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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: A birth cohort study
journal contributionposted on 2023-02-16, 01:10 authored by S Thomson, K Drummond, Martin O'HelyMartin O'Hely, C Symeonides, C Chandran, T Mansell, R Saffery, Peter SlyPeter Sly, J Mueller, Peter VuillerminPeter Vuillermin, AL Ponsonby
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.
Article numberARTN 107678
Publication classificationC1 Refereed article in a scholarly journal
PublisherPERGAMON-ELSEVIER SCIENCE LTD
CategoriesNo categories selected
Science & TechnologyLife Sciences & BiomedicineEnvironmental SciencesEnvironmental Sciences & EcologyEndocrine disrupting chemicalsMetabolomicsPyruvate metabolismWarburg EffectAutism spectrum disorderNeurodevelopmentOXIDATIVE STRESSGESTATIONAL EXPOSURERISK-FACTORSPROFILECHILDRENWOMENMETABOLOMICSPREVALENCEBEHAVIORSPREGNANCYChildPregnancyInfantInfant, NewbornFemaleHumansChild, PreschoolCohort StudiesDiethylhexyl PhthalateAutism Spectrum DisorderEnvironmental PollutantsAustraliaPhthalic AcidsEnvironmental ExposureEnergy MetabolismPrenatal Exposure Delayed EffectsMaternal ExposureBarwon Infant Study Investigator GroupAutismBrain DisordersPerinatal Period - Conditions Originating in Perinatal PeriodClinical ResearchConditions Affecting the Embryonic and Fetal PeriodsPediatricMental HealthIntellectual and Developmental Disabilities (IDD)Pediatric Research Initiative2.3 Psychological, social and economic factors2.2 Factors relating to the physical environment2 Aetiology2.1 Biological and endogenous factorsReproductive health and childbirth7 Affordable and Clean Energy