Publications by authors named "Ruth Morley"

60 Publications

Maternal alcohol consumption in pregnancy enhances arterial stiffness and alters vasodilator function that varies between vascular beds in fetal sheep.

J Physiol 2014 Jun 22;592(12):2591-603. Epub 2014 Apr 22.

Departments of Physiology, Monash University, Clayton, Victoria, 3800, Australia.

While the impact of alcohol consumption by pregnant women on fetal neurodevelopment has received much attention, the effects on the cardiovascular system are not well understood. We hypothesised that repeated exposure to alcohol (ethanol) in utero would alter fetal arterial reactivity and wall stiffness, key mechanisms leading to cardiovascular disease in adulthood. Ethanol (0.75 g (kg body weight)(-1)) was infused intravenously into ewes over 1 h daily for 39 days in late pregnancy (days 95-133 of pregnancy, term ∼147 days). Maternal and fetal plasma ethanol concentrations at the end of the hour were ∼115 mg dl(-1), and then declined to apparent zero over 8 h. At necropsy (day 134), fetal body weight and fetal brain-body weight ratio were not affected by alcohol infusion. Small arteries (250-300 μm outside diameter) from coronary, renal, mesenteric, femoral (psoas) and cerebral beds were isolated. Endothelium-dependent vasodilatation sensitivity was reduced 10-fold in coronary resistance arteries, associated with a reduction in endothelial nitric oxide synthase mRNA (P = 0.008). Conversely, vasodilatation sensitivity was enhanced 10-fold in mesenteric and renal resistance arteries. Arterial stiffness was markedly increased (P = 0.0001) in all five vascular beds associated with an increase in elastic modulus and, in cerebral vessels, with an increase in collagen Iα mRNA. Thus, we show for the first time that fetal arteries undergo marked and regionally variable adaptations as a consequence of repeated alcohol exposure. These alcohol-induced vascular effects occurred in the apparent absence of fetal physical abnormalities or fetal growth restriction.
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http://dx.doi.org/10.1113/jphysiol.2013.262873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4080940PMC
June 2014

Association of maternal and nutrient supply line factors with DNA methylation at the imprinted IGF2/H19 locus in multiple tissues of newborn twins.

Epigenetics 2013 Oct 5;8(10):1069-79. Epub 2013 Aug 5.

Department of Paediatrics; University of Melbourne; Parkville, VIC Australia; Early Life Epigenetics Group; Murdoch Childrens Research Institute (MCRI); Royal Children's Hospital; Parkville, VIC Australia.

Epigenetic events are crucial for early development, but can be influenced by environmental factors, potentially programming the genome for later adverse health outcomes. The insulin-like growth factor 2 (IGF2)/H19 locus is crucial for prenatal growth and the epigenetic state at this locus is environmentally labile. Recent studies have implicated maternal factors, including folate intake and smoking, in the regulation of DNA methylation at this locus, although data are often conflicting in the direction and magnitude of effect. Most studies have focused on single tissues and on one or two differentially-methylated regions (DMRs) regulating IGF2/H19 expression. In this study, we investigated the relationship between multiple shared and non-shared gestational/maternal factors and DNA methylation at four IGF2/H19 DMRs in five newborn cell types from 67 pairs of monozygotic and 49 pairs of dizygotic twins. Data on maternal and non-shared supply line factors were collected during the second and third trimesters of pregnancy and DNA methylation was measured via mass spectrometry using Sequenom MassArray EpiTyper analysis. Our exploratory approach showed that the site of umbilical cord insertion into the placenta in monochorionic twins has the strongest positive association with methylation in all IGF2/H19 DMRs (p<0.05). Further, evidence for tissue- and locus-specific effects were observed, emphasizing that responsiveness to environmental exposures in utero cannot be generalized across genes and tissues, potentially accounting for the lack of consistency in previous findings. Such complexity in responsiveness to environmental exposures in utero has implications for all epigenetic studies investigating the developmental origins of health and disease.
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http://dx.doi.org/10.4161/epi.25908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3891688PMC
October 2013

The Peri/postnatal Epigenetic Twins Study (PETS).

Twin Res Hum Genet 2013 Feb 22;16(1):13-20. Epub 2012 Nov 22.

Department of Paediatrics, Royal Children's Hospital, Melbourne, Australia.

The Peri/postnatal Epigenetic Twins Study (PETS) is a longitudinal cohort of 250 pairs of Australian twins and their mothers, who were recruited mid-way through pregnancy from January 2007 to September 2009. The study is centered on the developmental origins of health and disease paradigm (DOHaD) in which an adverse intrauterine environment predisposes the individual to complex disease in later life by reducing growth in utero and adversely altering developmental plasticity. Data concerning diet and lifestyle were collected from mothers during pregnancy, and samples of plasma and serum taken at 28 weeks' gestation. We attended 75% of all births, at which time we collected multiple biological samples including placenta, cord blood, and neonatal cheek cells, the latter from 91% of pairs. Chorionicity was recorded and zygosity was determined by DNA testing where necessary. Approximately 40% of the twins are monozygotic, two-thirds of which are dichorionic. Twins were seen again at 18 months of age and repeat blood and cheek swabs taken where possible. Studies of gene expression and the epigenetic marks of DNA methylation have so far revealed that twins exhibit a wide range of epigenetic discordance at birth, that one-third of the epigenome changes significantly between birth and 18 months; shared (maternal) environment, genetic factors, and non-shared intrauterine environment contribute to an increasing proportion of epigenetic variation at birth, respectively, and affect tissues differently, and that within-pair birth weight discordance correlates with epigenetic discordance in genes associated with lipid metabolism, supporting an epigenetic mechanism for DOHaD.
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http://dx.doi.org/10.1017/thg.2012.114DOI Listing
February 2013

Neonatal DNA methylation profile in human twins is specified by a complex interplay between intrauterine environmental and genetic factors, subject to tissue-specific influence.

Genome Res 2012 Aug 16;22(8):1395-406. Epub 2012 Jul 16.

Bioinformatics Unit, Murdoch Childrens Research Institute, Parkville, Victoria 3052, Australia.

Comparison between groups of monozygotic (MZ) and dizygotic (DZ) twins enables an estimation of the relative contribution of genetic and shared and nonshared environmental factors to phenotypic variability. Using DNA methylation profiling of ∼20,000 CpG sites as a phenotype, we have examined discordance levels in three neonatal tissues from 22 MZ and 12 DZ twin pairs. MZ twins exhibit a wide range of within-pair differences at birth, but show discordance levels generally lower than DZ pairs. Within-pair methylation discordance was lowest in CpG islands in all twins and increased as a function of distance from islands. Variance component decomposition analysis of DNA methylation in MZ and DZ pairs revealed a low mean heritability across all tissues, although a wide range of heritabilities was detected for specific genomic CpG sites. The largest component of variation was attributed to the combined effects of nonshared intrauterine environment and stochastic factors. Regression analysis of methylation on birth weight revealed a general association between methylation of genes involved in metabolism and biosynthesis, providing further support for epigenetic change in the previously described link between low birth weight and increasing risk for cardiovascular, metabolic, and other complex diseases. Finally, comparison of our data with that of several older twins revealed little evidence for genome-wide epigenetic drift with increasing age. This is the first study to analyze DNA methylation on a genome scale in twins at birth, further highlighting the importance of the intrauterine environment on shaping the neonatal epigenome.
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http://dx.doi.org/10.1101/gr.136598.111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3409253PMC
August 2012

Maternal vitamin D predominates over genetic factors in determining neonatal circulating vitamin D concentrations.

Am J Clin Nutr 2012 Jul 30;96(1):188-95. Epub 2012 May 30.

Cancer and Disease Epigenetics Group, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Australia.

Background: There are multiple potential regulators of neonatal vitamin D status of environmental, genetic, and epigenetic origins. The relation between these factors and circulating neonatal vitamin D has yet to be fully characterized.

Objective: The aim of this study was to examine the relative contribution of genetic factors, maternal circulating 25-hydroxyvitamin D [25(OH)D] concentrations, and the placental methylation level of the gene that encodes the primary catabolic enzyme of active vitamin D [25(OH)D-24-hydroxylase encoded by CYP24A1] to neonatal 25(OH)D concentrations.

Design: We used the classical twin study design to determine the genetic contribution to neonatal 25(OH)D. A total of 86 twin pairs (32 monozygotic and 54 dizygotic twin pairs) were included in this study. Serum 25(OH)D was measured by using a 25(OH)D kit. CYP24A1 promoter DNA methylation was measured by means of matrix-assisted laser desorption time-of-flight mass spectrometry.

Results: Maternal and neonatal 25(OH)D showed a strong association (R² = 0.19). Monozygotic and dizygotic within-pair serum 25(OH)D correlations were similar (R² = 0.71 and 0.67, respectively), which suggested no genetic effect. Placental CYP24A1 methylation did not show an association with maternal or neonatal 25(OH)D concentrations.

Conclusions: Our results suggest that maternal circulating 25(OH)D is the most significant regulator of neonatal circulating 25(OH)D concentrations, with underlying genetic factors playing a limited role. The placental methylation of the CYP24A1 promoter appears subject to a genetic influence, although no evidence of a relation between the methylation level of this gene and circulating maternal or neonatal 25(OH)D was apparent.
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http://dx.doi.org/10.3945/ajcn.112.035683DOI Listing
July 2012

Twinship influence on morbidity and mortality across the lifespan.

Int J Epidemiol 2012 Aug 9;41(4):1002-9. Epub 2012 May 9.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: Studies in twins may be questioned with respect to their representativeness of the general population, not least considering the potential importance of the fetal environment for future health and disease. To better understand the influence twinning may have on health, we investigated long-term health outcomes of twins, their singleton siblings and singletons from the population.

Methods: Morbidity and mortality in twins was contrasted to that of their singleton siblings. These singletons from families with twins were then compared with singletons of the population to further reveal potential twin family influences on health. Familial relations were identified through the Swedish Multi-Generation Register. Among individuals born between 1932 and 1958, the number of twins and their singleton siblings identified were 49,156 and 35,277, respectively. Outcomes were incident overall cancer, cardiovascular disease (CVD) and death, identified in national registers. Standardized survival functions were estimated using Cox proportional hazards regression and the corresponding cumulative risks plotted against age.

Results: Cumulative risks of cancer, CVD and death in twins did not differ from singletons of families with twins, who in turn were found to be similar to singletons of families without twins. As could be expected from these findings, no differences in risks were found when twins were compared with singletons of the population.

Conclusions: Despite their adverse intrauterine experience, twins do not seem to fare worse than singletons with respect to adult morbidity and mortality. The findings indicate that the unique experience of twinning does not lead to adverse long-term health outcomes.
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http://dx.doi.org/10.1093/ije/dys067DOI Listing
August 2012

Cohort profile: The peri/post-natal epigenetic twins study.

Int J Epidemiol 2012 Feb 3;41(1):55-61. Epub 2011 Oct 3.

Cancer and Disease Epigenetics Group, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.

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http://dx.doi.org/10.1093/ije/dyr140DOI Listing
February 2012

Vitamin D insufficiency is associated with impaired vascular endothelial and smooth muscle function and hypertension in young rats.

J Physiol 2011 Oct 1;589(Pt 19):4777-86. Epub 2011 Aug 1.

Department of Physiology, Monash University, Victoria 3800, Australia.

Increasing evidence links vitamin D deficiency and cardiovascular dysfunction in human adults. There is a worldwide increase in the prevalence of vitamin D deficiency in women of reproductive age, particularly dark-skinned and/or veiled women and their infants. We used a rat model to determine the functional impact of vitamin D deficiency during intra uterine and early life on resistance artery reactivity and blood pressure in the offspring as young adults. Rat dams were maintained on vitamin D deficient or replete chow before and during pregnancy and lactation. The offspring were maintained on the same chow until studied at 7-8 weeks of age. Conscious blood pressure was measured. Endothelial and smooth muscle function were tested in mesenteric arteries on a pressure myograph. Vitamin D deficient male and female offspring had a 10-fold lower serum 25-hydroxyvitamin D (P < 0.0001) and markedly elevated blood pressures (11-20 mmHg, P < 0.001) and heart rates (21-40 beats min(-1), P < 0.02) than control fed offspring. Serum calcium was unchanged. Mesenteric artery myogenic tone was doubled in vitamin D deficiency. Endothelium-derived nitric oxide-evoked dilation was halved in arteries from vitamin D deficient males and dioestrous females. Dilation attributed to endothelium-derived hyperpolarizing factor was all but abolished in vitamin D deficient oestrous females. Nitroprusside-evoked dilation was unaltered in arteries from males, but was markedly reduced in vessels of vitamin D deplete females. In conclusion, early life vitamin D deficiency is associated with endothelial vasodilator dysfunction, and this is likely to contribute to the accompanying elevation in blood pressure and an increased cardiovascular disease risk.
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http://dx.doi.org/10.1113/jphysiol.2011.214726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3213423PMC
October 2011

Expression discordance of monozygotic twins at birth: effect of intrauterine environment and a possible mechanism for fetal programming.

Epigenetics 2011 May 1;6(5):579-92. Epub 2011 May 1.

Bioinformatics Unit, University of Helsinki, Finland.

Within-pair comparison of monozygotic (MZ) twins provides an ideal model for studying factors that regulate epigenetic profile, by controlling for genetic variation. Previous reports have demonstrated epigenetic variability within MZ pairs, but the contribution of early life exposures to this variation remains unclear. As epigenetic marks govern gene expression, we have used gene expression discordance as a proxy measure of epigenetic discordance in MZ twins at birth in two cell types. We found strong evidence of expression discordance at birth in both cell types and some evidence for higher discordance in twin pairs with separate placentas. Genes previously defined as being involved in response to the external environment showed the most variable expression within pairs, independent of cell type, supporting the idea that even slight differences in intrauterine environment can influence expression profile. Focusing on birthweight, previously identified as a predisposing factor for cardiovascular, metabolic and other complex diseases, and using a statistical model that estimated association based on within-pair variation of expression and birthweight, we found some association between birthweight and expression of genes involved in metabolism and cardiovascular function. This study is the first to examine expression discordance in newborn twins. It provides evidence of a link between birthweight and activity of specific cellular pathways and, as evidence points to gene expression profiles being maintained through cell division by epigenetic factors, provides a plausible biological mechanism for the previously described link between low birthweight and increased risk of later complex disease.
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http://dx.doi.org/10.4161/epi.6.5.15072DOI Listing
May 2011

Birthweight and mortality in adulthood: a systematic review and meta-analysis.

Int J Epidemiol 2011 Jun 15;40(3):647-61. Epub 2011 Feb 15.

Department of Public Health, Norwegian University of Science and Technology, Trondheim, Norway.

Background: Small birth size may be associated with increased risk of cardiovascular diseases (CVD), whereas large birth size may predict increased risk of obesity and some cancers. The net effect of birth size on long-term mortality has only been assessed in individual studies, with conflicting results.

Methods: The Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines for conducting and reporting meta-analysis of observational studies were followed. We retrieved 22 studies that assessed the association between birthweight and adult mortality from all causes, CVD or cancer. The studies were systematically reviewed and those reporting hazard ratios (HRs) and 95% confidence intervals (95% CIs) per kilogram (kg) increase in birthweight were included in generic inverse variance meta-analyses.

Results: For all-cause mortality, 36,834 deaths were included and the results showed a 6% lower risk (adjusted HR = 0.94, 95% CI: 0.92-0.97) per kg higher birthweight for men and women combined. For cardiovascular mortality, the corresponding inverse association was stronger (HR = 0.88, 95% CI: 0.85-0.91). For cancer mortality, HR per kg higher birthweight was 1.13 (95% CI: 1.07-1.19) for men and 1.04 (95% CI: 0.98-1.10) for women (P(interaction) = 0.03). Residual confounding could not be eliminated, but is unlikely to account for the main findings.

Conclusion: These results show an inverse but moderate association of birthweight with adult mortality from all-causes and a stronger inverse association with cardiovascular mortality. For men, higher birthweight was strongly associated with increased risk of cancer deaths. The findings suggest that birthweight can be a useful indicator of processes that influence long-term health.
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http://dx.doi.org/10.1093/ije/dyq267DOI Listing
June 2011

Propensity scores: from naive enthusiasm to intuitive understanding.

Stat Methods Med Res 2012 Jun 24;21(3):273-93. Epub 2011 Jan 24.

Murdoch Childrens Research Institute, Melbourne, Australia.

Estimation of the effect of a binary exposure on an outcome in the presence of confounding is often carried out via outcome regression modelling. An alternative approach is to use propensity score methodology. The propensity score is the conditional probability of receiving the exposure given the observed covariates and can be used, under the assumption of no unmeasured confounders, to estimate the causal effect of the exposure. In this article, we provide a non-technical and intuitive discussion of propensity score methodology, motivating the use of the propensity score approach by analogy with randomised studies, and describe the four main ways in which this methodology can be implemented. We carefully describe the population parameters being estimated - an issue that is frequently overlooked in the medical literature. We illustrate these four methods using data from a study investigating the association between maternal choice to provide breast milk and the infant's subsequent neurodevelopment. We outline useful extensions of propensity score methodology and discuss directions for future research. Propensity score methods remain controversial and there is no consensus as to when, if ever, they should be used in place of traditional outcome regression models. We therefore end with a discussion of the relative advantages and disadvantages of each.
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http://dx.doi.org/10.1177/0962280210394483DOI Listing
June 2012

DNA methylation analysis of multiple tissues from newborn twins reveals both genetic and intrauterine components to variation in the human neonatal epigenome.

Hum Mol Genet 2010 Nov 10;19(21):4176-88. Epub 2010 Aug 10.

Developmental Epigenetics, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria 3052, Australia.

Mounting evidence from both animal and human studies suggests that the epigenome is in constant drift over the life course in response to stochastic and environmental factors. In humans, this has been highlighted by a small number of studies that have demonstrated discordant DNA methylation patterns in adolescent or adult monozygotic (MZ) twin pairs. However, to date, it remains unclear when such differences emerge, and how prevalent they are across different tissues. To address this, we examined the methylation of four differentially methylated regions associated with the IGF2/H19 locus in multiple birth tissues derived from 91 twin pairs: 56 MZ and 35 dizygotic (DZ). Tissues included cord blood-derived mononuclear cells and granulocytes, human umbilical vein endothelial cells, buccal epithelial cells and placental tissue. Considerable variation in DNA methylation was observed between tissues and between unrelated individuals. Most interestingly, methylation discordance was also present within twin pairs, with DZ pairs showing greater discordance than MZ pairs. These data highlight the variable contribution of both intrauterine environmental exposures and underlying genetic factors to the establishment of the neonatal epigenome of different tissues and confirm the intrauterine period as a sensitive time for the establishment of epigenetic variability in humans. This has implications for the effects of maternal environment on the development of the newborn epigenome and supports an epigenetic mechanism for the previously described phenomenon of 'fetal programming' of disease risk.
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http://dx.doi.org/10.1093/hmg/ddq336DOI Listing
November 2010

The utility of neonatal dried blood spots for the assessment of neonatal vitamin D status.

Paediatr Perinat Epidemiol 2010 May;24(3):303-8

Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol, Queensland, Australia.

Evidence suggests that low concentrations of 25-hydroxyvitamin D(3) (25OHD3) during gestation may be associated with a range of adverse health outcomes in later life. Retrospective estimation of perinatal vitamin D status using questionnaires is extremely unreliable and stored serum samples are rarely available. We aimed to validate the use of dried blood spots (DBS) to estimate perinatal vitamin D status and to determine whether inter-group differences in cord serum 25OHD3 are reflected in DBS. We examined 25OHD3 in 4-year-old frozen cord sera and matched DBS from neonates born at a hospital in Melbourne, Australia (n = 100). We examined the correlation between these values and also investigated whether the expected seasonal (winter/spring vs. summer/autumn) difference in serum 25OHD3 was reflected in DBS values. 25OHD3 was assayed in triplicate using tandem mass spectroscopy in both a 3 microL sample of cord serum and in matched 3 mm punches from archived DBS. 25OHD3 concentrations in neonatal cord serum and DBS were highly correlated (r = 0.85, P < 0.0001). As expected, serum 25OHD3 concentrations were higher in neonates born in summer/autumn (December to March) vs. winter/spring (April to November) (median 46.6 vs. 23.7 nmol/L, P < 0.0001). A comparable difference was seen in DBS values (17.8 vs. 10.5 nmol/L, P = 0.0001). Archived DBS samples provided a valid measure of perinatal vitamin D status and identified inter-seasonal differences in perinatal 25OHD3 concentrations. They could be used for case-control studies investigating the association between perinatal vitamin D status and later health outcomes.
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http://dx.doi.org/10.1111/j.1365-3016.2010.01105.xDOI Listing
May 2010

DNA methylation-mediated down-regulation of DNA methyltransferase-1 (DNMT1) is coincident with, but not essential for, global hypomethylation in human placenta.

J Biol Chem 2010 Mar 13;285(13):9583-9593. Epub 2010 Jan 13.

Developmental Epigenetics, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria 3052, Australia; Department of Paediatrics, University of Melbourne, Parkville, Victoria 3052, Australia. Electronic address:

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.
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http://dx.doi.org/10.1074/jbc.M109.064956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2843208PMC
March 2010

Maternal alcohol intake and offspring pulse wave velocity.

Neonatology 2010 28;97(3):204-11. Epub 2009 Oct 28.

Department of Paediatrics, University of Melbourne, Clayton, Vic., Australia.

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.
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http://dx.doi.org/10.1159/000252973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3701444PMC
August 2010

Maternal vitamin D deficiency leads to cardiac hypertrophy in rat offspring.

Reprod Sci 2010 Feb 13;17(2):168-76. Epub 2009 Oct 13.

Department of Anatomy & Developmental Biology, Monash University, Clayton, Victoria, Australia.

The aim of this study was to determine the effect of vitamin D deficiency from conception until 4 weeks of age on the development of the heart in rat offspring. Sprague-Dawley (SD) rats were fed either a vitamin D deplete or vitamin D-replete diet for 6 weeks prior to pregnancy, during pregnancy and throughout lactation. Cardiomyocyte number was determined in fixed hearts of offspring at postnatal day 3 and 4 weeks of age using an optical disector/fractionator stereological technique. In other litters, cardiomyocytes were isolated from freshly excised hearts to determine the proportion of mononucleated and binucleated cardiomyocytes. Maternal vitamin D deficiency had no effect on cardiomyocyte number, cardiomyocyte area, or the proportion of mononucleated/binucleated cardiomyocytes in 3-day-old male and female offspring. Importantly, however, vitamin D deficiency led to an increase in left ventricle (LV) volume that was accompanied by an increase in cardiomyocyte number and size, and in the proportion of mononucleated cardiomyocytes at 4 weeks of age. Our findings suggest that exposure to vitamin D deficiency in utero and early life leads to delayed maturation and subsequent enhanced growth (proliferation and hypertrophy) of cardiomyocytes in the LV. This may lead to altered cardiac function later in life.
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http://dx.doi.org/10.1177/1933719109349536DOI Listing
February 2010

A convergent model for placental dysfunction encompassing combined sub-optimal one-carbon donor and vitamin D bioavailability.

Med Hypotheses 2009 Dec 9;73(6):1023-8. Epub 2009 Oct 9.

Department of Paediatrics, Developmental Epigenetics, Murdoch Childrens Research Institute, University of Melbourne, Parkville, Victoria 3052, Australia.

We hypothesise that the risk of placental dysfunction/insufficiency rises cumulatively in response to several interdependent risk factors that convergently regulate 1,25-dihydroxyvitamin D (the biologically active form of vitamin D, [1,25-(OH)(2)D]) levels at the feto-maternal interface. These factors include; (i) disturbances in genetic or epigenetic regulation of one-carbon metabolism and/or vitamin D metabolism and (ii) insufficiency in maternal vitamin D or in dietary intake of micronutrients that are involved in one-carbon donation. We predict that the sub-optimal functioning of folate and vitamin D metabolic pathways, in concert, represents a potential novel risk pathway for adverse pregnancy outcomes. We base this prediction on five observations: In order to test this model, future epidemiological studies aimed at identifying risk factors for disorders linked to sub-optimal placental development and functioning, should: (a) measure circulating precursor molecules (including folate, vitamin B12, homocysteine, and vitamin D) in maternal and cord blood; (b) collect samples for examination of genotypic variation in both one-carbon and vitamin D regulatory genes and, (c) collect samples for examination of epigenetic status of genes regulating vitamin D homeostasis and action in the placenta.
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http://dx.doi.org/10.1016/j.mehy.2009.03.057DOI Listing
December 2009

Early diet and general cognitive outcome at adolescence in children born at or below 30 weeks gestation.

J Pediatr 2009 Aug 15;155(2):229-34. Epub 2009 May 15.

Childhood Nutrition Research Centre, UCL Institute of Child Health, London, UK.

Objective: To test the hypothesis that effects of early diet on cognition observed at age 8 years persist in adolescents born preterm at < or = 30 weeks gestational age.

Study Design: A subgroup from a preterm infant cohort recruited for a randomized trial studying the effects of early dietary intervention was assessed at age 16 years. IQ scores were compared between those assigned a high-nutrient diet (n = 49) or standard-nutrient diet (n = 46) in infancy at both 8 and 16 years.

Results: At age 8 years, the high-nutrient group had higher mean Verbal IQ (VIQ; P = .03), Performance IQ (P = .01), and Full-Scale IQ (P = .02) scores compared with the standard-nutrient group; the VIQ difference persisted at adolescence (P = .02). This effect was accounted for principally by a significant difference in the mean Verbal Comprehension Index score (P < .008).

Conclusions: A brief period of dietary intervention after preterm birth, principally between 26 and 34 weeks of gestation, affected IQ at age 16 years. A standard-nutrient diet was associated with lower VIQ, accounted for mainly by differences in verbal comprehension, which persisted after control of social factors.
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http://dx.doi.org/10.1016/j.jpeds.2009.02.030DOI Listing
August 2009

Placenta-specific methylation of the vitamin D 24-hydroxylase gene: implications for feedback autoregulation of active vitamin D levels at the fetomaternal interface.

J Biol Chem 2009 May 23;284(22):14838-48. Epub 2009 Feb 23.

Developmental Epigenetics, Murdoch Childrens Research Institute, Royal Children's Hospital, and Department of Paediatrics, University of Melbourne, Parkville, Victoria 3052, Australia.

Plasma concentrations of biologically active vitamin D (1,25-(OH)(2)D) are tightly controlled via feedback regulation of renal 1alpha-hydroxylase (CYP27B1; positive) and 24-hydroxylase (CYP24A1; catabolic) enzymes. In pregnancy, this regulation is uncoupled, and 1,25-(OH)(2)D 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.
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http://dx.doi.org/10.1074/jbc.M809542200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2685665PMC
May 2009

Prospects for epigenetic epidemiology.

Am J Epidemiol 2009 Feb 12;169(4):389-400. Epub 2009 Jan 12.

Orygen Youth Health Research Centre & Department of Psychiatry, University of Melbourne, Australia.

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.
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http://dx.doi.org/10.1093/aje/kwn380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3290967PMC
February 2009

Association between early-life factors and risk of child-onset Crohn's disease among Victorian children born 1983-1998: a birth cohort study.

Inflamm Bowel Dis 2009 Jun;15(6):858-66

Murdoch Childrens Research Institute, Royal Childrens Hospital, Melbourne, Victoria, Australia.

Background: The incidence of Crohn's disease (CD) with onset before age 16 has increased. Several perinatal characteristics have been associated with CD. Our objective was to examine the temporal change in CD incidence by period of birth and the extent that this could be attributed to perinatal characteristics associated with higher CD risk.

Methods: A record linkage study was conducted utilizing the perinatal records of Victorian births 1983-1998 inclusive and a state-based CD registry. Proportional hazards models were used to investigate the perinatal factors in relation to the onset of CD by age 16. Further, a nested case control study was conducted to examine the association between sibling exposure and CD risk.

Results: The CD incidence rate for births 1983-1998 was 2.01 (95% confidence interval [CI] 1.79, 2.27) per 100,000 child-years. A birth cohort effect was demonstrated, with higher CD risk for 1992-1998 versus 1983-1991 births (hazard ratio [HR] 1.56; 95% CI 1.18, 2.06). Perinatal characteristics associated with higher CD risk included urban location, higher socioeconomic status, married mother, a congenital abnormality and delivery by elective cesarean section. Sibling exposure during the first 6 years of life was not associated with CD risk. The increased CD incidence among more recent births was not accounted for by changes in these measured perinatal factors.

Conclusions: The temporal increase in CD incidence documented for births up to 1990 has continued for children born after 1991 and was not accounted for by temporal changes in the measured perinatal factors.
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http://dx.doi.org/10.1002/ibd.20842DOI Listing
June 2009

Future health implications of prenatal and early-life vitamin D status.

Nutr Rev 2008 Dec;66(12):710-20

National Centre for Epidemiology and Population Health, The Australian National University, Canberra, Australia.

Current or recent low vitamin D status (or proxy measures such as dietary intake or ambient ultraviolet radiation) is linked to several chronic diseases, including osteoporosis, cancers, and cardiovascular and autoimmune diseases. Low prenatal vitamin D status may also increase susceptibility to such diseases in later life via specific target organ effects and/or through changes to the developing immune system. Maternal vitamin D supplementation during pregnancy could be an important public health measure to decrease risk of a range of chronic diseases, but further research is required to clarify beneficial and adverse effects of high prenatal vitamin D.
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http://dx.doi.org/10.1111/j.1753-4887.2008.00126.xDOI Listing
December 2008

Archived Guthrie blood spots as a novel source for quantitative DNA methylation analysis.

Biotechniques 2008 Oct;45(4):423-4, 426, 428 passim

Developmental Epigenetics, Murdoch Childrens Research Institute, Royal Children's Hospital, Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.

Sodium bisulfite treatment followed by PCR and DNA sequencing is widely considered the gold standard for the analysis of DNA methylation patterns. However, this technique generally requires substantial quantities of genomic DNA as starting material and is often associated with degradation of DNA. Here, we assess the feasibility of performing bisulfite sequencing on DNA isolated from 3-mm diameter punches of dried blood Guthrie spots. We demonstrate that it is possible to perform bisulfite sequencing from both freshly prepared and archived dried blood spots, using a combination of high purity DNA extraction and efficient bisulfite conversion. With the number of new technologies available for DNA methylation studies, we have extended this analysis and have successfully used a high-throughput mass spectrometry method for DNA methylation analysis on these samples. This provides a new source of material for epigenetic analysis of birth samples and provides an invaluable reference point to track temporal change in epigenetic profiles possibly linked with health and disease.
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http://dx.doi.org/10.2144/000112945DOI Listing
October 2008

Variation in associations between allelic variants of the vitamin D receptor gene and onset of type 1 diabetes mellitus by ambient winter ultraviolet radiation levels: a meta-regression analysis.

Am J Epidemiol 2008 Aug 13;168(4):358-65. Epub 2008 Jun 13.

Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Australia.

Vitamin D receptor (VDR) gene polymorphisms may be associated with risk of developing type 1 diabetes mellitus (T1DM), but reports have been conflicting. The authors reexamined population-based case-control studies on selected VDR polymorphisms and T1DM to investigate whether variation in reported associations could be partly explained by differences in ambient winter ultraviolet radiation (UVR) levels. A meta-analysis of 16 studies from 19 regions (midwinter UVR range, 1.0-133.8 mW/m(2)) was conducted. The association between winter UVR and the log odds ratio was examined by meta-regression. For FokI and BsmI, the log odds ratio for the association between the F and B alleles and T1DM increased as regional winter UVR increased (p = 0.039 and p = 0.036, respectively). The association between the TaqI T allele and T1DM was reduced with increasing winter UVR (p = 0.040). Low winter regional UVR was associated with a higher proportion of controls carrying BsmI and ApaI uppercase alleles and a lower proportion of controls carrying TaqI uppercase alleles. These findings strengthen the case that VDR variants are involved in the etiology of T1DM. They suggest that environmental UVR may influence the association between VDR genotype and T1DM risk. Further work on VDR polymorphisms and T1DM should concomitantly examine the roles of past UVR exposure and vitamin D status.
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http://dx.doi.org/10.1093/aje/kwn142DOI Listing
August 2008

Adiposity gain during childhood, ACE I/D polymorphisms and metabolic outcomes.

Obesity (Silver Spring) 2008 Sep;16(9):2141-7

Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.

We aimed to (i) determine the relative importance of childhood gain in upper body adiposity for insulin resistance (IR) and triglyceridemia (TG); (ii) examine whether the associations between adiposity and metabolic indices were more evident in those with the ACE DD genotype. We examined a birth cohort study of 292 children with measures in the neonatal period (day 4) including subscapular and triceps skinfolds; repeat skinfold measures at age 8, cardiorespiratory (CR) fitness, IR by the homeostasis model assessment (HOMA) equation (HOMA-IR) and serum triglyceride (TG) concentrations and measures of ACE I/D gene variants. A multiple linear regression analysis incorporating a life course approach was undertaken. Childhood gain in upper body adiposity was positively associated with HOMA-IR and TG independently of neonatal skinfolds (P < or = 0.02). The magnitude of these associations was higher among those of the ACE DD genotype. For example, subscapular skinfold gain was not strongly associated with HOMA-IR or TG among those with II or ID genotype (b = 0.03, P = 0.05; b = 0.02, P = 0.18 respectively) but was positively associated among those with the DD genotype (b = 0.11, P = 0.001; b = 0.08, P = 0.003); difference in effect P = 0.05; P = 0.01 respectively. Upper body fat accumulation during childhood was positively associated with HOMA-IR and TG independently of neonatal skinfolds. Further, the stronger associations for those with the ACE DD genotype is consistent with randomised controlled trial findings that ACE inhibition is associated with a reduced risk of developing type 2 diabetes. Further work is required to confirm and extend these findings.
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http://dx.doi.org/10.1038/oby.2008.302DOI Listing
September 2008

Maternal vitamin D in pregnancy may influence not only offspring bone mass but other aspects of musculoskeletal health and adiposity.

Med Hypotheses 2008 Aug 29;71(2):266-9. Epub 2008 Apr 29.

Epidemiology and Biostatistics Unit, Department of Clinical and Biomedical Sciences: Barwon Health, The University of Melbourne, Australia.

Osteoporotic fractures, falls and obesity are major health problems in developed nations. Evidence suggests that there are antenatal factors predisposing to these conditions. Data are emerging from Australia and elsewhere to suggest that maternal vitamin D status in pregnancy affects intrauterine skeletal mineralisation and skeletal growth together with muscle development and adiposity. Given that low levels of vitamin D have been documented in many urbanised populations, including those in countries with abundant sunlight, an important issue for public health is whether maternal vitamin D insufficiency during pregnancy has adverse effects on offspring health. The developing fetus may be exposed to low levels of vitamin D during critical phases of development as a result of maternal hypovitaminosis D. We hypothesise that this may have adverse effects on offspring musculoskeletal health and other aspects of body composition. Further research focused on the implications of poor gestational vitamin D nutrition is warranted as these developmental effects are likely to have a sustained influence on health during childhood and in adult life. We suggest that there is a clear rationale for randomised clinical trials to assess the potential benefits and harmful effects of vitamin D supplementation during pregnancy.
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http://dx.doi.org/10.1016/j.mehy.2008.01.033DOI Listing
August 2008

A health transition: birth weights, households and survival in an Australian working-class population sample born 1857-1900.

Soc Sci Med 2008 Mar 8;66(5):1070-83. Epub 2008 Jan 8.

School of Population Health, University of Melbourne, Victoria, Australia.

There is increasing interest in life course epidemiology. In this article we investigated the relationship between characteristics at birth and survival and year of birth and survival. We have detailed information about birth characteristics and cause of death for 8584 subjects from a cohort of 16,272 registered live births to European Australians in a charity hospital in Melbourne between 1857 and 1900. Women giving birth at the hospital were among the poorest in Melbourne, with almost half unmarried. The adult death certificates of the subjects were traced until 1985. We found that infant mortality was substantially higher in babies who were illegitimate, firstborn, had younger mothers, a birth weight <6lb or were a preterm birth. These factors had a weaker association with child mortality and were not associated with adult survival time. Infant mortality was substantially lower in the cohort born 1891-1900 (36%) than previously (58%), a major improvement not seen for child mortality or adult lifespan. Likely reasons for this improvement are the introduction of antisepsis in maternity wards, enforced registration and police supervision of persons other than their mother who cared for babies, strictly monitored feeding practices and a mandatory autopsy and coronial enquiry for such babies who died. We conclude that this is an early example of a successful public health intervention.
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http://dx.doi.org/10.1016/j.socscimed.2007.11.040DOI Listing
March 2008

'Are you asking me if we had sex to conceive?' To whom do parents of twins disclose mode of conception and what do they feel about being asked?

Twin Res Hum Genet 2007 Dec;10(6):886-91

University of Melbourne Department of Paediatrics, Royal Children's Hospital, Flemington Road, Parkville, VIC, Australia.

There are no data on whether parents of twins will disclose mode of conception to researchers or to their children, who will be informants in adulthood. We sent 1600 questionnaires about this via the Victorian branch of the Australian Multiple Birth Association, to be returned anonymously. Parents were asked how their twins were conceived and whether those who used assisted conception would disclose this to researchers studying assisted conception, twin pregnancy or twin children, or to their children. Comments were invited. Altogether 975 (61%) questionnaires were returned and 389 (40%) indicated use of some form of assisted conception: 75 (19%) ovarian stimulation alone, 165 (42%) In Vitro Fertilisation, 132 (34%) Intracytoplasmic Sperm Injection, and 17 (4%) Gamete Intrafallopian Transfer, with 20 reporting use of donor eggs and thirteen donor sperm. Of those using assisted conception, the proportion reporting that they would not, or may not, tell researchers was 5% for assisted conception studies, 6% for twin pregnancy studies, and 7% for studies of twin children, while 7% reported that they would not, or may not, tell their children. From the comments (from 374/975; 38%) it was clear that questions about mode of conception can be offensive to some parents of twins, unless there is a need to know. Further, the question 'are your twins natural?' should be avoided. We believe the question 'Did you need medical help to conceive your twins', followed up with specific questions, is more acceptable.
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http://dx.doi.org/10.1375/twin.10.6.886DOI Listing
December 2007