Selenium-associated DNA methylation modifications in placenta and neurobehavioral development of newborns: An epigenome-wide study of two U.S. birth cohorts

Abstract

Selenium (Se) levels in pregnancy have been linked to the neurobehavioral development of the offspring. DNA methylation is a potential mechanism underlying the impact of environmental exposure on fetal development; however, very few studies have been done on elucidating the role of DNA methylation linking prenatal Se and child neurobehavior. We aimed to investigate the associations between placental Se concentration and epigenome-wide DNA methylation in two U.S. cohorts, and to assess the association between Se-related DNA methylation modifications and newborns’ neurobehavior. We measured placental Se concentration of 343 newborns enrolled in the New Hampshire Birth Cohort Study and in 141 infants in the Rhode Island Child Health Study. Genome-wide placental DNA methylation was measured by HumanMethylation450 Bead Chip, and the newborn neurobehavioral development was assessed by the NICU Network Neurobehavioral Scales (NNNS). We meta-analyzed the associations between placental Se concentration and DNA methylation in each cohort, adjusting for covariates. We also fit multiple linear regression and ordinal logistic regression for methylation and newborn NNNS summary scores. We identified five Se-related differentially methylated CpG sites, among which the selenium concentration was positively associated with cg09674502 ( GFI1 ) methylation ( β -coefficient = 1.11, FDR-adjusted p -value = 0.045), and for one percent methylation level increase in cg09674502, there was 15% reduced odds of higher muscle tone in the arms, legs and trunk of newborns, given our model (OR [95% Confidence Interval, CI] = 0.85 [0.77, 0.95]). Moreover, the odds of a higher level of hypotonicity versus a lower level of hypotonicity is 1.76 times greater for one IQR increase in selenium concentration in the placenta, given our model (OR [95% CI] = 1.76 [1.12, 2.82]). Placental selenium concentration was inversely associated with muscle tone of newborns, and hypermethylation of GFI1 could be a potential mechanism underlying this association.