Academic journal article Environmental Health Perspectives

Identification of DNA Methylation Changes in Newborns Related to Maternal Smoking during Pregnancy

Academic journal article Environmental Health Perspectives

Identification of DNA Methylation Changes in Newborns Related to Maternal Smoking during Pregnancy

Article excerpt


Cigarette smoke contains > 7,000 chemicals, of which hundreds are known to be harmful and at least 69 are known to cause cancer [Centers for Disease Control and Prevention (CDC) 2010]. Although the significant health effects of smoking are well recognized, smoking remains the largest preventable cause of death in the United States (CDC 2010). In addition to the deleterious direct effects on the person who smokes, smoking can also have indirect effects, for example, on the developing embryo or fetus. Maternal smoking during pregnancy is associated with substantial infant morbidity and mortality (Dietz et al. 2010). Although smoking is a modifiable risk behavior that influences the health of both the infant and the mother, only about 45% of women who report that they smoke 3 months before pregnancy quit during pregnancy (CDC 2012). Exposure to the fetus thus remains an important area of research, with little known about the molecular changes that occur in newborns in response to exposure in utero. Further, if these changes persist for an extended period of time (or are permanent), they could have implications for disease development later in life.

The "developmental origins of disease" hypothesis (Gluckman and Hanson 2004) proposes that environmental exposures occurring during development can cause biological changes that influence disease susceptibility later in life. One potential mechanism is through an alteration of the fetal epigenome, which may have long-term consequences (Waterland and Michels 2007). One of the most well-studied forms of epigenetic modification is DNA methylation, which occurs predominantly at position C5 of cytosine in cytosine-guanine dinucleotides (CpGs). DNA methylation plays an important role in human health and has been associated with a growing number of diseases including cancer, imprinting disorders, and repeat-instability diseases (Robertson 2005).

Several studies have examined DNA methylation changes associated with indirect maternal tobacco smoke exposure in utero [reviewed by Suter et al. (2013)]. These studies have examined changes in DNA from placenta, cord blood, buccal cells, or granulocytes by taking either a targeted (i.e., one or a few genes) or a more global approach (i.e., epigenome-wide). However, only one study to date has used a high-density DNA methylation array (the Illumina HumanMethylation450 BeadChip), to assess DNA methylation in newborns related to maternal smoking during pregnancy (Joubert et al. 2012).

To further explore DNA methylation changes in infants related to maternal smoking during pregnancy, we performed an epigenome-wide association study (EWAS) using whole blood from 889 infants in the Norway Facial Clefts Study (NCL), including 287 whose mothers smoked during the first trimester. As a replication set, we used publically available results [obtained from Supplemental, Table S1, in Joubert et al. (2012)] and considered two levels of replication: a) site level at the exact CpG and b) gene level for other CpG sites in or near the same gene. In addition, we considered the overlap between smoking-associated methylation in adults and newborns, with special focus on genes that may be unique to each.


Study population. The present study is based on infants from the NCL. NCL is a national population-based case-control study of cleft lip and cleft palate, disorders characterized by the incomplete fusion of the lip and/or palate during development. The study design has been previously described in detail (Wilcox et al. 2007). Briefly, between the years 1996 and 2001, all families of newborns referred for cleft surgery in Norway were contacted; 88% of those eligible agreed to participate (n = 573). Controls were selected by a random sampling of roughly 4 per 1,000 live births in Norway during that same time period; 76% of those eligible agreed to participate (n = 763). NCL was approved by the Norwegian Data Inspectorate and Regional Medical Ethics Committee of Western Norway, and informed consent was provided by both the mother and father. …

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