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 ENVIRONAGE 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.
Highlights
According to the “Developmental Origins of Health and Disease” hypothesis, prenatal exposures can result in adverse health conditions later in life by increasing disease susceptibility through epigenetic programming (Barker, 1995)
When analyzed only in neonates born to mothers without gestational diabetes (n = 848), the median cord blood insulin level was unchanged (18.75–50.7), while for neonates born to mothers with gestational diabetes (n = 34) the median value was 37.11 pmol/L (25.29– 65.63)
Cord blood insulin levels have not been described in association with insulin resistance in later life yet, and these two parameters are not interchangeable
Summary
According to the “Developmental Origins of Health and Disease” hypothesis, prenatal exposures can result in adverse health conditions later in life by increasing disease susceptibility through epigenetic programming (Barker, 1995). Metabolic factors including elevated insulin levels in early life are generally not regarded as harmful, especially when they are within physiological range. As the baseline production of mitochondrial-generated ROS increases, the ETC itself and even the mitochondrial DNA (mtDNA) are damaged (Yakes and Van Houten, 1997). Increased cellular ROS levels can have a self-amplifying effect, leading to energy depletion and mitochondrial dysfunction. One possible mechanism that links mitochondrial dysfunction to insulin resistance might be the alteration of energy-dependent epigenetic processes through changes in the energetic status of the cell. Previous research has already revealed associations between insulin levels and methylation of the mitochondrial transcription factor A (TFAM) (r = −0.49, p < 0.04; Sookoian et al, 2010), and between insulin resistance and mtDNA methylation (4.6-fold higher in insulin-resistant vs insulin-sensitive subjects, p < 0.05; Zheng et al, 2015), which is indicative for an epigenetic link between both factors in adults
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