Selenium-associated decrease of mir-216a and mir-217 expression in placenta and their associations with neurobehavioral development at birth: a genome-wide study of two U.S. birth cohorts

Abstract

Background: As an essential micronutrient, selenium plays a vital role in fetal development. MicroRNA expression modification is a potential mechanism linking dietary exposures and fetal neurobehavioral development; however, very few studies have sought to elucidate whether microRNA expression is responsive to selenium in humans. We aimed to investigate the associations between selenium concentration in the placenta, a critical developmental organ, and microRNA expression, and to assess the association between selenium-associated microRNAs and newborns’ neurobehavior. Methods: Our study included 394 newborns (280 from New Hampshire Birth Cohort Study, 114 from Rhode Island Child Health Study). Placental selenium concentrations were quantified using inductively coupled plasma mass spectrometry, and genome-wide microRNA and mRNA transcripts were measured using RNA-seq. Newborn neurobehavioral development was assessed by the NICU Network Neurobehavioral Scales. We fitted generalized additive models with smoothing splines for selenium and microRNAs in the pooled data of the two cohorts, adjusting for covariates. We fitted multiple linear regression and ordinal logistic regression for microRNAs and newborn NNNS summary scores, adjusting for covariates. Results: We identified a reverse J-shaped association between selenium concentration and the expression of mir216a/mir217 cluster (edf = 2, FDR-adjusted p-value = 4.14 × 10-5) in placenta, and we observed that a doubling in mir216a/mir217 expression was associated with a 0.13 and 0.19 decrease in self-regulation score of newborns (p-value = 0.03 and 0.08). Moreover, self-regulation was positively associated with the expression of mir216a/mir217-targeted TXNRD2, a selenoprotein coding gene (β = 0.83, p-value = 0.04). Conclusions: The selenium-associated modification of mir216a/mir217 expression in the placenta might provide a partial mechanism for neurobehavioral developmental effects of prenatal selenium exposure in offspring.