Infant circulating MicroRNAs as biomarkers of effect in fetal alcohol spectrum disorders

Amanda H Mahnke,Alexander M Tseng,Ernesta M Meintjes,Sandra W Jacobson,Georgios D Sideridis,Rajesh C Miranda,Nihal A Salem,R Colin Carter,Joseph L Jacobson,Aniruddha B Rathod,Neil C Dodge,Christopher D Molteno

doi:10.1038/s41598-020-80734-y

Abstract

Prenatal alcohol exposure (PAE) can result in cognitive and behavioral disabilities and growth deficits. Because alcohol-related neurobehavioral deficits may occur in the absence of overt dysmorphic features or growth deficits, there is a need to identify biomarkers of PAE that can predict neurobehavioral impairment. In this study, we assessed infant plasma extracellular, circulating miRNAs (exmiRNAs) obtained from a heavily exposed Cape Town cohort to determine whether these can be used to predict PAE-related growth restriction and cognitive impairment. PAE, controlling for smoking as a covariate, altered 27% of expressed exmiRNAs with clinically-relevant effect sizes (Cohen’s d ≥ 0.4). Moreover, at 2 weeks, PAE increased correlated expression of exmiRNAs across chromosomes, suggesting potential co-regulation. In confirmatory factor analysis, the variance in expression for PAE-altered exmiRNAs at 2 weeks and 6.5 months was best described by three-factor models. Pathway analysis found that factors at 2 weeks were associated with (F1) cell maturation, cell cycle inhibition, and somatic growth, (F2) cell survival, apoptosis, cardiac development, and metabolism, and (F3) cell proliferation, skeletal development, hematopoiesis, and inflammation, and at 6.5 months with (F1) neurodevelopment, neural crest/mesoderm-derivative development and growth, (F2) immune system and inflammation, and (F3) somatic growth and cardiovascular development. Factors F3 at 2 weeks and F2 at 6.5 months partially mediated PAE-induced growth deficits, and factor F3 at 2 weeks partially mediated effects of PAE on infant recognition memory at 6.5 months. These findings indicate that infant exmiRNAs can help identify infants who will exhibit PAE-related deficits in growth and cognition.

Highlights

Prenatal alcohol exposure (PAE) can result in cognitive and behavioral disabilities and growth deficits
The 3 dimensional (3D) methodology showed that about half of the heavily exposed (HE) nonsyndromal children who appeared to lack the distinctive facial anomalies when examined by dysmorphologists, had subtle, difficult-to-detect facial features, resembling those seen in fetal alcohol syndrome (FAS) and partial FAS (PFAS), and that these children had deficits in verbal IQ and learning and memory comparable to those in FAS and PFAS
The mothers of infants in the alcohol-exposed group reported consuming an average of 4.5 oz absolute alcohol (AA)/occasion (128 g; 133 ml; ≈ 9 standard drinks/occasion) across pregnancy on an average of 1–2 days/week. 26 of the 31 controls (83.9%) abstained from drinking during the pregnancy

Summary

Introduction

Prenatal alcohol exposure (PAE) can result in cognitive and behavioral disabilities and growth deficits. The 3D methodology showed that about half of the heavily exposed (HE) nonsyndromal children who appeared to lack the distinctive facial anomalies when examined by dysmorphologists, had subtle, difficult-to-detect facial features, resembling those seen in FAS and PFAS, and that these children had deficits in verbal IQ and learning and memory comparable to those in FAS and PFAS. These sophisticated facial imaging procedures are not yet available and cost-efficient for routine clinical practice. There is, a need for alternative, less expensive biomarkers of effect that can identify which exposed nonsyndromal children may be developmentally compromised by PAE26

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