Abstract
BackgroundEpigenetic modifications, including DNA methylation, act as one potential mechanism underlying the detrimental effects associated with prenatal tobacco smoke (PTS) exposure. Methylation in a gene called AXL was previously reported to differ in response to PTS.MethodsWe investigated the association between PTS and epigenetic changes in AXL and how this was related to childhood asthma phenotypes. We tested the association between PTS and DNA methylation at multiple CpG loci of AXL at birth using Pyrosequencing in two separate study populations, the Children’s Health Study (CHS, n = 799) and the Newborn Epigenetic Study (NEST, n = 592). Plasma cotinine concentration was used to validate findings with self-reported smoking status. The inter-relationships among AXL mRNA and miR-199a1 expression, PTS, and AXL methylation were examined. Lastly, we evaluated the joint effects of AXL methylation and PTS on the risk of asthma and related symptoms at age 10 years old.ResultsPTS was associated with higher methylation level in the AXL gene body in both CHS and NEST subjects. In the pooled analysis, exposed subjects had a 0.51% higher methylation level in this region compared to unexposed subjects (95% CI 0.29, 0.74; p < 0.0001). PTS was also associated with 21.2% lower expression of miR-199a1 (95% CI − 37.9, − 0.1; p = 0.05), a microRNA known to regulate AXL expression. Furthermore, the combination of higher AXL methylation and PTS exposure at birth increased the risk of recent episodes of bronchitic symptoms in childhood.ConclusionsPTS was associated with methylation level of AXL and the combination altered the risk of childhood bronchitic symptoms.
Highlights
Epigenetic modifications, including DNA methylation, act as one potential mechanism underlying the detrimental effects associated with prenatal tobacco smoke (PTS) exposure
Both studies were enriched for participants exposed to PTS, and a higher proportion of exposed subjects were observed in Newborn Epigenetic Study (NEST) (51%) than Children’s Health Study (CHS) (27%)
We further evaluated the association between maternal smoking and AXL methylation in NEST subjects using plasma cotinine concentration categorized as nonsmoker (0–1 ng/ml), passive smoker (1–10 ng/ml), and active smoker (> 10 ng/ml) (Additional file 1: Table S3)
Summary
Epigenetic modifications, including DNA methylation, act as one potential mechanism underlying the detrimental effects associated with prenatal tobacco smoke (PTS) exposure. Previous studies have associated prenatal tobacco smoke (PTS) exposure with low birth weight [2], preterm delivery [3], increased asthmatic symptoms, and reduced pulmonary function in childhood [4, 5], as well as cancer in adult life [6]. Studies have shown that AXL and its major ligand growth-arrest-specific 6 (GAS6) play an anti-inflammation role by limiting the production of Toll-like receptor (TLR)-induced proinflammatory cytokines [15]. Few studies have addressed the epigenetic regulation of AXL in the pathogenesis of childhood asthma [19]. The role that PTS may play in modifying these processes is unknown
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