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Infant circulating MicroRNAs as biomarkers of effect in fetal alcohol spectrum disorders
Amanda H Mahnke1,2, Georgios D Sideridis3, Nihal A Salem4
1Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, Bryan, TX, 77807, USA. mahnke@tamu.edu.
Insights
Biomarkers in infant plasma extracellular miRNAs (exmiRNAs) can predict growth and cognitive deficits in infants exposed to alcohol before birth. This discovery aids in early identification and intervention for prenatal alcohol spectrum disorder (PASD).
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Prenatal alcohol exposure (PAE) causes cognitive and behavioral disabilities, and growth deficits.
- Existing methods for diagnosing PAE-related issues are limited, especially when overt physical signs are absent.
- There is a critical need for reliable biomarkers to predict neurobehavioral impairment resulting from PAE.
Purpose of the Study:
- To investigate infant plasma extracellular miRNAs (exmiRNAs) as potential biomarkers for PAE-related growth restriction and cognitive impairment.
- To determine if exmiRNA expression patterns can predict specific developmental deficits in infants exposed to alcohol prenatally.
- To explore the co-regulation and pathway associations of exmiRNAs in response to PAE.
Main Methods:
- Analysis of infant plasma exmiRNAs from a heavily exposed cohort in Cape Town.
- Statistical analysis including Cohen's d for effect sizes and confirmatory factor analysis.
- Pathway analysis to identify biological processes associated with altered exmiRNA expression patterns.
Main Results:
- PAE significantly altered 27% of expressed exmiRNAs, with clinically relevant effect sizes.
- PAE increased correlated exmiRNA expression across chromosomes at 2 weeks postpartum, suggesting co-regulation.
- Specific exmiRNA factor models at 2 weeks and 6.5 months were associated with developmental pathways and partially mediated PAE-induced growth and cognitive deficits.
Conclusions:
- Infant plasma exmiRNAs serve as promising biomarkers for identifying infants at risk for PAE-related growth and cognitive deficits.
- These exmiRNA profiles can aid in early detection and potential intervention for neurodevelopmental impairments linked to prenatal alcohol exposure.
- The findings highlight the potential of exmiRNAs in understanding the molecular mechanisms underlying PAE's impact on development.
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.
