Fetal Exposomes and Child Development: Using DNA Methylation Levels of Imprinted Genes as an Indicator
Date Issued
2015
Date
2015
Author(s)
Ku, Mei-Sheng
Abstract
Background In utero exposures have been suggested to be linked to adverse birth outcomes, neurodevelopment or child behavior, but the underlying mechanism remains elusive. DNA methylation, an essential epigenetic modification, of candidate imprinted genes might provide a quantitative screening marker for the effects of prenatal exposures on the development and neurobehavioral development of the infants, even the risk of developing certain disease in later life. Objective The objective of this study is to investigate the relationship between multiple fetal exposomes during pregnancy, epigenetic modifications and child birth and neurobehavioral outcomes at follow-up 2 and 7 years old, by quantifying DNA methylation levels of imprinted genes. Methods A total of 465 mother-infant pairs were included in this study from Taiwan Birth Panel Study (TBPS), collecting from 2004 to 2005. Fetal exposomes, including cotinine, 18 metals, 2 organophosphorous Pesticides, 4 perfluorinated compounds (PFCs) and 3 phenols, 4 phthalate metabolites were detected in umbilical cord blood and spot mother’s urine samples. Besides, DNA methylation levels of MEST and PEG3 imprinted gene were measured in leukocytes from umbilical cord blood. This study made use of data from structured questionnaires、fetal exposomes and DNA methylation levels to estimate the association between prenatal exposures, DNA mehtlyation levels of imprinted genes as well as child outcomes by partial least squares (PLS) regression and generalized linear mixed model. Results This study identified 11 relatively important factors among 32 fetal exposomes. Among these 11 exposomes, higher level group of Cu (pos1:-0.34, P=0.0357; pos3:-0.35, P=0.0277), Mo (pos1:β= -0.38, P=0.026; pos2:β= -0.35, P=0.0358), all level group of Ba (pos5: L-β=0.48, P=0.0359; M-β=0.66, P=0.0071; H-β=0.54, P=0.0322), and PFOS (L-β=-0.39, P=0.0148: H-β= -0.41, P=0.0128) were likely to alter methylation levels of MEST gene, whereas all level group of Cu (L-β=0.59, P=0.0042; M-β=0.57, P=0.0075; H-β=0.64, P=0.0022), low level group of Zn (β=0.45, P=0.0471), Ba (β=0.51, P=0.0151), Co (pos3:β=-0.46, P=0.0294; pos5: β=-0.49, P= 0.032) and low level group of cotinine (β=0.58, P=0.0267) might have differential methylation effects on PEG3 gene. Beside, hypo- or hypermethylation of MEST (CTCF binding region) might have increased risk of low birth size (<Q1: OR=2.41, 95% CI=1.12-5.16; >Q3:OR=2.73, 95% CI=1.20-6.25).Further, hypermethylation of 2 CpGs on MEST ( promoter region) gene had increased risk of having behavior problem (pos3: OR=4.12, 95% CI=1.34-12.66; pos4: OR=3.79, 95% CI=1.21-11.89), compared with reference group, after adjusting for child sex, maternal education, maternal BMI and SGA. The same phenomenon was observed in hypomethylation of position 1 and 4 of MEST (CTCF binding region) (pos1: OR=5.02, 95% CI=1.49-16.98; pos4: OR=4.71, 95% CI=1.36-16.27). At some CpGs of PEG3, hyper- or hypermethylation might have protective effects on adverse child outcomes. Conclusion Our study indicates that there were 11 out of 32 fetal exposomes accounting for infant birth weight. Among them, three metals (Cu、Mo、Ba) and perfluorinated compounds(PFOS) might be associated with methylation levels of MEST imprinted gene, while four metals (Cu、Zn、Co、Ba) and cotinine (metabolite of nicotine) were correlated to methylation levels of PEG3. Moreover, either the increased or decreased methylation of imprinted genes as a result of different levels of fetal exposomes was likely to have increased risk of child birth outcomes and child neurodevelopment at 2 years old.
Subjects
Fetal exposomes
DNA methylation
imprinted gene
neurobehavioral development
Type
thesis
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