Paediatrics (RCH) - Research Publications

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    Emotional symptoms and inflammatory biomarkers in childhood: Associations in two Australian birth cohorts
    Lange, K ; Pham, C ; Fedyszyn, IE ; Cook, F ; Burgner, DP ; Olsson, CA ; Downes, M ; Priest, N ; Mansell, T ; Tang, MLK ; Ponsonby, A-L ; Symeonides, C ; Loughman, A ; Vuillermin, P ; Kerr, JA ; Gray, L ; Sly, PD ; Lycett, K ; Carlin, JB ; Saffery, R ; Wake, M ; O'Connor, M (Elsevier, 2024-01-01)
    BACKGROUND: An increasing body of evidence supports associations between inflammation and mental health difficulties, but the onset and directionality of these relationships are unclear. METHODS: Data sources: Barwon Infant Study (BIS; n = 500 4-year-olds) and Longitudinal Study of Australian Children (LSAC; n = 1099 10-13-year-olds). MEASURES: Strengths and Difficulties Questionnaire emotional symptoms at 4, 10-11 and 12-13 years, and circulating levels of two inflammatory biomarkers, high-sensitivity C-reactive protein (hsCRP) and glycoprotein acetyls (GlycA), at 4 and 11-12 years. ANALYSIS: Adjusted quantile regression models examining cross-sectional associations between emotional symptoms and inflammation in 4-year-olds (BIS), and cross-lagged associations in 10-13-year-olds (LSAC). RESULTS: We identified a small association between higher emotional symptoms at 10-11 years and higher GlycA levels a year later (standardised coefficient β = 0.09; 95%CI: 0.02 to 0.15). Sex-stratified analyses revealed this association was stronger for boys (β = 0.13; 95%CI: 0.04 to 0.21) than girls (β = 0.01; 95%CI: -0.09 to 0.11). These associations were not observed for hsCRP. There was little evidence of an association between higher GlycA or hsCRP at 11-12 years and emotional symptoms a year later, or cross-sectional associations between emotional symptoms and hsCRP or GlycA at 4 years. LIMITATIONS: A single time-point of biomarker collection in late childhood precluded adjustment for baseline inflammatory biomarkers. CONCLUSIONS: Our results support the direction of association from emotional symptoms to inflammation in late childhood, with potential sex differences. This adds to the body of evidence that addressing emotional symptoms in childhood is a major priority in optimising overall health throughout the life course.
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    Maternal oxidative stress during pregnancy associated with emotional and behavioural problems in early childhood: implications for foetal programming
    Pham, C ; Thomson, S ; Chin, S-T ; Vuillermin, P ; O'Hely, M ; Burgner, D ; Tanner, S ; Saffery, R ; Mansell, T ; Bong, S ; Holmes, E ; Sly, PD ; Gray, N ; Ponsonby, A-L ; Barwon, ISIG (SPRINGERNATURE, 2023-09)
    Childhood mental disorders, including emotional and behavioural problems (EBP) are increasingly prevalent. Higher maternal oxidative stress (OS) during pregnancy (matOSpreg) is linked to offspring mental disorders. Environmental factors contribute to matOSpreg. However, the role of matOSpreg in childhood EBP is unclear. We investigated the associations between (i) matOSpreg and offspring EBP; (ii) social and prenatal environmental factors and matOSpreg; and (iii) social and prenatal factors and childhood EBP and evaluated whether matOSpreg mediated these associations. Maternal urinary OS biomarkers, 8-hydroxyguanosine (8-OHGua; an oxidative RNA damage marker) and 8-hydroxy-2'-deoxyguanosine (8-OHdG; an oxidative DNA damage marker), at 36 weeks of pregnancy were quantified by liquid chromatography-mass spectrometry in a population-derived birth cohort, Barwon Infant Study (n = 1074 mother-infant pairs). Social and prenatal environmental factors were collected by mother-reported questionnaires. Offspring total EBP was measured by Child Behavior Checklist Total Problems T-scores at age two (n = 675) and Strengths and Difficulties Questionnaire Total Difficulties score at age four (n = 791). Prospective associations were examined by multivariable regression analyses adjusted for covariates. Mediation effects were evaluated using counterfactual-based mediation analysis. Higher maternal urinary 8-OHGua at 36 weeks (mat8-OHGua36w) was associated with greater offspring total EBP at age four (β = 0.38, 95% CI (0.07, 0.69), P = 0.02) and age two (β = 0.62, 95% CI (-0.06, 1.30), P = 0.07). Weaker evidence of association was detected for 8-OHdG. Five early-life factors were associated with both mat8-OHGua36w and childhood EBP (P-range < 0.001-0.05), including lower maternal education, socioeconomic disadvantage and prenatal tobacco smoking. These risk factor-childhood EBP associations were partly mediated by higher mat8-OHGua36w (P-range = 0.01-0.05). Higher matOSpreg, particularly oxidant RNA damage, is associated with later offspring EBP. Effects of some social and prenatal lifestyle factors on childhood EBP were partly mediated by matOSpreg. Future studies are warranted to further elucidate the role of early-life oxidant damage in childhood EBP.
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    The distribution of dietary choline intake and serum choline levels in Australian women during pregnancy and associated early life factors
    Staskova, L ; Marx, WL ; Dawson, S ; O'Hely, M ; Mansell, T ; Saffery, R ; Burgner, D ; Collier, F ; Novakovic, B ; Vuillermin, PJ ; Field, C ; Dewey, D ; Ponsonby, A-L (SPRINGER HEIDELBERG, 2023-10)
    BACKGROUND: Maternal dietary choline has a central role in foetal brain development and may be associated with later cognitive function. However, many countries are reporting lower than recommended intake of choline during pregnancy. METHODS: Dietary choline was estimated using food frequency questionnaires in pregnant women participating in population-derived birth cohort, the Barwon Infant Study (BIS). Dietary choline is reported as the sum of all choline-containing moieties. Serum total choline-containing compounds (choline-c), phosphatidylcholine and sphingomyelin were measured using nuclear magnetic resonance metabolomics in the third trimester. The main form of analysis was multivariable linear regression. RESULTS: The mean daily dietary choline during pregnancy was 372 (standard deviation (SD) 104) mg/day. A total of 236 women (23%) had adequate choline intake (440 mg/day) based on the Australian and New Zealand guidelines, and 27 women (2.6%) took supplemental choline ([Formula: see text] 50 mg/dose) daily during pregnancy. The mean serum choline-c in pregnant women was 3.27 (SD 0.44) mmol/l. Ingested choline and serum choline-c were not correlated (R2) = - 0.005, p = 0.880. Maternal age, maternal weight gain in pregnancy, and a pregnancy with more than one infant were associated with higher serum choline-c, whereas gestational diabetes and environmental tobacco smoke during preconception and pregnancy were associated with lower serum choline-c. Nutrients or dietary patterns were not associated with variation in serum choline-c. CONCLUSION: In this cohort, approximately one-quarter of women met daily choline recommendations during pregnancy. Future studies are needed to understand the potential impact of low dietary choline intake during pregnancy on infant cognition and metabolic intermediaries.
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    Hair and cord blood element levels and their relationship with air pollution, dietary intake, gestational diabetes mellitus, and infant neurodevelopment
    Xia, Y-Y ; de Seymour, J ; Yang, X-J ; Zhou, L-W ; Liu, Y ; Yang, Y ; Beck, KL ; Conlon, CA ; Mansell, T ; Novakovic, B ; Saffery, R ; Han, T-L ; Zhang, H ; Baker, PN (CHURCHILL LIVINGSTONE, 2023-10)
    BACKGROUND & AIMS: Exposure to a range of elements, air pollution, and specific dietary components in pregnancy has variously been associated with gestational diabetes mellitus (GDM) risk or infant neurodevelopmental problems. We measured a range of pregnancy exposures in maternal hair and/or infant cord serum and tested their relationship to GDM and infant neurodevelopment. METHODS: A total of 843 pregnant women (GDM = 224, Non-GDM = 619) were selected from the Complex Lipids in Mothers and Babies cohort study. Forty-eight elements in hair and cord serum were quantified using inductively coupled plasma-mass spectrometry analysis. Binary logistic regression was used to estimate the associations between hair element concentrations and GDM risk, while multiple linear regression was performed to analyze the relationship between hair/cord serum elements and air pollutants, diet exposures, and Bayley Scales of infant neurodevelopment at 12 months of age. RESULTS: After adjusting for maternal age, BMI, and primiparity, we observed that fourteen elements in maternal hair were associated with a significantly increased risk of GDM, particularly Ta (OR = 9.49, 95% CI: 6.71, 13.42), Re (OR = 5.21, 95% CI: 3.84, 7.07), and Se (OR = 5.37, 95% CI: 3.48, 8.28). In the adjusted linear regression model, three elements (Rb, Er, and Tm) in maternal hair and infant cord serum were negatively associated with Mental Development Index scores. For dietary exposures, elements were positively associated with noodles (Nb), sweetened beverages (Rb), poultry (Cs), oils and condiments (Ca), and other seafood (Gd). In addition, air pollutants PM2.5 (LUR) and PM10 were negatively associated with Ta and Re in maternal hair. CONCLUSIONS: Our findings highlight the potential influence of maternal element exposure on GDM risk and infant neurodevelopment. We identified links between levels of these elements in both maternal hair and infant cord serum related to air pollutants and dietary factors.
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    Effects of prenatal alcohol exposure on infant lung function, wheeze, and respiratory infections in Australian children.
    Vilcins, D ; Blake, TL ; Sly, PD ; Saffery, R ; Ponsonby, A-L ; Burgner, D ; Tang, MLK ; Reid, N ; Barwon Infant Study Investigator Group, (Wiley, 2023-12)
    BACKGROUND: Prenatal alcohol exposure (PAE) is a known risk factor for a range of adverse outcomes, such as facial dysmorphism, adverse birth outcomes, and neurodevelopmental changes. Preclinical research shows that PAE also inhibits lung development, lowers surfactant protein expression, has detrimental effects on alveolar macrophages, and decreases both T and B cell numbers. However, clinical evidence of respiratory impacts from PAE is limited. This study explored whether lung function, wheeze, and incidence of respiratory infections differ in children with PAE compared with unexposed children. METHODS: Data from the Barwon Infant Study (n = 1074) were examined. PAE data were extracted from maternal questionnaires at trimesters 1 and 2 (combined), and trimester 3, and included as "total standard drinks" during each trimester and total pregnancy intake, a binary yes/no for PAE, and binge drinking (>5 standard drinks in one session). Respiratory outcomes were parent-reported wheeze, lung function (measured by multiple breath washout), and parent report and medical record indicators of health service attendances for respiratory conditions. Linear and logistic regressions were performed to quantify relationships between PAE and respiratory outcomes, controlling for socioeconomic status, birthweight, sex, gestational age, and maternal smoking. RESULTS: Binge drinking was associated with increased health service attendance for respiratory condition(s) in the first 12 months of life (OR = 5.0, 95% CI (1.7, 20.7), p = 0.008). We did not find a relationship between binary PAE and binge drinking with lung function at 4 weeks of age or wheeze at 12 months. The number of standard drinks consumed in trimester two was associated with a lower lung clearance index (β = -0.011 turnovers, 95% CI (-0.0200, -0.0013), p = 0.03), and a small increase in functional residual capacity (β = 0.34 mL, 95% CI (0.02, 0.66), p = 0.04). CONCLUSIONS: We found an association between binge drinking and health service utilization for respiratory conditions in infancy, but no evidence that low-level PAE was associated with adverse respiratory outcomes.
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    Immuno-epigenomic analysis identifies attenuated interferon responses in naive CD4 T cells of adolescents with peanut and multifood allergy
    Imran, S ; Neeland, MR ; Peng, S ; Vlahos, A ; Martino, D ; Dharmage, SC ; Tang, MLK ; Sawyer, S ; Dang, TD ; McWilliam, V ; Peters, RL ; Koplin, JJ ; Perrett, KP ; Novakovic, B ; Saffery, R (WILEY, 2022-11)
    BACKGROUND: IgE-mediated food allergies have been linked to suboptimal naïve CD4 T (nCD4T) cell activation in infancy, underlined by epigenetic and transcriptomic variation. Similar attenuated nCD4T cell activation in adolescents with food allergy have also been reported, but these are yet to be linked to specific epigenetic or transcriptional changes. METHODS: We generated genome-wide DNA methylation data in purified nCD4 T cells at quiescence and following activation in a cohort of adolescents (aged 10-15 years old) with peanut allergy (peanut only or peanut + ≥1 additional food allergy) (FA, n = 29), and age-matched non-food allergic controls (NA, n = 18). Additionally, we assessed transcriptome-wide gene expression and cytokine production in these cells following activation. RESULTS: We found widespread changes in DNA methylation in both NA and FA nCD4T cells in response to activation, associated with the T cell receptor signaling pathway. Adolescents with FA exhibit unique DNA methylation signatures at quiescence and post-activation at key genes involved in Th1/Th2 differentiation (RUNX3, RXRA, NFKB1A, IL4R), including a differentially methylated region (DMR) at the TNFRSF6B promoter, linked to Th1 proliferation. Combined analysis of DNA methylation, transcriptomic data and cytokine output in the same samples identified an attenuated interferon response in nCD4T cells from FA individuals following activation, with decreased expression of several interferon genes, including IFN-γ and a DMR at a key downstream gene, BST2. CONCLUSION: We find that attenuated nCD4T cell responses from adolescents with food allergy are associated with specific epigenetic variation, including disruption of interferon responses, indicating dysregulation of key immune pathways that may contribute to a persistent FA phenotype. However, we recognize the small sample size, and the consequent restraint on reporting adjusted p-value statistics as limitations of the study. Further study is required to validate these findings.
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    Placental DNA methylation in pregnancies complicated by maternal diabetes and/or obesity: State of the art and research gaps
    Hjort, L ; Novakovic, B ; Cvitic, S ; Saffery, R ; Damm, P ; Desoye, G (TAYLOR & FRANCIS INC, 2022-12-09)
    Maternal diabetes and/or obesity in pregnancy are undoubtedly associated with later disease-risk in the offspring. The placenta, interposed between the mother and the foetus, is a potential mediator of this risk through epigenetic mechanisms, including DNA methylation. In recent years, multiple studies have identified differentially methylated CpG sites in the placental tissue DNA in pregnancies complicated by diabetes and obesity. We reviewed all published original research relevant to this topic and analysed our findings with the focus of identifying overlaps, contradictions, and gaps. Most studies focused on the association of gestational diabetes and/or hyperglycaemia in pregnancy and DNA methylation in placental tissue at term. We identified overlaps in results related to specific candidate genes, but also observed a large research gap of pregnancies affected by type 1 diabetes. Other unanswered questions relate to analysis of specific placental cell types and the timing of DNA methylation change in response to diabetes and obesity during pregnancy. Maternal metabolism is altered already in the first trimester involving structural and functional changes in the placenta, but studies into its effects on placental DNA methylation during this period are lacking and urgently needed. Foetal sex is also an important determinant of pregnancy outcome, but only few studies have taken this into account. Collectively, we provide a reference work for researchers working in this large and evolving field. Based on the results of the literature review, we formulate suggestions for future focus of placental DNA methylation studies in pregnancies complicated by diabetes and obesity.
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    Rodents on a high-fat diet born to mothers with gestational diabetes exhibit sex-specific lipidomic changes in reproductive organs
    Wang, A ; Luo, B ; Chen, Z ; Xia, Y ; Chen, C ; Qi, H ; Baker, PN ; Saffery, R ; Han, T-L ; Zhang, H (SCIENCE PRESS, 2022-05)
    Maternal gestatonal diabetes mellitus (GDM) and offspring high-fat diet (HFD) have been shown to have sex-specific detrimental effects on the health of the offspring. Maternal GDM combined with an offspring HFD alters the lipidomic profiles of offspring reproductive organs with sex hormones and increases insulin signaling, resulting in offspring obesity and diabetes. The pre-pregnancy maternal GDM mice model is established by feeding maternal C57BL/6 mice and their offspring are fed with either a HFD or a low-fat diet (LFD). Testis, ovary and liver are collected from offspring at 20 weeks of age. The lipidomic profiles of the testis and ovary are characterized using gas chromatography-mass spectrometry. Male offspring following a HFD have elevated body weight. In reproductive organs and hormones, male offspring from GDM mothers have decreased testes weights and testosterone levels, while female offspring from GDM mothers show increased ovary weights and estrogen levels. Maternal GDM aggravates the effects of an offspring HFD in male offspring on the AKT pathway, while increasing the risk of developing inflammation when expose to a HFD in female offspring liver. Testes are prone to the effect of maternal GDM, whereas ovarian metabolite profiles are upregulated in maternal GDM and downregulated in offspring following an HFD. Maternal GDM and an offspring HFD have different metabolic effects on offspring reproductive organs, and PUFAs may protect against detrimental outcomes in the offspring, such as obesity and diabetes.
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    Amplification of the PLAG-family genes-PLAGL1 and PLAGL2-is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification
    Keck, M-K ; Sill, M ; Wittmann, A ; Joshi, P ; Stichel, D ; Beck, P ; Okonechnikow, K ; Sievers, P ; Wefers, AK ; Roncaroli, F ; Avula, S ; McCabe, MG ; Hayden, JT ; Wesseling, P ; Ora, I ; Nister, M ; Kranendonk, MEG ; Tops, BBJ ; Zapotocky, M ; Zamecnik, J ; Vasiljevic, A ; Fenouil, T ; Meyronet, D ; von Hoff, K ; Schuller, U ; Loiseau, H ; Figarella-Branger, D ; Kramm, CM ; Sturm, D ; Scheie, D ; Rauramaa, T ; Pesola, J ; Gojo, J ; Haberler, C ; Brandner, S ; Jacques, T ; Oates, AS ; Saffery, R ; Koscielniak, E ; Baker, SJ ; Yip, S ; Snuderl, M ; Din, NU ; Samuel, D ; Schramm, K ; Blattner-Johnson, M ; Selt, F ; Ecker, J ; Milde, T ; von Deimling, A ; Korshunov, A ; Perry, A ; Pfister, SM ; Sahm, F ; Solomon, DA ; Jones, DTW (SPRINGER, 2023-01)
    Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/β-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.
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    Fat-Soluble Vitamers: Parent-Child Concordance and Population Epidemiology in the Longitudinal Study of Australian Children
    Arachchige, GRP ; Pook, CJ ; Jones, B ; Coe, M ; Saffery, R ; Wake, M ; Thorstensen, EB ; O'Sullivan, JM (MDPI, 2022-12)
    Fat-soluble vitamers (FSV) are a class of diverse organic substances important in a wide range of biological processes, including immune function, vision, bone health, and coagulation. Profiling FSV in parents and children enables insights into gene-environment contributions to their circulating levels, but no studies have reported on the population epidemiology of FSV in these groups as of yet. In this study, we report distributions of FSV, their parent-child concordance and variation by key characteristics for 2490 children (aged 11-12 years) and adults (aged 28-71 years) in the Child Health CheckPoint of the Longitudinal Study of Australian Children. Ten A, D, E and K vitamers were quantified using a novel automated LC-MS/MS method. All three K vitamers (i.e., K1, MK-4, MK-7) and 1-α-25(OH)2D3 were below the instrument detection limit and were removed from the present analysis. We observed a strong vitamer-specific parent-child concordance for the six quantifiable A, D and E FSVs. FSV concentrations all varied by age, BMI, and sex. We provide the first cross-sectional population values for multiple FSV. Future studies could examine relative genetic vs. environmental determinants of FSV, how FSV values change longitudinally, and how they contribute to future health and disease.