398 - Exploratory analysis of scalable biomarkers of toxic stress in the first year of life

Publication Number: 398.4657

Kameelah L. Gateau, Fetal and Neonatal Institute, Division of Neonatology, Children's Hospital Los Angeles, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States; Xaiowu Gai, Medical College of Wisconsin, Milwaukee, WI, United States; Dejerianne Ostrow, CHLA, LA, CA, United States; Alexander Markowitz, Children's Hospital Los Angeles, Los Angeles, CA, United States; Pat Levitt, Children's Hospital Los Angeles, Los Angeles, CA, United States

Background: Experiencing adversity and stress early in childhood increases the risk for altered developmental trajectories that lead to lifelong impacts on health. Toxic stress response, a dysregulation of neuro-endocrine-immune function, links early adversity to poor health. This maladaptation has been proposed to converge on mitochondrial function and is measurable via mitochondrial DNA copy number (mtDNAcn) and mitochondrial double stranded RNA (mtdsRNA). Studies have also shown that experiencing early life stress is intergenerationally transmissible via epigenetic CpG methylation. However, current screening practices for early adversity utilize retrospective Adverse Childhood Experience (ACES) questionnaires that do not inform of the biologic processes associated with early life stress.

Objective: Develop a predictive panel of biomarkers that can identify children at risk for and exhibiting toxic stress and can be collected in primary pediatric care settings. We hypothesize that infants whose mothers have high ACES scores will have different methylation patterns than infants whose mothers have low ACEs scores. Also, higher mtDNAcn and mtdsRNA will correlate with worse infant development.

Design/Methods: Mitochondrial markers of adversity were measured via buccal swabs in maternal-infant dyads to evaluate differentially methylated CpG regions of nuclear encoded mitochondrial proteins, mtDNAcn, and mtdsRNA. Maternal adversity was assessed via the ACES questionnaire. The Bayley 4 was used to assess infant development at 6 and 12 months.

Results: Differential methylation analysis of 24 maternal-infant dyads showed differential methylation of nuclear encoded mitochondrial genes GPC5-IT1 (log2 FC = 8.4, FDR = 0.05) and ARPC5 (log2 FC = -0.63, FDR = 0.10) among maternal-infant dyads with high (>4) maternal ACES vs low maternal ( < 4) ACEs (Figure 1). There were also trends showing higher mtDNAcn and mtdsRNA mitochondrial markers being negatively correlated with cognitive and motor development at 12 months (Table 1).

Conclusion(s): This exploratory analysis showing differential methylation of CpG regions in maternal-infant dyads with high vs low ACEs provides insight on the pathophysiologic pathways that may put infants at risk of toxic stress long before they experience adversity themselves. The methylation data along with the trends of mitochondrial markers correlating with worse infant development shows great promise on the identification of biomarkers of toxic stress. Larger studies at later developmental time points are needed to fully elucidate the relations between these markers and infant neurodevelopment.

Figure 1.
a) Heat map of maternal and infant methylome profiles at 6 and 12 months. b). Differentially methylated regions of nuclear encoded mitochondrial genes seen in mothers with high ACES and their infants.



Table 1
Pairwise Pearson correlations between maternal and infant mitochondrial DNA copy number, mitochondrial double stranded RNA and Motor and Cognitive Bayley Scores at 12-months.



Figure 1.
a) Heat map of maternal and infant methylome profiles at 6 and 12 months. b). Differentially methylated regions of nuclear encoded mitochondrial genes seen in mothers with high ACES and their infants.



Table 1
Pairwise Pearson correlations between maternal and infant mitochondrial DNA copy number, mitochondrial double stranded RNA and Motor and Cognitive Bayley Scores at 12-months.