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Article ; Online: Increased maternal non-oxidative energy metabolism mediates association between prenatal di-(2-ethylhexyl) phthalate (DEHP) exposure and offspring autism spectrum disorder symptoms in early life

Sarah Thomson / Katherine Drummond / Martin O'Hely / Christos Symeonides / Chitra Chandran / Toby Mansell / Richard Saffery / Peter Sly / Jochen Mueller / Peter Vuillermin / Anne-Louise Ponsonby

Environment International, Vol 171, Iss , Pp 107678- (2023)

A birth cohort study

2023

Abstract: Prenatal phthalate exposure has previously been linked to the development of autism spectrum disorder (ASD). However, the underlying biological mechanisms remain unclear. We investigated whether maternal and child central carbon metabolism is involved as ...

Abstract	Prenatal phthalate exposure has previously been linked to the development of autism spectrum disorder (ASD). However, the underlying biological mechanisms remain unclear. We investigated whether maternal and child central carbon metabolism is involved as part of the Barwon Infant Study (BIS), a population-based birth cohort of 1,074 Australian children. We estimated phthalate daily intakes using third-trimester urinary phthalate metabolite concentrations and other relevant indices. The metabolome of maternal serum in the third trimester, cord serum at birth and child plasma at 1 year were measured by nuclear magnetic resonance. We used the Small Molecule Pathway Database and principal component analysis to construct composite metabolite scores reflecting metabolic pathways. ASD symptoms at 2 and 4 years were measured in 596 and 674 children by subscales of the Child Behavior Checklist and the Strengths and Difficulties Questionnaire, respectively. Multivariable linear regression analyses demonstrated (i) prospective associations between higher prenatal di-(2-ethylhexyl) phthalate (DEHP) levels and upregulation of maternal non-oxidative energy metabolism pathways, and (ii) prospective associations between upregulation of these pathways and increased offspring ASD symptoms at 2 and 4 years of age. Counterfactual mediation analyses indicated that part of the mechanism by which higher prenatal DEHP exposure influences the development of ASD symptoms in early childhood is through a maternal metabolic shift in pregnancy towards non-oxidative energy pathways, which are inefficient compared to oxidative metabolism. These results highlight the importance of the prenatal period and suggest that further investigation of maternal energy metabolism as a molecular mediator of the adverse impact of prenatal environmental exposures such as phthalates is warranted.
Keywords	Endocrine disrupting chemicals ; Metabolomics ; Pyruvate metabolism ; Warburg Effect ; Autism spectrum disorder ; Neurodevelopment ; Environmental sciences ; GE1-350
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Cord blood lipid correlation network profiles are associated with subsequent attention-deficit/hyperactivity disorder and autism spectrum disorder symptoms at 2 years

EBioMedicine, Vol 100, Iss , Pp 104949- (2024)

a prospective birth cohort studyResearch in context

2024

Abstract: Summary: Background: Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are neurodevelopmental conditions with early life origins. Alterations in blood lipids have been linked to ADHD and ASD; however, prospective early ... ...

Abstract	Summary: Background: Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are neurodevelopmental conditions with early life origins. Alterations in blood lipids have been linked to ADHD and ASD; however, prospective early life data are limited. This study examined (i) associations between the cord blood lipidome and ADHD/ASD symptoms at 2 years of age, (ii) associations between prenatal and perinatal predictors of ADHD/ASD symptoms and cord blood lipidome, and (iii) mediation by the cord blood lipidome. Methods: From the Barwon Infant Study cohort (1074 mother-child pairs, 52.3% male children), child circulating lipid levels at birth were analysed using ultra-high-performance liquid chromatography-tandem mass spectrometry. These were clustered into lipid network modules via Weighted Gene Correlation Network Analysis. Associations between lipid modules and ADHD/ASD symptoms at 2 years, assessed with the Child Behavior Checklist, were explored via linear regression analyses. Mediation analysis identified indirect effects of prenatal and perinatal risk factors on ADHD/ASD symptoms through lipid modules. Findings: The acylcarnitine lipid module is associated with both ADHD and ASD symptoms at 2 years of age. Risk factors of these outcomes such as low income, Apgar score, and maternal inflammation were partly mediated by higher birth acylcarnitine levels. Other cord blood lipid profiles were also associated with ADHD and ASD symptoms. Interpretation: This study highlights that elevated cord blood birth acylcarnitine levels, either directly or as a possible marker of disrupted cell energy metabolism, are on the causal pathway of prenatal and perinatal risk factors for ADHD and ASD symptoms in early life. Funding: The foundational work and infrastructure for the BIS was sponsored by the Murdoch Children's Research Institute, Deakin University, and Barwon Health. Subsequent funding was secured from the Minderoo Foundation, the European Union's Horizon 2020 research and innovation programme ...
Keywords	Lipidomics ; Cord blood ; Fatty acids ; Acylcarnitine ; Autism spectrum disorder symptoms ; Attention-deficit/hyperactivity disorder symptoms ; Medicine ; R ; Medicine (General) ; R5-920
Subject code	150
Language	English
Publishing date	2024-02-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Early life infection and proinflammatory, atherogenic metabolomic and lipidomic profiles in infancy

Toby Mansell / Richard Saffery / Satvika Burugupalli / Anne-Louise Ponsonby / Mimi LK Tang / Martin O'Hely / Siroon Bekkering / Adam Alexander T Smith / Rebecca Rowland / Sarath Ranganathan / Peter D Sly / Peter Vuillermin / Fiona Collier / Peter Meikle / David Burgner / Barwon Infant Study Investigator Group

eLife, Vol

a population-based cohort study

2022 Volume 11

Abstract: 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, ... ...

Abstract	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 ...
Keywords	inflammation ; metabolomic ; lipidomic ; infection ; paediatric ; Barwon Infant Study ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	300
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Shortened Infant Telomere Length Is Associated with Attention Deficit/Hyperactivity Disorder Symptoms in Children at Age Two Years

Cindy Pham / Regan Vryer / Martin O’Hely / Toby Mansell / David Burgner / Fiona Collier / Christos Symeonides / Mimi L. K. Tang / Peter Vuillermin / Lawrence Gray / Richard Saffery / Anne-Louise Ponsonby / on behalf of the Barwon Infant Study Investigator Group

International Journal of Molecular Sciences, Vol 23, Iss 4601, p

A Birth Cohort Study

2022 Volume 4601

Abstract: 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 ... ...

Abstract	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.
Keywords	attention deficit/hyperactivity disorder ; inattention/hyperactivity/impulsivity symptoms ; telomere length ; environmental factors ; young children ; epidemiology ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	150
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Predictors with regard to ingestion, inhalation and dermal absorption of estimated phthalate daily intakes in pregnant women

Eva J. Sugeng / Christos Symeonides / Martin O'Hely / Peter Vuillermin / Peter D. Sly / Soumini Vijayasarathy / Kristie Thompson / Angela Pezic / Jochen F. Mueller / Anne-Louise Ponsonby

Environment International, Vol 139, Iss , Pp - (2020)

The Barwon infant study

2020

Abstract: Human exposure to phthalate chemicals, used in consumer product plastics, occurs throughout the day. Phthalate levels in pregnant women are associated with offspring health effects including obesity and neurodevelopmental problems. Knowledge of ... ...

Abstract	Human exposure to phthalate chemicals, used in consumer product plastics, occurs throughout the day. Phthalate levels in pregnant women are associated with offspring health effects including obesity and neurodevelopmental problems. Knowledge of predictors of exposure is necessary in order to effectively reduce phthalate exposure. The present study aims to identify predictors of phthalate levels in Australian pregnant women from the Barwon Infant study birth cohort. Maternal urine samples from 841 women were analyzed for phthalate metabolites. Maternal diet and food preparation practices, use of volatile household products, household characteristics and personal care product use were assessed with questionnaires. All maternal urine contained phthalate metabolites. Maternal prenatal high-fat milk consumption was associated with higher benzyl butyl phthalate (BBzP) (p < 0.001), and bis(2-ethylhexyl) phthalate (DEHP) (p = 0.0023). Higher phthalate levels were associated with consumption of tinned food (fish and tomatoes). Diethyl phthalate (DEP) levels were significantly higher when women reported using air freshener (35% increase, p = 0.01), aerosols (40% increase, p = 0.005), hair treatment chemicals (28% increase, p = 0.031), and chlorine (34% increase, p = 0.009) compared to no use. Maternal phthalate levels did not vary by reported plastic avoidance during pregnancy. The study showed that phthalate exposure is ubiquitous and increased by multiple factors. Future intervention studies to reduce phthalate levels among pregnant women will need to take into account the variety of sources identified in this study.
Keywords	Phthalate exposure ; Daily intake ; Pregnant women ; Exposure predictors ; Maternal diet ; Volatile product use ; Environmental sciences ; GE1-350
Subject code	610
Language	English
Publishing date	2020-06-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Gut microbiota composition during infancy and subsequent behavioural outcomes

Amy Loughman / Anne-Louise Ponsonby / Martin O'Hely / Christos Symeonides / Fiona Collier / Mimi L.K. Tang / John Carlin / Sarath Ranganathan / Katrina Allen / Angela Pezic / Richard Saffery / Felice Jacka / Leonard C. Harrison / Peter D. Sly / Peter Vuillermin

EBioMedicine, Vol 52, Iss , Pp - (2020)

2020

Abstract: Background: Despite intense interest in the relationship between gut microbiota and brain development, longitudinal data from human studies are lacking. This study aimed to investigate the relationship between the composition of gut microbiota during ... ...

Abstract	Background: Despite intense interest in the relationship between gut microbiota and brain development, longitudinal data from human studies are lacking. This study aimed to investigate the relationship between the composition of gut microbiota during infancy and subsequent behavioural outcomes. Methods: A subcohort of 201 children with behavioural outcome measures was identified within a longitudinal, Australian birth-cohort study. The faecal microbiota were analysed at 1, 6, and 12 months of age. Behavioural outcomes were measured at 2 years of age. Findings: In an unselected birth cohort, we found a clear association between decreased normalised abundance of Prevotella in faecal samples collected at 12 months of age and increased behavioural problems at 2 years, in particular Internalizing Problem scores. This association appeared independent of multiple potentially confounding variables, including maternal mental health. Recent exposure to antibiotics was the best predictor of decreased Prevotella. Interpretation: Our findings demonstrate a strong association between the composition of the gut microbiota in infancy and subsequent behavioural outcomes; and support the importance of responsible use of antibiotics during early life. Funding: This study was funded by the National Health and Medical Research Council of Australia (1082307, 1147980, 1129813), The Murdoch Children's Research Institute, Barwon Health, Deakin University, Perpetual Trustees, and The Shepherd Foundation. The funders had no involvement in the data collection, analysis or interpretation, trial design, recruitment or any other aspect pertinent to the study. Keywords: Infant, Behaviour, Microbiota, Gut-brain axis
Keywords	Medicine ; R ; Medicine (General) ; R5-920
Subject code	360
Language	English
Publishing date	2020-02-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Maternal prenatal gut microbiota composition predicts child behaviour

Samantha L. Dawson / Martin O'Hely / Felice N. Jacka / Anne-Louise Ponsonby / Christos Symeonides / Amy Loughman / Fiona Collier / Margarita Moreno-Betancur / Peter Sly / David Burgner / Mimi L.K. Tang / Richard Saffery / Sarath Ranganathan / Michael A. Conlon / Leonard C Harrison / Susanne Brix / Karsten Kristiansen / Peter Vuillermin

EBioMedicine, Vol 68, Iss , Pp 103400- (2021)

2021

Abstract: Background: Murine studies demonstrate that maternal prenatal gut microbiota influences brain development and behaviour of offspring. No human study has related maternal gut microbiota to behavioural outcomes during early life. This study aimed to ... ...

Abstract	Background: Murine studies demonstrate that maternal prenatal gut microbiota influences brain development and behaviour of offspring. No human study has related maternal gut microbiota to behavioural outcomes during early life. This study aimed to evaluate relationships between the prenatal faecal microbiota, prenatal diet and childhood behaviour. Methods: A sub-cohort of 213 mothers and 215 children were selected from a longitudinal pre-birth cohort. Maternal prenatal exposure measures collected during the third trimester included the faecal microbiota (generated using 16S rRNA amplicon sequencing), and dietary intake. The behavioural outcome used the Childhood Behaviour Checklist at age two. Models were adjusted for prenatal diet, smoking, perceived stress, maternal age and sample batch. Findings: We found evidence that the alpha diversity of the maternal faecal microbiota during the third trimester of pregnancy predicts child internalising behaviour at two years of age (−2·74, (−4·71, −0·78), p = 0·01 (Wald test), R2=0·07). Taxa from butyrate-producing families, Lachnospiraceae and Ruminococcaceae, were more abundant in mothers of children with normative behaviour. A healthy prenatal diet indirectly related to decreased child internalising behaviours via higher alpha diversity of maternal faecal microbiota. Interpretation: These findings support animal studies showing that the composition of maternal prenatal gut microbiota is related to offspring brain development and behaviour. Our findings highlight the need to evaluate potential impacts of the prenatal gut microbiota on early life brain development. Funding: This study was funded by the National Health and Medical Research Council of Australia (1082307, 1147980), Murdoch Children's Research Institute, Barwon Health and Deakin University.
Keywords	Pregnancy ; Microbiota ; Diet ; Gut-brain axis ; Children ; Behaviour ; Medicine ; R ; Medicine (General) ; R5-920
Subject code	360
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Disordered clusters of Bak dimers rupture mitochondria during apoptosis

Rachel T Uren / Martin O’Hely / Sweta Iyer / Ray Bartolo / Melissa X Shi / Jason M Brouwer / Amber E Alsop / Grant Dewson / Ruth M Kluck

eLife, Vol

2017 Volume 6

Abstract: During apoptosis, Bak and Bax undergo major conformational change and form symmetric dimers that coalesce to perforate the mitochondrial outer membrane via an unknown mechanism. We have employed cysteine labelling and linkage analysis to the full length ... ...

Abstract	During apoptosis, Bak and Bax undergo major conformational change and form symmetric dimers that coalesce to perforate the mitochondrial outer membrane via an unknown mechanism. We have employed cysteine labelling and linkage analysis to the full length of Bak in mitochondria. This comprehensive survey showed that in each Bak dimer the N-termini are fully solvent-exposed and mobile, the core is highly structured, and the C-termini are flexible but restrained by their contact with the membrane. Dimer-dimer interactions were more labile than the BH3:groove interaction within dimers, suggesting there is no extensive protein interface between dimers. In addition, linkage in the mobile Bak N-terminus (V61C) specifically quantified association between dimers, allowing mathematical simulations of dimer arrangement. Together, our data show that Bak dimers form disordered clusters to generate lipidic pores. These findings provide a molecular explanation for the observed structural heterogeneity of the apoptotic pore.
Keywords	Bak ; apoptotic pore ; oligomer ; Bcl-2 proteins ; cell death ; disordered cluster ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	612
Language	English
Publishing date	2017-02-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Maternal carriage of Prevotella during pregnancy associates with protection against food allergy in the offspring

Peter J. Vuillermin / Martin O’Hely / Fiona Collier / Katrina J. Allen / Mimi L. K. Tang / Leonard C. Harrison / John B. Carlin / Richard Saffery / Sarath Ranganathan / Peter D. Sly / Lawrence Gray / John Molloy / Angela Pezic / Michael Conlon / David Topping / Karen Nelson / Charles R. Mackay / Laurence Macia / Jennifer Koplin /

Samantha L. Dawson / Margarita Moreno-Betancur / Anne-Louise Ponsonby / the J. Craig Venter Institute / the BIS Investigator Group

Nature Communications, Vol 11, Iss 1, Pp 1-

2020 Volume 7

Abstract: Incidence of food allergy in westernized populations is associated with low abundance of Prevotella. Here, the authors analyse the microbiome of a mother-infant prebirth cohort and find that maternal carriage, but not infant carriage, of P. copri during ... ...

Abstract	Incidence of food allergy in westernized populations is associated with low abundance of Prevotella. Here, the authors analyse the microbiome of a mother-infant prebirth cohort and find that maternal carriage, but not infant carriage, of P. copri during pregnancy predicts the absence of food allergy in the offspring.
Keywords	Science ; Q
Language	English
Publishing date	2020-03-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Maternal carriage of Prevotella during pregnancy associates with protection against food allergy in the offspring

Samantha L. Dawson / Margarita Moreno-Betancur / Anne-Louise Ponsonby / the J. Craig Venter Institute / the BIS Investigator Group

Nature Communications, Vol 11, Iss 1, Pp 1-

2020 Volume 7

Abstract	Incidence of food allergy in westernized populations is associated with low abundance of Prevotella. Here, the authors analyse the microbiome of a mother-infant prebirth cohort and find that maternal carriage, but not infant carriage, of P. copri during pregnancy predicts the absence of food allergy in the offspring.
Keywords	Science ; Q
Language	English
Publishing date	2020-03-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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