Paediatrics (RCH) - Research Publications

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    Early life infection and proinflammatory, atherogenic metabolomic and lipidomic profiles in infancy: a population-based cohort study.
    Mansell, T ; Saffery, R ; Burugupalli, S ; Ponsonby, A-L ; Tang, MLK ; O'Hely, M ; Bekkering, S ; Smith, AAT ; Rowland, R ; Ranganathan, S ; Sly, PD ; Vuillermin, P ; Collier, F ; Meikle, P ; Burgner, D ; Barwon Infant Study Investigator Group, (eLife Sciences Publications, Ltd, 2022-05-10)
    Background: The risk of adult onset cardiovascular and metabolic (cardiometabolic) disease accrues from early life. Infection is ubiquitous in infancy and induces inflammation, a key cardiometabolic risk factor, but the relationship between infection, inflammation, and metabolic profiles in early childhood remains unexplored. We investigated relationships between infection and plasma metabolomic and lipidomic profiles at age 6 and 12 months, and mediation of these associations by inflammation. Methods: Matched infection, metabolomics, and lipidomics data were generated from 555 infants in a pre-birth longitudinal cohort. Infection data from birth to 12 months were parent-reported (total infections at age 1, 3, 6, 9, and 12 months), inflammation markers (high-sensitivity C-reactive protein [hsCRP]; glycoprotein acetyls [GlycA]) were quantified at 12 months. Metabolic profiles were 12-month plasma nuclear magnetic resonance metabolomics (228 metabolites) and liquid chromatography/mass spectrometry lipidomics (776 lipids). Associations were evaluated with multivariable linear regression models. In secondary analyses, corresponding inflammation and metabolic data from birth (serum) and 6-month (plasma) time points were used. Results: At 12 months, more frequent infant infections were associated with adverse metabolomic (elevated inflammation markers, triglycerides and phenylalanine, and lower high-density lipoprotein [HDL] cholesterol and apolipoprotein A1) and lipidomic profiles (elevated phosphatidylethanolamines and lower trihexosylceramides, dehydrocholesteryl esters, and plasmalogens). Similar, more marked, profiles were observed with higher GlycA, but not hsCRP. GlycA mediated a substantial proportion of the relationship between infection and metabolome/lipidome, with hsCRP generally mediating a lower proportion. Analogous relationships were observed between infection and 6-month inflammation, HDL cholesterol, and apolipoprotein A1. Conclusions: Infants with a greater infection burden in the first year of life had proinflammatory and proatherogenic plasma metabolomic/lipidomic profiles at 12 months of age that in adults are indicative of heightened risk of cardiovascular disease, obesity, and type 2 diabetes. These findings suggest potentially modifiable pathways linking early life infection and inflammation with subsequent cardiometabolic risk. Funding: The establishment work and infrastructure for the BIS was provided by the Murdoch Children's Research Institute (MCRI), Deakin University, and Barwon Health. Subsequent funding was secured from National Health and Medical Research Council of Australia (NHMRC), The Shepherd Foundation, The Jack Brockhoff Foundation, the Scobie & Claire McKinnon Trust, the Shane O'Brien Memorial Asthma Foundation, the Our Women's Our Children's Fund Raising Committee Barwon Health, the Rotary Club of Geelong, the Minderoo Foundation, the Ilhan Food Allergy Foundation, GMHBA, Vanguard Investments Australia Ltd, and the Percy Baxter Charitable Trust, Perpetual Trustees. In-kind support was provided by the Cotton On Foundation and CreativeForce. The study sponsors were not involved in the collection, analysis, and interpretation of data; writing of the report; or the decision to submit the report for publication. Research at MCRI is supported by the Victorian Government's Operational Infrastructure Support Program. This work was also supported by NHMRC Senior Research Fellowships to ALP (1008396); DB (1064629); and RS (1045161) , NHMRC Investigator Grants to ALP (1110200) and DB (1175744), NHMRC-A*STAR project grant (1149047). TM is supported by an MCRI ECR Fellowship. SB is supported by the Dutch Research Council (452173113).
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    Prenatal exposure to phthalates and peripheral blood and buccal epithelial DNA methylation in infants: An epigenome-wide association study
    England-Mason, G ; Merrill, SM ; Gladish, N ; Moore, SR ; Giesbrecht, GF ; Letourneau, N ; MacIsaac, JL ; MacDonald, AM ; Kinniburgh, DW ; Ponsonby, A-L ; Saffery, R ; Martin, JW ; Kobor, MS ; Dewey, D (PERGAMON-ELSEVIER SCIENCE LTD, 2022-05-01)
    BACKGROUND: Prenatal exposure to phthalates has been associated with adverse health and neurodevelopmental outcomes. DNA methylation (DNAm) alterations may be a mechanism underlying these effects, but prior investigations of prenatal exposure to phthalates and neonatal DNAm profiles are limited to placental tissue and umbilical cord blood. OBJECTIVE: Conduct an epigenome-wide association study (EWAS) of the associations between prenatal exposure to phthalates and DNAm in two accessible infant tissues, venous buffy coat blood and buccal epithelial cells (BECs). METHODS: Participants included 152 maternal-infant pairs from the Alberta Pregnancy Outcomes and Nutrition (APrON) study. Maternal second trimester urine samples were analyzed for nine phthalate metabolites. Blood (n = 74) or BECs (n = 78) were collected from 3-month-old infants and profiled for DNAm using the Infinium HumanMethylation450 (450K) BeadChip. Robust linear regressions were used to investigate the associations between high (HMWPs) and low molecular weight phthalates (LMWPs) and change in methylation levels at variable Cytosine-phosphate-Guanine (CpG) sites in infant tissues, as well as the sensitivity of associations to potential confounders. RESULTS: One candidate CpG in gene RNF39 reported by a previous study examining prenatal exposure to phthalates and cord blood DNAm was replicated. The EWAS identified 12 high-confidence CpGs in blood and another 12 in BECs associated with HMWPs and/or LMWPs. Prenatal exposure to bisphenol A (BPA) associated with two of the CpGs associated with HMWPs in BECs. DISCUSSION: Prenatal exposure to phthalates was associated with DNAm variation at CpGs annotated to genes associated with endocrine hormone activity (i.e., SLCO4A1, TPO), immune pathways and DNA damage (i.e., RASGEF1B, KAZN, HLA-A, MYO18A, DIP2C, C1or109), and neurodevelopment (i.e., AMPH, NOTCH3, DNAJC5). Future studies that characterize the stability of these associations in larger samples, multiple cohorts, across tissues, and investigate the potential associations between these biomarkers and relevant health and neurodevelopmental outcomes are needed.
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    Accelerated Epigenetic Aging in Peripheral Blood does not Predict Demen-tia Risk
    Fransquet, PD ; Lacaze, P ; Saffery, R ; Shah, RC ; Vryer, R ; Murray, A ; Woods, RL ; Ryan, J (BENTHAM SCIENCE PUBL LTD, 2021-01-01)
    BACKGROUND: There is strong evidence that epigenetic age acceleration is associated with increased risk of later-life diseases and all-cause mortality. However, there is currently limited evidence that suggests accelerated epigenetic age is associated with dementia risk. OBJECTIVE: This study aims to clarify whether epigenetic biomarkers of accelerated aging can predict dementia risk, which is an important consideration as aging is the greatest risk factor for the disease. METHODS: DNA methylation was measured in peripheral blood samples provided by 160 participants from the ASPirin in Reducing Events in the Elderly study, including 73 pre-symptomatic dementia cases and 87 controls matched for age, sex, and smoking and education status. Epigenetic age was calculated using Horvath, Hannum, GrimAge and PhenoAge DNA methylation clocks, and age acceleration (the disparity between chronological age and epigenetic age) was determined. RESULTS: There was no difference in age acceleration between dementia cases and controls. In males, only Hannum's intrinsic epigenetic age acceleration was increased in pre-symptomatic dementia cases compared to controls (Δ +1.8 years, p = 0.03). CONCLUSION: These findings provide no strong evidence that accelerated epigenetic aging measured in peripheral blood can predict dementia risk.
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    Twin-twin transfusion syndrome is associated with alterations in the metabolic profile of maternal plasma in early gestation: a pilot study
    Yang, Y ; Wen, L ; Han, T-L ; Zhang, L ; Fu, H ; Gan, J ; Saffery, R ; Tong, C ; Li, J ; Qi, H ; Baker, PN ; Kilby, MD (WILEY, 2021-03-23)
    OBJECTIVE: Twin-twin transfusion syndrome (TTTS) causes perinatal mortality and morbidity in monochorionic twins. The early recognition of and interventional therapy for TTTS is associated with a more favorable overall prognosis. However, the prediction by the use of ultrasound in the first trimester has relatively poor sensitivity and specificity. This study aimed to identify metabolic biomarkers to aid in ultrasound screening of TTTS. METHODS: Maternal plasma was prospectively collected between 11 and 15 weeks of gestation in apparently uncomplicated monochorionic-diamniotic twin pregnancies. This cohort was divided into: (i) patients who were subsequently diagnosed with TTTS by using ultrasound; (ii) uncomplicated matched controls. Metabolome was profiled by using gas chromatography-mass spectrometry. RESULTS: The levels of fatty acids, organic acids, oxaloacetic acid, and beta-alanine were significantly lower in the TTTS maternal plasma at 11-15 weeks of gestation, and methionine and glycine were also higher (p < 0.05, FDR<0.12). Generally, in TTTS pregnancies, the metabolisms of amino acid, carbohydrate, cofactors, vitamins, and purine were "down-regulated"; whereas bile secretion and pyrimidine metabolism were "upregulated." CONCLUSIONS: The metabolomics scanning of early gestation maternal plasma may identify those pregnancies that subsequently develop TTTS; in particular, downregulated fatty acid levels may be biologically plausible to be implicated in the pathogenesis of TTTS.
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    Shortened Infant Telomere Length Is Associated with Attention Deficit/Hyperactivity Disorder Symptoms in Children at Age Two Years: A Birth Cohort Study
    Pham, C ; Vryer, R ; O'Hely, M ; Mansell, T ; Burgner, D ; Collier, F ; Symeonides, C ; Tang, MLK ; Vuillermin, P ; Gray, L ; Saffery, R ; Ponsonby, A-L (MDPI, 2022-05-01)
    Environmental factors can accelerate telomere length (TL) attrition. Shortened TL is linked to attention deficit/hyperactivity disorder (ADHD) symptoms in school-aged children. The onset of ADHD occurs as early as preschool-age, but the TL-ADHD association in younger children is unknown. We investigated associations between infant TL and ADHD symptoms in children and assessed environmental factors as potential confounders and/or mediators of this association. Relative TL was measured by quantitative polymerase chain reaction in cord and 12-month blood in the birth cohort study, the Barwon Infant Study. Early life environmental factors collected antenatally to two years were used to measure confounding. ADHD symptoms at age two years were evaluated by the Child Behavior Checklist Attention Problems (AP) and the Attention Deficit/Hyperactivity Problems (ADHP). Associations between early life environmental factors on TL or ADHD symptoms were assessed using multivariable regression models adjusted for relevant factors. Telomere length at 12 months (TL12), but not at birth, was inversely associated with AP (β = -0.56; 95% CI (-1.13, 0.006); p = 0.05) and ADHP (β = -0.66; 95% CI (-1.11, -0.21); p = 0.004). Infant secondhand smoke exposure at one month was independently associated with shorter TL12 and also higher ADHD symptoms. Further work is needed to elucidate the mechanisms that influence TL attrition and early neurodevelopment.
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    The Distinct Role of the HDL Receptor SR-BI in Cholesterol Homeostasis of Human Placental Arterial and Venous Endothelial Cells
    Strahlhofer-Augsten, M ; Schliefsteiner, C ; Cvitic, S ; George, M ; Lang-Olip, I ; Hirschmugl, B ; Marsche, G ; Lang, U ; Novakovic, B ; Saffery, R ; Desoye, G ; Wadsack, C (MDPI, 2022-05-01)
    As opposed to adults, high-density lipoprotein (HDL) is the main cholesterol carrying lipoprotein in fetal circulation. The major HDL receptor, scavenger receptor class B type I (SR-BI), contributes to local cholesterol homeostasis. Arterial endothelial cells (ECA) from human placenta are enriched with cholesterol compared to venous endothelial cells (ECV). Moreover, umbilical venous and arterial plasma cholesterol levels differ markedly. We tested the hypothesis that the uptake of HDL-cholesteryl esters differs between ECA and ECV because of the differential expression of SR-BI. We aimed to identify the key regulators underlying these differences and the functional consequences. Immunohistochemistry was used for visualization of SR-BI in situ. ECA and ECV were isolated from the chorionic plate of human placenta and used for RT-qPCR, Western Blot, and HDL uptake assays with 3H- and 125I-labeled HDL. DNA was extracted for the methylation profiling of the SR-BI promoter. SR-BI regulation was studied by exposing ECA and ECV to differential oxygen concentrations or shear stress. Our results show elevated SR-BI expression and protein abundance in ECA compared to ECV in situ and in vitro. Immunohistochemistry demonstrated that SR-BI is mainly expressed on the apical side of placental endothelial cells in situ, allowing interaction with mature HDL circulating in the fetal blood. This was functionally linked to a higher increase of selective cholesterol ester uptake from fetal HDL in ECA than in ECV, and resulted in increased cholesterol availability in ECA. SR-BI expression on ECV tended to decrease with shear stress, which, together with heterogeneous immunostaining, suggests that SR-BI expression is locally regulated in the placental vasculature. In addition, hypomethylation of several CpG sites within the SR-BI promoter region might contribute to differential expression of SR-BI between chorionic arteries and veins. Therefore, SR-BI contributes to a local cholesterol homeostasis in ECA and ECV of the human feto-placental vasculature.
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    The Metabolic Signatures of Surviving Cotwins in Cases of Single Intrauterine Fetal Death During Monochorionic Diamniotic Pregnancy: A Prospective Case-Control Study
    Liu, X ; Fu, H ; Wen, L ; Zhu, F ; Wu, Y ; Chen, Z ; Saffery, R ; Chen, C ; Qi, H ; Tong, C ; Baker, PN ; Kilby, MD (FRONTIERS MEDIA SA, 2022-04-08)
    Introduction: Single intrauterine fetal death (sIUFD) in monochorionic diamniotic (MCDA) twin pregnancy may be associated with adverse clinical outcomes and possible metabolic changes in the surviving co-twin. Metabolomic profiling has not been undertaken before in these complex twin pregnancies. Methods: In this prospectively collected case-control study, three cross-cohort comparisons were made between sIUFD MCDA (n = 16), uncomplicated MCDA (n = 16, eight pairs), and uncomplicated singleton pregnancies (n = 8). To identify major sources of variation within the sIUFD MCDA cohort, a secondary comparison was conducted between spontaneous sIUFD (n = 8) and sIUFD in MCDA twins due to selective termination of a single abnormal fetus by radiofrequency ablation (RFA) (n = 8). Metabolomics analysis of placental tissue and umbilical cord plasma was performed using LC-MS profiling. The underlying metabolic networks and pathways were analyzed by web-based platforms. Associations and statistical correlations of all identified differential metabolites with neonatal birthweight and birth length were assessed by multivariable linear regression, adjusted for maternal age and gestation. Results: Across four comparisons, 131 and 111 differential metabolites were identified in placental tissue and cord plasma, respectively, with the highest variation seen between the spontaneous vs. single-induced IUFD in MCDA twins by RFA in the cord plasma. Conversely, the number of viable fetuses and the presence of sIUFD in MCDA twins had the highest impact on metabolite variation in placental tissue. Compounds correlated with fetal growth including placental acylcarnitines and gangliosides, along with specific amino acids (e.g., histidinyl-hydroxyproline), xenobiotics and biliverdin in cord plasma. Conclusion: sIUFD in MCDA twin pregnancy correlates with distinctive metabolic signatures, mostly in fatty acyls and complex lipids, in placental tissue and cord plasma of the surviving cotwin. Some metabolites are also associated with fetal growth.
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    Comprehensive Metabolomic Profiling of Cord Blood and Placental Tissue in Surviving Monochorionic Twins Complicated by Twin-Twin Transfusion Syndrome With or Without Fetoscopic Laser Coagulation Surgery: A Retrospective Cohort Study
    Liu, T ; Wen, L ; Huang, S ; Han, T-L ; Zhang, L ; Fu, H ; Li, J ; Tong, C ; Qi, H ; Saffery, R ; Baker, PN ; Kilby, MD (FRONTIERS MEDIA SA, 2022-04-21)
    Objectives: To investigate metabolomic perturbations caused by twin-twin transfusion syndrome, metabolic changes associated with fetoscopic laser coagulation in both placental tissue and cord plasma, and to investigate differential metabolites pertinent to varying fetal outcomes, including hemodynamic status, birth weight, and cardiac function, of live-born babies. Methods: Placental tissue and cord plasma samples from normal term or uncomplicated preterm-born monochorionic twins and those complicated by twin-twin transfusion syndrome treated with or without fetoscopic laser coagulation were analyzed by high-performance liquid chromatography metabolomic profiling. Sixteen comparisons of different co-twin groups were performed. Partial least squares-discriminant analysis, metabolic pathway analysis, biomarker analysis, and Spearman's correlation analysis were conducted based on differential metabolites used to determine potential biomarkers in different comparisons and metabolites that are pertinent to neonatal birth weight and left ventricular ejection fraction. Results: These metabolomic investigations showed that the cord plasma metabolome has a better performance in discriminating fetuses among different hemodynamic groups than placental tissue. The metabolic alteration of twin-twin transfusion syndrome in these two types of samples centers on fatty acid and lipid metabolism. The fetoscopic laser coagulation procedure improves the metabolomic change brought by this syndrome, making the metabolomes of the treated group less distinguishable from those of the control and preterm birth groups. Certain compounds, especially lipids and lipid-like molecules, are noted to be potential biomarkers of this morbid disease and pertinent to neonatal birth weight and ejection fraction. Conclusions: Fetoscopic laser coagulation can ameliorate the metabolomic alteration caused by twin-twin transfusion syndrome in placental tissue and cord plasma, which are involved mainly in fatty acid and lipid-like molecule metabolism. Certain lipids and lipid-like molecules are helpful in differentiating co-twins of different hemodynamic statuses and are significantly correlated with neonatal birth weight or ejection fraction.
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    A Pathway-Based Genetic Score for Oxidative Stress: An Indicator of Host Vulnerability to Phthalate-Associated Adverse Neurodevelopment
    Tanner, S ; Thomson, S ; Drummond, K ; O'Hely, M ; Symeonides, C ; Mansell, T ; Saffery, R ; Sly, PD ; Collier, F ; Burgner, D ; Sugeng, EJ ; Dwyer, T ; Vuillermin, P ; Ponsonby, A-L (MDPI, 2022-04-01)
    The developing brain is highly sensitive to environmental disturbances, and adverse exposures can act through oxidative stress. Given that oxidative stress susceptibility is determined partly by genetics, multiple studies have employed genetic scores to explore the role of oxidative stress in human disease. However, traditional approaches to genetic score construction face a range of challenges, including a lack of interpretability, bias towards the disease outcome, and often overfitting to the study they were derived on. Here, we develop an alternative strategy by first generating a genetic pathway function score for oxidative stress (gPFSox) based on the transcriptional activity levels of the oxidative stress response pathway in brain and other tissue types. Then, in the Barwon Infant Study (BIS), a population-based birth cohort (n = 1074), we show that a high gPFSox, indicating reduced ability to counter oxidative stress, is linked to higher autism spectrum disorder risk and higher parent-reported autistic traits at age 4 years, with AOR values (per 2 additional pro-oxidant alleles) of 2.10 (95% CI (1.12, 4.11); p = 0.024) and 1.42 (95% CI (1.02, 2.01); p = 0.041), respectively. Past work in BIS has reported higher prenatal phthalate exposure at 36 weeks of gestation associated with offspring autism spectrum disorder. In this study, we examine combined effects and show a consistent pattern of increased neurodevelopmental problems for individuals with both a high gPFSox and high prenatal phthalate exposure across a range of outcomes, including high gPFSox and high DEHP levels against autism spectrum disorder (attributable proportion due to interaction 0.89; 95% CI (0.62, 1.16); p < 0.0001). The results highlight the utility of this novel functional genetic score and add to the growing evidence implicating gestational phthalate exposure in adverse neurodevelopment.
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    Triiodothyronine (T3) Induces Limited Transcriptional and DNA Methylation Reprogramming in Human Monocytes
    Shepherd, R ; Kim, B ; Saffery, R ; Novakovic, B (MDPI, 2022-03-01)
    Thyroid hormones have immunomodulatory roles, but their effects on the transcriptome and epigenome of innate immune cell types remain unexplored. In this study, we investigate the effects of triiodothyronine (T3) on the transcriptome and methylome of human monocytes in vitro, both in resting and lipopolysaccharide (LPS)-stimulated conditions. In resting monocytes, 5 µM T3 affected the expression of a small number of monocyte-to-macrophage differentiation-associated genes, including TLR4 (p-value < 0.05, expression fold change >1.5). T3 attenuated a small proportion of monocyte-to-macrophage differentiation-associated DNA methylation changes, while specifically inducing DNA methylation changes at several hundred differentially methylated CpG probes (DMPs) (p-value < 0.05, Δβ > 0.05). In LPS-stimulated monocytes, the presence of T3 attenuated the effect of 27% of LPS-induced DMPs (p-value < 0.05, Δβ > 0.05). Interestingly, co-stimulation with T3 + LPS induced a unique DNA methylation signature that was not observed in the LPS-only or T3-only exposure groups. Our results suggest that T3 induces limited transcriptional and DNA methylation remodeling in genes enriched in metabolism and immune processes and alters the normal in vitro LPS response. The overlap between differentially expressed genes and genes associated with DMPs was minimal; thus, other epigenetic mechanisms may underpin the expression changes. This research provides insight into the complex interplay between thyroid hormones, epigenetic remodeling, and transcriptional dynamics in monocytes.