Altered placental DNA methylation patterns associated with maternal smoking: current perspectives

Abstract

The developmental origins of health and disease hypothesis states that adverse early life exposures can have lasting, detrimental effects on lifelong health. Exposure to maternal cigarette smoking during pregnancy is associated with morbidity and mortality in offspring, including increased risks for miscarriage, stillbirth, low birth weight, preterm birth, asthma, obesity, altered neurobehavior, and other conditions. Maternal cigarette smoking during pregnancy interferes with placental growth and functioning, and it has been proposed that this may occur through the disruption of normal and necessary placental epigenetic patterns. Epigenome-wide association studies have identified a number of differentially methylated placental genes that are associated with maternal smoking during pregnancy, including RUNX3, PURA, GTF2H2, GCA, GPR135, and HKR1. The placental methylation status of RUNX3 and NR3C1 has also been linked to adverse infant outcomes, including preterm birth and low birth weight, respectively. Candidate gene analyses have also found maternal smoking-associated placental methylation differences in the NR3C1, CYP1A1, HTR2A, and HSD11B2 genes, as well as in the repetitive elements LINE-1 and AluYb8. The differential methylation patterns of several genes have been confirmed to also exhibit altered gene expression patterns, including CYP1A1, CYP19A1, NR3C1, and HTR2A. Placental methylation patterns associated with maternal smoking during pregnancy may be largely gene-specific and tissue-specific and, to a lesser degree, involve global changes. It is important for future research to investigate the mechanistic roles that these differentially methylated genes may play in mediating the association between maternal smoking during pregnancy and disease in later life, as well as to elucidate the potential influence of emerging tobacco product use during pregnancy, including the use of electronic cigarettes, on placental epigenetics.

Small-Magnitude Effect Sizes in Epigenetic End Points are Important in Children’s Environmental Health Studies: The Children’s Environmental Health and Disease Prevention Research Center’s Epigenetics Working Group

“…In turn, these changes can manifest later in life and have the capacity to modulate physiological function and susceptibility to disease. Research also is emerging that investigates the placenta as a target tissue by which to study exposures at the maternal–fetal interface (Li Q et al 2015; Maccani and Maccani 2015; Paquette et al 2015; Schroeder and LaSalle 2013). …”

Assessment of global DNA methylation in the first trimester fetal tissues exposed to maternal cigarette smoking

“…In the term placentas, the DNA methylation level of AluYb8 was significantly higher among infants prenatally exposed to cigarette smoke, whereas no significant DNA methylation changes were observed for LINE - 1 and gene-associated loci [36]. Another study of term placenta samples also failed to find any significant association between LINE - 1 DNA methylation and PEMCS [38] but, notably, gene-associated CpG site-specific DNA methylation alterations have been described in the placenta [28, 33, 39, 40]. In the cord blood, using methyl-specific ELISA-based methodology, global DNA hypomethylation was observed in newborns from PEMCS and second-hand smoking exposure [41].…”

Commentary on Niemeläet al. (2017): Maternal smoking during pregnancy-an independent risk factor of postnatal health disorders

“…Prenatal nicotine exposure alters pulmonary function via α7 nicotinic acetylcholinergic receptors, modifies cytokine profiles and induces phenotypic changes in immune cells [17]. Smoking induced epigenetic changes can occur at several levels (histone modification, RNA mediated gene regulation, etc) but the most studied and plausible mechanism is alterations in DNA methylation leading to altered gene expression, changes that can occur at placental or fetal level [18,19].…”