In utero tobacco exposure epigenetically modifies placental CYP1A1 expression

Abstract

The metabolic pathways utilized 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 two-phases: in phase I CYP1A1 catalyzes conversion into harmful hydrophilic DNA adducts, while 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 while deletion of fetal GSTT1 significantly modified birth weight in smokers, no polymorphism fully accounted for fetal growth restriction. Since smoking upregulates CYP1A1 expression, we hypothesized that non-allelic (epigenetic) dysregulation of placental CYP1A1 expression via alterations in DNA methylation (meCpG) may further modify fetal growth. In the present manuscript, 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<0.05). To fully characterize CYP1A1 meCpG status, bisulfite modification and sequencing of the entire proximal 1 kb promoter (containing 59 CpG sites) was performed. CpG sites immediately proximal to the 5′-XRE transcription factor binding element were significantly hypomethylated among smokers (55.6% vs 45.9% meCpG, p=0.027), a finding which uniquely correlated with placental gene expression (r=0.737, p=0.007). Thus in utero tobacco exposure significantly increases placental CYP1A1 expression in association with differential methylation at a critical XRE element.

DNA methylation of the CYP1A1 enhancer is associated with smoking‐induced genetic alterations in human lung

“…Based on previous studies, DNA methylation of these regions may regulate CYP1A1 mRNA levels. 19,21,22 A total of 120 adjacent histologically normal human lung tissue samples from early stage lung cancer patients were analyzed (Table 1). In all tissues, the region A of the enhancer was more methylated [33.14% 6 4.42 (mean 6 SEM)] than the region B (2.54% 6 0.57).…”

“…17,18 In vitro, methylation of cytosine-phosphate-guanosine (CpG) in the XRE inhibits binding of the AHR complex and DNA methylation may regulate CYP1A1 expression in different human tissues. [19][20][21][22][23] We hypothesized that DNA methylation could be involved in inter-individual differences in CYP1A1 gene expression in human lung and play a role in lung cancer development. We quantitatively assess the DNA methylation levels of the CYP1A1 enhancer in histologically normal and tumor lung tissues as well as in a panel of human lung cells.…”

The Impact of Traditional Food and Lifestyle Behavior on Epigenetic Burden of Chronic Disease

“…Human/ cohort study Association between maternal smoking and placental and cord blood methylation [103,[254][255][256][257]261] Fetal growth restriction Rat Association between maternal nicotine exposure and asthma [258] Increased asthma risk in F2 offsprings…”

“…In addition to its long term epigenetic effects, maternal and paternal history have been associated with extensive placental and cord blood DNA methylation changes that are thought to mediate some of the harmful multigenerational effects of smoking (Table 2). [103,[253][254][255][256][257][258][259][260][261] However, the most compelling evidence for the contribution of smoking to epigenetic modulation of disease risk is that from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort in which fathers who had started smoking around the prepubertal age of 11 had male offsprings with significantly higher BMIs by age 9. The implication is that these obese boys were at increased risk of adult obesity and other obesity-associated health problems including many NCCDs due to lifestyle choices of their parents.…”

Epigenetic mechanisms in physiologic and pathologic pregnancies

“…Igazolták, hogy a dohányzás hatására a CYP1A1-gén expressziója a CpG-szigetek metilációs mintázatának a megváltozása következtében módosul [73]. A CYP1A1 elsődleges funkciója a karcinogén anyagok, így a dohányfüstben is megtalálható policiklikus aromás szénhidrátok lebontása.…”