Dataset Information

Cord blood leptin and insulin levels in association with mitochondrial DNA content.

ABSTRACT:

Background

The developmental origins of health and disease theory states that a disturbance in the early life environment can contribute to disease risk in later life. Leptin and insulin are anorectic hormones involved in energy homeostasis and are crucial for foetal growth. Disturbances in the levels of these hormones contribute to obesity and diabetes. In adults, altered mitochondrial function is an important hallmark of metabolic disorders, including obesity and diabetes. However, the mitochondrial effects of early life metabolic variation are unexplored. We investigated whether there is an association between metabolic hormones and mitochondrial DNA (mtDNA) content in early life.

Methods

The study included 236 newborns from the FLEHS III birth cohort, Flanders (Belgium). Relative mtDNA content of cord blood leukocytes was determined using quantitative PCR. Cord blood levels of leptin and insulin were determined using immunoassays. We studied the association between these metabolic hormones and mtDNA content using multiple linear regression models, while accounting for covariates and potential confounders.

Results

Leptin and insulin levels were positively associated with cord blood mtDNA content. mtDNA content was respectively 4.49% (95% CI 1.15-7.93; p?=?0.008) and 1.60% (95% CI 0.31-2.91; p?=?0.02) higher for a interquartile range increase of respectively cord blood leptin and insulin levels. In a sensitivity analysis, we observed that insulin and leptin were independently associated to mtDNA content and that insulin was stronger associated to mtDNA content in boys than in girls.

Conclusion

Neonatal metabolic hormones were associated with cord blood mtDNA content, which suggests that in early life the variation of mtDNA content might accommodate or reflect changes in the metabolic status.

SUBMITTER: Vriens A

PROVIDER: S-EPMC6090601 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Publications

Cord blood leptin and insulin levels in association with mitochondrial DNA content.

Vriens Annette A Plusquin Michelle M Baeyens Willy W Bruckers Liesbeth L Den Hond Elly E Loots Ilse I Nelen Vera V Schoeters Greet G Janssen Bram G BG Nawrot Tim S TS

Journal of translational medicine 20180813 1

<h4>Background</h4>The developmental origins of health and disease theory states that a disturbance in the early life environment can contribute to disease risk in later life. Leptin and insulin are anorectic hormones involved in energy homeostasis and are crucial for foetal growth. Disturbances in the levels of these hormones contribute to obesity and diabetes. In adults, altered mitochondrial function is an important hallmark of metabolic disorders, including obesity and diabetes. However, the ...[more]

PMID: 30103773

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Project description: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.

Project description:INTRODUCTION:Lead (Pb) crosses the placenta and can cause oxidative stress, reduced fetal growth and neurological problems. The principal source of oxidative stress in human cells is mitochondria. Therefore, disruption of normal mitochondrial function during pregnancy may represent a primary mechanism behind the adverse effects of lead. We sought to assess the association of Pb exposure during pregnancy with mitochondrial DNA (mtDNA) content, a sensitive marker of mitochondrial function, in cord blood. MATERIALS AND METHODS:This study comprised mother-infant pairs from the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study, a prospective birth-cohort that enrolled 1050 pregnant women from Mexico City who were receiving prenatal care between December 2007 and July 2011. Quantitative PCR was used to calculate relative MtDNA content (mitochondrial-to-nuclear DNA ratio (mtDNA/nDNA)) in cord blood. Lead concentrations in both maternal blood (2nd and 3rd trimester and at delivery day) and in cord blood were measured by ICP-MS. Multivariable regression models adjusting for multiple confounders were fitted with 410 mother-infant pairs for whom complete data for mtDNA content, lead levels, and covariates were available. RESULTS:Maternal blood Pb measured in the second (mean 3.79??g/dL, SD 2.63; ??=?0.059, 95% CI 0.008, 0.111) and third trimester (mean 3.90??g/dL; SD 2.84; ??=?0.054, 95% CI 0.002, 0.107) during pregnancy and PB in cord blood (mean 3.50??g/dL, SD 2.59; ??=?0.050, 95% CI 0.004; 0.096) were associated with increased cord blood mtDNA content (mean 1.46, SD 0.44). In two-way interaction analyses, cord blood Pb marginally interacted with gestational age leading to an increase in mtDNA content for pre-term births (Benjamini-Hochberg False Discovery Rate correction; BH-FDR?=?0.08). CONCLUSION:This study shows that lead exposure in pregnancy alters mtDNA content in cord blood; therefore, alteration of mtDNA content might be a mechanism underlying the toxicity of lead.

Dataset Information

Cord blood leptin and insulin levels in association with mitochondrial DNA content.

Background

Methods

Results

Conclusion

Publications

Cord blood leptin and insulin levels in association with mitochondrial DNA content.

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