placenta / Q000201:enzymology / Q000378:metabolism*; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D012906:Smoke; D012907:Smoking / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D012906:Smoke; D019363:Cytochrome P-450 CYP1A1
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