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1.  Maternal Alcohol Intake and Offspring Pulse Wave Velocity 
Neonatology  2009;97(3):204-211.
Background
Intrauterine exposure to alcohol may affect cardiovascular development, increasing risk of cardiovascular malformations. Intrauterine exposure to light maternal alcohol intake has been reported to affect human umbilical arterial contractility, and adult sheep exposed in utero have had altered cerebrovascular reactivity. In human adults, alcohol intake affects arterial stiffness.
Objectives
We investigated whether intrauterine exposure to alcohol was associated with childhood pulse wave velocity (PWV), a measure of arterial stiffness.
Methods
On postnatal day 4, mothers of 147 twin pairs born in Tasmania from 1991 to 1993 reported alcohol intake during each trimester of pregnancy. At 9 years, child PWV was assessed over carotid-femoral and femoral-dorsalis pedis arterial segments by applanation tonometry.
Results
Carotid-femoral PWV was 0.2 m/s (95% CI 0.06, 0.4) higher (indicating stiffer vessels) in children whose mothers drank alcohol in the 2nd trimester rather than abstained, after adjusting for potential confounding factors. A similar effect was not seen for femoral-dorsalis pedis PWV. Findings were independent of child blood pressure which correlated strongly with PWV. Alcohol intake varied little between trimesters, so it was not possible to assess the effect of timing of exposure.
Conclusions
Carotid-femoral PWV in adults is predictive of cardiovascular morbidity and mortality. The degree of continuity between childhood and adulthood PWV is unknown, but as we found an association between prenatal alcohol exposure and carotid-femoral PWV at 9 years, a permanent change in vessel wall structure or function is possible. These findings need to be confirmed in other and larger cohorts, and mechanistic animal studies are needed.
doi:10.1159/000252973
PMCID: PMC3701444  PMID: 19864927
Fetus; Ethanol; Pulse wave velocity; Blood pressure
3.  Prospects for Epigenetic Epidemiology 
American Journal of Epidemiology  2009;169(4):389-400.
Epigenetic modification can mediate environmental influences on gene expression and can modulate the disease risk associated with genetic variation. Epigenetic analysis therefore holds substantial promise for identifying mechanisms through which genetic and environmental factors jointly contribute to disease risk. The spatial and temporal variance in epigenetic profile is of particular relevance for developmental epidemiology and the study of aging, including the variable age at onset for many common diseases. This review serves as a general introduction to the topic by describing epigenetic mechanisms, with a focus on DNA methylation; genetic and environmental factors that influence DNA methylation; epigenetic influences on development, aging, and disease; and current methodology for measuring epigenetic profile. Methodological considerations for epidemiologic studies that seek to include epigenetic analysis are also discussed.
doi:10.1093/aje/kwn380
PMCID: PMC3290967  PMID: 19139055
DNA methylation; environment; epigenesis, genetic; folic acid
4.  DNA Methylation-mediated Down-regulation of DNA Methyltransferase-1 (DNMT1) Is Coincident with, but Not Essential for, Global Hypomethylation in Human Placenta 
The Journal of Biological Chemistry  2010;285(13):9583-9593.
The genome of extraembryonic tissue, such as the placenta, is hypomethylated relative to that in somatic tissues. However, the origin and role of this hypomethylation remains unclear. The DNA methyltransferases DNMT1, -3A, and -3B are the primary mediators of the establishment and maintenance of DNA methylation in mammals. In this study, we investigated promoter methylation-mediated epigenetic down-regulation of DNMT genes as a potential regulator of global methylation levels in placental tissue. Although DNMT3A and -3B promoters lack methylation in all somatic and extraembryonic tissues tested, we found specific hypermethylation of the maintenance DNA methyltransferase (DNMT1) gene and found hypomethylation of the DNMT3L gene in full term and first trimester placental tissues. Bisulfite DNA sequencing revealed monoallelic methylation of DNMT1, with no evidence of imprinting (parent of origin effect). In vitro reporter experiments confirmed that DNMT1 promoter methylation attenuates transcriptional activity in trophoblast cells. However, global hypomethylation in the absence of DNMT1 down-regulation is apparent in non-primate placentas and in vitro derived human cytotrophoblast stem cells, suggesting that DNMT1 down-regulation is not an absolute requirement for genomic hypomethylation in all instances. These data represent the first demonstration of methylation-mediated regulation of the DNMT1 gene in any system and demonstrate that the unique epigenome of the human placenta includes down-regulation of DNMT1 with concomitant hypomethylation of the DNMT3L gene. This strongly implicates epigenetic regulation of the DNMT gene family in the establishment of the unique epigenetic profile of extraembryonic tissue in humans.
doi:10.1074/jbc.M109.064956
PMCID: PMC2843208  PMID: 20071334
Development Differentiation/Tissue; DNA/Methylation; DNA/Methyltransferase; Epigenetics; Gene Transcription; Extraembryonic Tissue; Placenta; Trophoblast
5.  Placenta-specific Methylation of the Vitamin D 24-Hydroxylase Gene 
The Journal of Biological Chemistry  2009;284(22):14838-14848.
Plasma concentrations of biologically active vitamin D (1,25-(OH)2D) are tightly controlled via feedback regulation of renal 1α-hydroxylase (CYP27B1; positive) and 24-hydroxylase (CYP24A1; catabolic) enzymes. In pregnancy, this regulation is uncoupled, and 1,25-(OH)2D levels are significantly elevated, suggesting a role in pregnancy progression. Epigenetic regulation of CYP27B1 and CYP24A1 has previously been described in cell and animal models, and despite emerging evidence for a critical role of epigenetics in placentation generally, little is known about the regulation of enzymes modulating vitamin D homeostasis at the fetomaternal interface. In this study, we investigated the methylation status of genes regulating vitamin D bioavailability and activity in the placenta. No methylation of the VDR (vitamin D receptor) and CYP27B1 genes was found in any placental tissues. In contrast, the CYP24A1 gene is methylated in human placenta, purified cytotrophoblasts, and primary and cultured chorionic villus sampling tissue. No methylation was detected in any somatic human tissue tested. Methylation was also evident in marmoset and mouse placental tissue. All three genes were hypermethylated in choriocarcinoma cell lines, highlighting the role of vitamin D deregulation in this cancer. Gene expression analysis confirmed a reduced capacity for CYP24A1 induction with promoter methylation in primary cells and in vitro reporter analysis demonstrated that promoter methylation directly down-regulates basal promoter activity and abolishes vitamin D-mediated feedback activation. This study strongly suggests that epigenetic decoupling of vitamin D feedback catabolism plays an important role in maximizing active vitamin D bioavailability at the fetomaternal interface.
doi:10.1074/jbc.M809542200
PMCID: PMC2685665  PMID: 19237542
6.  Within pair association between birth weight and blood pressure at age 8 in twins from a cohort study 
BMJ : British Medical Journal  1999;319(7221):1325-1329.
Objectives
To study the association between birth weight and blood pressure in children from multiple pregnancies (multiplets), mostly twins, to determine whether maternal or genetic factors are responsible for the association.
Design
Cohort study.
Setting
Southern Tasmania.
Subjects
888 children including 104 multiplets (32 monozygotic, 72 dizygotic).
Main outcome measure
Systolic blood pressure (mm Hg).
Results
Blood pressure decreased with birth weight and increased with current body mass. After adjustment for age and body mass, systolic blood pressure changed by −1.94 mm Hg (95% confidence interval −2.89 to –0.98) per 1 kg increase in birth weight of singletons. For multiplets, blood pressure changed by −7.0 mm Hg (−10.1 to −3.9) for each 1 kg increase in birth weight. This was little altered in within pair analyses (−5.3, −13.8 to 3.2) and was similar for both monozygotic (−6.5, −22.5 to 9.4) and dizygotic (−4.9, −15.8 to 6.0) pairs.
Conclusion
Because the association between birth weight and blood pressure was largely unchanged in within pair analyses, exposures originating in the mother (such as nutritional status) cannot be wholly responsible. The association also remained within monozygotic pairs, suggesting that genetic predisposition is not wholly responsible either. The principal causal pathway must concern mechanisms within the fetoplacental unit. The stronger association in multiplets suggests that factors adversely influencing both blood pressure and birth weight are more prevalent in multiple pregnancies.
Key messagesLow birthweight is associated with high blood pressure from an early ageMaternal factors, including diet during pregnancy, cannot wholly explain the association between fetal development and later risk of cardiovascular diseaseBecause the association between blood pressure and birthweight remained in monozygotic twins, genetic factors are unlikely to be responsible for the associationImportant causes of the association seem to be operating within the fetoplacental unit during fetal lifeFurther research should now focus on placental function and fetal exposures
PMCID: PMC28277  PMID: 10567134

Results 1-6 (6)