Regulating role of fetal thyroid hormones on placental mitochondrial DNA methylation: epidemiological evidence from the ENVIRAGE birth cohort study.

Background: Fetal development largely depends on thyroid hormone availability and proper placental function with an important role played by placental mitochondria. The biological mechanisms by which thyroid hormones exert their effects on mitochondrial function are not well understood. We investigated the role of fetal thyroid hormones on placental mitochondrial DNA (mtDNA) content and mtDNA methylation. We collected placental tissue and cord blood from 305 mother-child pairs that were enrolled between February 2010 and June 2014 in the ENVIRAGE (ENVIRonmental influence early AGEing) birth cohort (province of Limburg, Belgium). Placental mtDNA content was determined by qPCR and placental mtDNA methylation by bisulfite-pyrosequencing in two regions, i.e., the - control region and 12S ribosomal RNA (). The levels of free thyroid hormones (FT, FT) and thyroid-stimulating hormone (TSH) were measured in cord blood.

Results: Cord blood FT and FT were inversely associated with placental mtDNA methylation at the ( ≤ 0.01) and ( ≤ 0.05) regions, whereas a positive association was observed for both hormones with placental mtDNA content ( ≤ 0.04). Assuming causality, we estimated that and methylation mediated, respectively, 77% [indirect effect +14.61% (95% CI 2.64 to 27.98%,  = 0.01)] and 47% [indirect effect +8.60% (95% CI 1.23 to 16.50%,  = 0.02] of the positive association between FT and placental mtDNA content. Mediation models with FT gave similar results but the estimated effect proportions were smaller compared with those of FT (54% and 24%, respectively).

Conclusions: We showed that epigenetic modification at specific loci of the mitochondrial genome could intervene with the thyroid-dependent regulation of mitochondrial DNA copy numbers.