Serotonin Transporter Gene (SLC6A4) Methylation Associates With Neonatal Intensive Care Unit Stay and 3‐Month‐Old Temperament in Preterm Infants

Abstract

Preterm birth and Neonatal Intensive Care Unit (NICU) stay are early adverse stressful experiences, which may result in an altered temperamental profile. The serotonin transporter gene (SLC6A4), which has been linked to infant temperament, is susceptible to epigenetic regulation associated with early stressful experience. This study examined a moderation model in which the exposure to NICU-related stress and SLC6A4 methylation moderated infant temperament at 3 months of age. SLC6A4 methylation at 20 CpG sites was quantified in preterm infants (N = 48) and full-term infants (N = 30) from Italian middle-class families. Results suggested that in preterm infants NICU-related stress might be associated with alterations of serotonergic tone as a consequence of SLC6A4 methylation, which in turn, might associate with temperamental difficulties assessed at 3 months of age.

Incorporating epigenetic mechanisms to advance fetal programming theories

“…A large literature across multiple laboratories suggests that infants exposed to high levels of prenatal stress may be born with a more reactive phenotype (Davis et al, 2007; Gutteling et al, 2005; Huizink, Robles De Medina, Mulder, Visser, & Buitelaar, 2002; Montirosso et al, 2016). This type of biobehavioral reactivity in infancy may be adaptive in a stressful early postnatal environment.…”

Transformative Role of Epigenetics in Child Development Research: Commentary on the Special Section

“…In addition to four articles in this special section that focus on a key gene in the glucocorticoid feedback loop ( NR3C1 , cited earlier), there are two further examples of this in the special section. One focuses on a gene that operates in the serotonergic system ( SLC6A4 ), and in this study greater DNA methylation was associated with more difficulties of temperament at 3 months old among preterm infants but not full‐term infants (Montirosso et al., ). A key finding is that SLC6A4 methylation at a number of CpG sites was more pronounced among the premature infants following a stay in a neonatal intensive care unit, a likely significant early life stressor, compared to their methylation status at birth.…”

Using Principles of Behavioral Epigenetics to Advance Research on Early‐Life Stress

“…Exposure to prenatal depression was associated with less self‐regulation, more lethargy, and hypotonia (low tone or floppiness) in newborns, but only if the infants had high levels of methylation of a specific CpG site of NR3C1 . In other research with epigenetic moderators, the effect of birth status (infants born at term vs. those born preterm) on temperamental indicators (duration of orienting and approach) depended on DNA methylation of the serotonin transporter gene SLC6A4 . Only preterm infants with greater methylation of SLC6A4 had poorer attention and were more inhibited.…”

“…Only four studies with humans have examined epigenetic processes as moderators of early‐life stress on behavioral outcomes . We wondered whether the effect of exposure to prenatal maternal depression on newborns' behavior depended on DNA methylation of NR3C1 , given that methylation of this gene may be related to altered neuroendocrine responses to stress .…”