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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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Prenatal phthalate chemicals may have adverse effects on brain development by various mechanisms including oxidant damage. However, birth cohort findings have been conflicting. This study aimed to (i) investigate the interplay between maternal prenatal phthalate levels, infant genetic vulnerability to oxidative stress, and child neurodevelopment and (ii) examine combined putative oxidant exposures. In a population-based birth cohort of 1064 women with prenatal recruitment in Victoria, Australia, maternal urine was collected at 36 weeks of pregnancy and phthalate metabolite concentrations measured. An unweighted genetic score for oxidative stress was made using a candidate gene approach. Cognition was assessed using the BAYLEY-III at two years (n = 678). Parents completed questionnaires for doctor diagnosed autism spectrum disorder (ASD) (1.4 %), ASD traits (4.9 %) and child inattention/hyperactivity (n = 791). Analyses included multiple linear and logistic regression. Higher prenatal phthalate levels and a higher oxidative stress genetic score were each associated with subsequent ASD. Several oxidative stress-related SNPs modified the association between prenatal phthalates and ASD and other outcomes. Consistent patterns were evident across gene score-phthalate combinations for cognition, ASD, ASD traits and inattention/hyperactivity. Other putative oxidant factors such as prenatal smoking further increased risk. Prenatal phthalate levels and infant oxidative stress-related genetic vulnerability are associated with adverse neurodevelopment. Combined exposures are important. Current recommendations and regulation on maternal phthalate exposure during pregnancy require re-evaluation., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)