Mapping prenatal predictors and neurobehavioral outcomes of an epigenetic marker of neonatal inflammation - A longitudinal population-based study.

BACKGROUND: DNA methylation levels at specific sites can be used to proxy C-reactive protein (CRP) levels, providing a potentially more stable and accurate indicator of sustained inflammation and associated health risk. However, its use has been primarily limited to adults or preterm infants, and little is known about determinants for - or offspring outcomes of - elevated levels of this epigenetic proxy in cord blood. The aim of this study was to comprehensively map prenatal predictors and long-term neurobehavioral outcomes of neonatal inflammation, as assessed with an epigenetic proxy of inflammation in cord blood, in the general pediatric population. METHODS: Our study was embedded in the prospective population-based Generation R Study (n = 2,394). We created a methylation profile score of CRP (MPS-CRP) in cord blood as a marker of neonatal inflammation and validated it against serum CRP levels in mothers during pregnancy, as well as offspring at birth and in childhood. We then examined (i) which factors (previously associated with sustained inflammation) explain variability in MPS-CRP at birth, including a wide range of prenatal lifestyle and clinical conditions, pro-inflammatory exposures, as well as child genetic liability to elevated CRP levels; and (ii) whether MPS-CRP at birth associates with child neurobehavioral outcomes, including global structural MRI and DTI measures (child mean age 10 and 14 years) as well as psychiatric symptoms over time (Child Behavioral Checklist, at mean age 1.5, 3, 6, 10 and 14 years). RESULTS: MPS-CRP at birth was validated with serum CRP in cord blood (cut-off > 1 mg/L) (AUC = 0.72). Prenatal lifestyle pro-inflammatory factors explained a small part (i.e., < 5%) of the variance in the MPS-CRP at birth. No other prenatal predictor or the polygenic score of CRP in the child explained significant variance in the MPS-CRP at birth. The MPS-CRP at birth prospectively associated with a reduction in global fractional anisotropy over time on mainly a nominal threshold (ß = -0.014, SE = 0.007, p = 0.032), as well as showing nominal associations with structural differences (amygdala [(ß = 0.016, SE = 0.006, p = 0.010], cerebellum [(ß = -0.007, SE = 0.003, p = 0.036]). However, no associations with child psychiatric symptoms were observed. CONCLUSION: Prenatal exposure to lifestyle-related pro-inflammatory factors was the only prenatal predictor that accounted for some of the individual variability in MPS-CRP levels at birth. Further, while the MPS-CRP prospectively associated with white matter alterations over time, no associations were observed at the behavioral level. Thus, the relevance and potential utility of using epigenetic data as a marker of neonatal inflammation in the general population remain unclear. In the future, the use of epigenetic proxies for a wider range of immune markers may lend further insights into the relationship between neonatal inflammation and adverse neurodevelopment within the general pediatric population.

Incredible years parenting program buffers prospective association between parent-reported harsh parenting and epigenetic age deceleration in children with externalizing behavior.

Harsh parenting has been shown to increase the risk of physical and mental health problems in later life. To improve our understanding of these risks and how they can be mitigated, we investigated associations of harsh parenting with a clinically relevant biomarker, epigenetic age deviation (EAD), using data from a randomized-control trial of the Incredible Years (IY) parenting program. This study included 281 children aged 4-8 years who were screened for heightened externalizing behavior and whose parents were randomly allocated to either IY or care-as-usual (CAU). Parents reported on their own parenting practices and their child's externalizing behavior at baseline and at a follow-up assessment approximately three years later. Epigenetic age, based on the Pediatric Buccal Epigenetic (PedBE) clock, was estimated from child DNA methylation derived from saliva collected at the follow-up assessment. PedBE clock estimates were regressed on chronological age as a measure of EAD. Moderation analyses using multiple regression revealed that harsher parenting at baseline predicted epigenetic age deceleration in children that received CAU (b = -.21, 95% CI[-0.37, -0.05]), but no association was found in children whose parents were allocated to IY (b = -.02, 95% CI [-0.13, 0.19]). These results highlight a prospective association between harsh parenting and children's EAD and indicate a potential ameliorating effect of preventive intervention. Future work is needed to replicate these findings and understand individual differences in children's responses to harsh parenting in relation to epigenetic aging.

DNA methylation variation after a parenting program for child conduct problems: Findings from a randomized controlled trial.

This study investigated associations of the Incredible Years (IY) parenting program with children's DNA methylation. Participants were 289 Dutch children aged 3-9 years (75% European ancestry, 48% female) with above-average conduct problems. Saliva was collected 2.5 years after families were randomized to IY or care as usual (CAU). Using an intention-to-treat approach, confirmatory multiple-regression analyses revealed no significant differences between the IY and CAU groups in children's methylation levels at the NR3C1 and FKBP5 genes. However, exploratory epigenome-wide analyses revealed nine differentially methylated regions between groups, coinciding with SLAMF1, MITF, FAM200B, PSD3, SNX31, and CELSR1. The study provides preliminary evidence for associations of IY with children's salivary methylation levels and highlights the need for further research into biological outcomes of parenting programs.

Maternal sensitivity and child internalizing and externalizing behavior: a mediating role for glucocorticoid receptor gene (NR3C1) methylation?

The early caregiving environment can have lasting effects on child mental health. Animal models suggest that glucocorticoid receptor gene (NR3C1) DNA methylation plays a mediating role in linking more responsive caregiving to improved behavioral outcomes by its impact on the stress regulatory system. In this longitudinal study, we examined whether children's NR3C1 methylation levels mediate an effect of maternal sensitivity in infancy on levels of child internalizing and externalizing behavior in a community sample. Maternal sensitivity of 145 mothers was rated at infant age 5 weeks, 12 months, and 30 months by observing mother-infant interactions. Buccal DNA methylation was assessed in the same children at age 6 years and maternal-reported internalizing and externalizing behavior was assessed at age 6 and 10 years. Higher sensitivity at age 5 weeks significantly predicted lower DNA methylation levels at two NR3C1 CpG loci, although methylation levels at these loci did not mediate an effect of maternal sensitivity on levels of child internalizing and externalizing behavior. Overall, the study provides evidence that maternal sensitivity in early infancy is associated with DNA methylation levels at loci involved in stress regulation, but the significance of this finding for child mental health remains unclear.

The Use of Information and Communication Technologies in Family Support across Europe: A Narrative Review.

The COVID-19 pandemic has accelerated the use of information and communication technology (ICT) to deliver parenting and mental health support services to families. This narrative review illustrates the diverse ways in which ICT is being used across Europe to provide family support to different populations. We distinguish between the use of ICT in professional-led and peer-led support and provide implementation examples from across Europe. We discuss the potential advantages and disadvantages of different ways of using ICT in family support and the main developments and challenges for the field more generally, guiding decision-making as to how to use ICT in family support, as well as critical reflections and future research on its merit.

When mummy and daddy get under your skin: A new look at how parenting affects children's DNA methylation, stress reactivity, and disruptive behavior.

Child maltreatment is a global phenomenon that affects the lives of millions of children. Worldwide, as many as one in three to six children encounter physical, sexual, or emotional abuse from their caregivers. Children who experience abuse often show alterations in stress reactivity. Although this alteration may reflect a physiological survival response, it can nevertheless be harmful in the long run-increasing children's disruptive behavior and jeopardizing their development in multiple domains. But can we undo this process in at-risk children? Based on several lines of pioneering research, we hypothesize that we indeed can. Specifically, we hypothesize that highly dysfunctional parenting leads to an epigenetic pattern in children's glucocorticoid genes that contributes to stress dysregulation and disruptive behavior. However, we also hypothesize that it is possible to "flip the methylation switch" by improving parenting with known-effective parenting interventions in at-risk families. We predict that improved parenting will change methylation in genes in the glucocorticoid pathway, leading to improved stress reactivity and decreased disruptive behavior in children. Future research testing this theory may transform developmental and intervention science, demonstrating how parents can get under their children's skins-and how this mechanism can be reversed.