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Genetic and epigenetic influences associated with intrauterine growth restriction due to in utero tobacco exposure.

ABSTRACT: While many fetuses are exposed to tobacco in utero, not all experience adverse outcomes as a result of this exposure. Mechanisms leading to the attenuation of fetal birth weight and adverse pregnancy outcomes are complex. Therefore many studies have begun to focus, not only on the contribution of maternal and fetal genes to phenotypic outcome, but also on epigenetic changes associated with exposure to maternal tobacco smoke. In this review, we detail the epidemiologic evidence associating an adverse pregnancy outcome to maternal tobacco use. We provide a brief summary of studies demonstrating an association between maternal and fetal gene polymorphisms with low birth weight in response to maternal tobacco exposure. We also review the literature showing epigenetic changes in the offspring associated with in utero tobacco exposure. The complex interplay of genomic and epigenomic factors may contribute to specific phenotypic outcomes and can help begin to elucidate the differential susceptibilities to tobacco smoke in utero.

SUBMITTER: Suter M

PROVIDER: S-EPMC5084836 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Genetic and epigenetic influences associated with intrauterine growth restriction due to in utero tobacco exposure.

Suter Melissa M Abramovici Adi A Aagaard-Tillery Kjersti K

Pediatric endocrinology reviews : PER 20101201 2

While many fetuses are exposed to tobacco in utero, not all experience adverse outcomes as a result of this exposure. Mechanisms leading to the attenuation of fetal birth weight and adverse pregnancy outcomes are complex. Therefore many studies have begun to focus, not only on the contribution of maternal and fetal genes to phenotypic outcome, but also on epigenetic changes associated with exposure to maternal tobacco smoke. In this review, we detail the epidemiologic evidence associating an adv ...[more]

PMID: 21150839

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Project description:Intrauterine growth restriction (IUGR), which refers to reduced fetal growth in the context of placental insufficiency, is etiologically heterogeneous. IUGR is associated not only with perinatal morbidity and mortality but also with adult-onset disorders, such as cardiovascular disease and diabetes, posing a major health burden. Placental epigenetic dysregulation has been proposed as one mechanism that causes IUGR; however, the spectrum of epigenetic pathophysiological mechanisms leading to IUGR remains to be elucidated. Monozygotic monochorionic twins are particularly affected by IUGR, in the setting of severe discordant growth. Because monozygotic twins have the same genotype at conception and a shared maternal environment, they provide an ideal model system for studying epigenetic dysregulation of the placenta.We compared genome-wide placental DNA methylation patterns of severely growth-discordant twins to identify novel candidate genes for IUGR. Snap-frozen placental samples for eight severely growth-discordant monozygotic monochorionic twin pairs were obtained at delivery from each twin. A high-resolution DNA methylation array platform was used to identify methylation differences between IUGR and normal twins. Our analysis revealed differentially methylated regions in the promoters of eight genes: DECR1, ZNF300, DNAJA4, CCL28, LEPR, HSPA1A/L, GSTO1, and GNE. The largest methylation differences between the two groups were in the promoters of DECR1 and ZNF300. The significance of these group differences was independently validated by bisulfite pyrosequencing, implicating aberrations in fatty acid beta oxidation and transcriptional regulation, respectively. Further analysis of the array data identified methylation changes most prominently affecting the Wnt and cadherin pathways in the IUGR cohort.Our results suggest that IUGR in monozygotic twins is associated with impairments in lipid metabolism and transcriptional regulation as well as cadherin and Wnt signaling. We show that monozygotic monochorionic twins discordant for growth provide a useful model to study one type of the epigenetic placental dysregulation that drives IUGR.

Project description:BackgroundIntrauterine growth restriction (IUGR) affects 5-10% of all newborns and is associated with a high risk of abnormal neurodevelopment. The timing and patterns of brain reorganization underlying IUGR are poorly documented. We developed a rabbit model of IUGR allowing neonatal neurobehavioral assessment and high resolution brain diffusion magnetic resonance imaging (MRI). The aim of the study was to describe the pattern and functional correlates of fetal brain reorganization induced by IUGR.Methodology/principal findingsIUGR was induced in 10 New Zealand fetal rabbits by ligation of 40-50% of uteroplacental vessels in one horn at 25 days of gestation. Ten contralateral horn fetuses were used as controls. Cesarean section was performed at 30 days (term 31 days). At postnatal day +1, neonates were assessed by validated neurobehavioral tests including evaluation of tone, spontaneous locomotion, reflex motor activity, motor responses to olfactory stimuli, and coordination of suck and swallow. Subsequently, brains were collected and fixed and MRI was performed using a high resolution acquisition scheme. Global and regional (manual delineation and voxel based analysis) diffusion tensor imaging parameters were analyzed. IUGR was associated with significantly poorer neurobehavioral performance in most domains. Voxel based analysis revealed fractional anisotropy (FA) differences in multiple brain regions of gray and white matter, including frontal, insular, occipital and temporal cortex, hippocampus, putamen, thalamus, claustrum, medial septal nucleus, anterior commissure, internal capsule, fimbria of hippocampus, medial lemniscus and olfactory tract. Regional FA changes were correlated with poorer outcome in neurobehavioral tests.ConclusionsIUGR is associated with a complex pattern of brain reorganization already at birth, which may open opportunities for early intervention. Diffusion MRI can offer suitable imaging biomarkers to characterize and monitor brain reorganization due to fetal diseases.

Dataset Information

Genetic and epigenetic influences associated with intrauterine growth restriction due to in utero tobacco exposure.

Publications

Genetic and epigenetic influences associated with intrauterine growth restriction due to in utero tobacco exposure.

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