Impact of gestational chronodisruption on fetal cardiac genomics

Nov 9, 2013Journal of molecular and cellular cardiology

Effects of disrupted daily rhythms during pregnancy on fetal heart gene activity

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Abstract

Significant differential expression was found for 383 transcripts in the fetal heart of rats exposed to constant light compared to those in a normal light/dark cycle.

280 transcripts were up-regulated and 103 down-regulated in the fetal heart due to gestational chronodisruption.
42 of the differentially expressed transcripts exhibited a change in gene expression of 1.5-fold or greater.
Altered gene networks included those associated with cardiovascular disease, steroid production, and heart muscle growth.
A 2.1-fold increase in Hmga1 mRNA, related to transcription factor activity, was observed.
Up-regulation of specific microRNAs and down-regulation of their target genes were identified.
Fetal cardiac transcriptome dysregulation may contribute to left ventricular hypertrophy in adult offspring from chronodisrupted pregnancies.

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We recently reported that gestational chronodisruption induces fetal growth restriction and marked effects on fetal adrenal physiology. Here, whole-transcriptome profiling was used to test whether gestational chronodisruption modifies gene expression in the fetal heart, potentially altering cardiac development. At day 10 of gestation (E10), pregnant rats were randomized in two groups: constant light (LL) and control 12 h light/12 h dark photoperiod (LD). RNA isolated from E18 heart was subjected to microarray analysis (Affymetrix platform for 28,000 genes). Integrated transcriptional changes were assessed by gene ontology and pathway analysis. Significant differential expression was found for 383 transcripts in LL relative to LD fetal heart (280 up-regulated and 103 down-regulated); with 42 of them displaying a 1.5-fold or greater change in gene expression. Deregulated markers of cardiovascular disease accounted for alteration of diverse gene networks in LL fetal heart, including local steroidogenesis and vascular calcification, as well as cardiac hypertrophy, stenosis and necrosis/cell death. DNA integrity was also overrepresented, including a 2.1-fold increase of Hmga1 mRNA, which encodes for a profuse architectural transcription factor. microRNA analysis revealed up-regulation of miRNAs 218-1 and 501 and concurrent down-regulation of their validated target genes. In addition, persistent down-regulation of Kcnip2 mRNA and hypertrophy of the left ventricle were found in the heart from 90 days-old offspring from LL mothers. The dysregulation of a relevant fraction of the fetal cardiac transcriptome, together with the diversity and complexity of the gene networks altered by gestational chronodisruption, suggest enduring molecular changes which may shape the hypertrophy observed in the left ventricle of adult LL offspring.

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Impact of gestational chronodisruption on fetal cardiac genomics

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