IUGR prevents IGF-1 upregulation in juvenile male mice by perturbing postnatal IGF-1 chromatin remodeling

Abstract

Background: Intrauterine growth restriction (IUGR) offspring with rapid catch-up growth are at increased risk for early obesity especially in males. Persistent insulin-like growth factor-1 (IGF-1) reduction is an important risk factor. Using a mouse model of maternal hypertension-induced IUGR, we examined IGF-1 levels, promoter DNA methylation, and histone H3 covalent modifications at birth (D1). We additionally investigated whether prenatal perturbations could reset at preadolescence (D21). Methods: IUGR was induced via maternal thromboxane A 2 -analog infusion in mice. results: IUGR uniformly decreased D1 IGF-1 mRNA and protein levels with reduced promoter 1 (P1) transcription and increased P1 DNA methylation. IUGR males also had increased H3K4ac at exon 5 and 3′ distal UTR. At D21, IUGR males continued to have decreased IGF-1 levels, originating from both P1 and P2 with reduced 1A variant. IUGR males also had decreased activation mark of H3K4me3 at P1 compared with sham males. In contrast, D21 IUGR females normalized their IGF-1 levels, in association with an increased activation mark of H3K4me3 at P1 compared with sham females. conclusion: IUGR uniformly affected D1 hepatic IGF-1 epigenetic modifications in both sexes. However, at preadolescence, IUGR males are unable to correct for the prenatal reduction possibly due to a more perturbed IGF-1 chromatin structure.i ntrauterine growth restriction (IUGR) predisposes offspring toward early-onset metabolic syndrome. This predisposition is particularly pertinent with rapid postnatal catch-up growth and affects males more than females (1). The molecular mechanisms underlying this sex-specific predisposition remain elusive. Insulin-like growth factor 1 (IGF-1), a major regulator of growth and metabolism, has generated significant interest in the field (2). IGF-1 disruption has been implicated in aberrant growth and development of metabolic syndrome in both IUGR humans and animal models (3-6). In particular, decreased IGF-1 have been observed in IUGR humans who ultimately develop metabolic syndrome as adults (7,8).The IGF-1 gene is an ideal candidate to examine IUGR's effects not only because of its growth and metabolic properties but because of its complex gene structure allowing for developmental-and tissue-specific expression. The majority of serum IGF-1 is synthesized from the liver (9). The IGF-1 gene is regulated by two alternative promoters, promoter P1 initiates transcription from exon 1 while promoter P2 from exon 2. P1 is active in fetal life, whereas P2 becomes upregulated at ~3 wk of life when growth hormone exerts its effects on the rodent IGF-1 gene (10). The rodent IGF-1 gene also has an alternatively spliced exon, with the A variant excluding exon 5 and the B variant includes exon 5. Both alternative promoter selection and alternative exon splicing require specific epigenetic modifications to direct transcriptional machinery for specific mRNA transcript generation (11,12).Given that prenatal insults are known to affect gene-specific DNA methylation a...

Altered Transcription Factor Binding and Gene Bivalency in Islets of Intrauterine Growth Retarded Rats

“…Many studies have demonstrated that intrauterine growth restriction is associated with epigenetic changes in different tissues of the offspring [18,[128][129][130][131][132][133][134][135][136], and several implicate epigenetic mechanisms in pancreatic β-cell failure and development of T2D [13,15,17,135,[137][138][139][140]. In our IUGR model, we have previously demonstrated in adult rats that IUGR induces genome-wide changes in DNA methylation at key loci in islets [23].…”

Intrauterine growth restriction causes cellular, molecular, and behavioral deficits consistent with abnormal dentate gyrus neurogenesis in mice

“…Such a lack of knowledge not only impedes our ability to counsel families about mechanisms of disease, but also hinders our ability to design therapy targeted at improving learning and memory function. Recognizing this gap, our laboratory developed a mouse model of IUGR that closely mimics human IUGR (11,12,(18)(19)(20) in order to dissect the functional, cellular, and molecular phenotypes of the developing IUGR hippocampus.…”

Current evidence and outcomes for retinopathy of prematurity prevention: insight into novel maternal and placental contributions

“…While, as noted previously, this model of placental insufficiency does demonstrate decreased severity of pre-retinal neovascularization in the OIR model, there are limitations to this approach including the extreme degree and abrupt onset of hemodynamic insufficiency, which likely does not fully recapitulate preeclamptic pathophysiology now believed to be a systemic condition [186]. Alternative models, including chronic systemic delivery of a thromboxane A2 analog which is commonly overproduced in preeclampsia, represents a more systemic model of preeclamptic pathophysiology and thus, may better inform relative to the human condition [192][193][194].…”