Scoping Review of Early Toxic Stress and Epigenetic Alterations in the Neonatal Intensive Care Unit.

BACKGROUND: Preterm infants are uniquely vulnerable to early toxic stress exposure while in the neonatal intensive care unit (NICU) and also being at risk for suboptimal neurodevelopmental outcomes. However, the complex biological mechanisms responsible for variations in preterm infants' neurodevelopmental outcomes because of early toxic stress exposure in the NICU remain unknown. Innovative preterm behavioral epigenetics research offers a possible mechanism and describes how early toxic stress exposure may lead to epigenetic alterations, potentially affecting short- and long-term outcomes. OBJECTIVE: The aim of this study was to review the relationships between early toxic stress exposures in the NICU and epigenetic alterations in preterm infants. The measurement of early toxic stress exposure in the NICU and effect of epigenetic alterations on neurodevelopmental outcomes in preterm infants were also examined. METHODS: We conducted a scoping review of the literature published between January 2011 and December 2021 using databases PubMed, CINAHL, Cochrance Library, PsycINFO, and Web of Science. Primary data-based research that examined epigenetics, stress, and preterm infants or NICU were included. RESULTS: A total of 13 articles from nine studies were included. DNA methylations of six specific genes were studied in relation to early toxic stress exposure in the NICU: SLC6A4, SLC6A3, OPRMI, NR3C1, HSD11B2, and PLAGL1. These genes are responsible for regulating serotonin, dopamine, and cortisol. Poorer neurodevelopmental outcomes were associated with alterations in DNA methylation of SLC6A4, NR3C1, and HSD11B2. Measurements of early toxic stress exposure in the NICU were inconsistent among the studies. DISCUSSION: Epigenetic alterations secondary to early toxic stress exposures in the NICU may be associated with future neurodevelopmental outcomes in preterm infants. Common data elements of toxic stress exposure in preterm infants are needed. Identification of the epigenome and mechanisms by which early toxic stress exposure leads to epigenetic alterations in this vulnerable population will provide evidence to design and test individualized intervention.