The Cord Blood Insulin and Mitochondrial DNA Content Related Methylome

Abstract

Mitochondrial dysfunction seems to play a key role in the etiology of insulin resistance. At birth, a link has already been established between mitochondrial DNA (mtDNA) content and insulin levels in cord blood. In this study, we explore shared epigenetic mechanisms of the association between mtDNA content and insulin levels, supporting the developmental origins of this link. First, the association between cord blood insulin and mtDNA content in 882 newborns of the ENVIR ON AGE birth cohort was assessed. Cord blood mtDNA content was established via qPCR, while cord blood levels of insulin were determined using electrochemiluminescence immunoassays. Then the cord blood DNA methylome and transcriptome were determined in 179 newborns, using the human 450K methylation Illumina and Agilent Whole Human Genome 8 × 60 K microarrays, respectively. Subsequently, we performed an epigenome-wide association study (EWAS) adjusted for different maternal and neonatal variables. Afterward, we focused on the 20 strongest associations based on p -values to assign transcriptomic correlates and allocate corresponding pathways employing the R packages ReactomePA and RDAVIDWebService. On the regional level, we examined differential methylation using the DMRcate and Bumphunter packages in R. Cord blood mtDNA content and insulin were significantly correlated ( r = 0.074, p = 0.028), still showing a trend after additional adjustment for maternal and neonatal variables ( p = 0.062). We found an overlap of 33 pathways which were in common between the association with cord blood mtDNA content and insulin levels, including pathways of neurodevelopment, histone modification, cytochromes P450 (CYP)-metabolism, and biological aging. We further identified a DMR annotated to Repulsive Guidance Molecule BMP Co-Receptor A ( RGMA ) linked to cord blood insulin as well as mtDNA content. Metabolic variation in early life represented by neonatal insulin levels and mtDNA content might reflect or accommodate alterations in neurodevelopment, histone modification, CYP-metabolism, and aging, indicating etiological origins in epigenetic programming. Variation in metabolic hormones at birth, reflected by molecular changes, might via these alterations predispose children to metabolic diseases later in life. The results of this study may provide important markers for following targeted studies.

Interrelationships and determinants of aging biomarkers in cord blood

“…The generation of important co-substrates required for histone phosphorylation, acetylation and deacetylation processes, such as adenosine triphosphate (ATP), acetyl CoA, flavin adenine dinucleotide, and nicotinamide adenine dinucleotide depends again on mitochondrial activity [ 74 ]. In a study of the ENVIR ON AGE cohort investigating the relationship between epigenome-wide methylation with cord blood insulin and mtDNA content, several pathways and differentially methylated regions (DMRs) also pointed in the direction of histone modification as one of the underlying mechanisms connecting these factors [ 75 ]. Dysfunctions in mitochondrial activity represented by alterations in mtDNA content may, therefore, have direct effects on global DNA methylation profiles [ 76 , 77 ].…”

Developmental programming of mitochondrial biology: a conceptual framework and review

“…[77] Moreover, one association appeared to persist (cg08973675 (SLC25A28)) in a subsequent look-up population of 4-and 8-year-old children. Two recent studies demonstrated 34 significant differentially methylated nDNA regions in relation to cord blood mtDNAcn [90] and an association between mtDNA methylation load and newly discovered mitochondrial peptides [97]. Although no human study appears to have prospectively followed mitochondrial function in individuals from birth to adulthood, mtDNA density is lower at birth in infants exposed to metabolic stress [78,88], positively associates with cord blood insulin [90,96], and is prospectively associated with insulin resistance [102], diabetes onset [26] and cardiovascular disease [25] in adulthood.…”

Breastfeeding predicts blood mitochondrial DNA content in adolescents

“…A positive association between metabolic hormones (i.e. leptin and insulin) and mtDNA content in early life has been reported 26,27 . Breast milk contains the hormone leptin, which may reduce psychosocial stress in infants 48 .…”

“…A lower mtDNA copy number is a potential biomarker for type 2 diabetes mellitus 24 , while an increased mtDNA copy number is linked with a lower risk of metabolic syndrome in adults 25 . Furthermore, mtDNA content has been positively associated with metabolic hormones such as leptin and insulin in early life 26,27 . In addition, a reduced mtDNA copy number has also been associated with aging [28][29][30] and has been suggested as a biomarker for age-related neurodegenerative diseases, such as Parkinson's disease 31 .…”