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.
摘要：
以前，产前邻苯二甲酸盐暴露与自闭症谱系障碍（ASD）的发展有关。然而,潜在的生物学机制仍不清楚.作为Barwon婴儿研究（BIS）的一部分，我们调查了母婴中心碳代谢是否涉及，1,074名澳大利亚儿童的基于人口的出生队列。我们使用孕晚期尿邻苯二甲酸酯代谢物浓度和其他相关指标估算了邻苯二甲酸酯的每日摄入量。孕晚期母体血清代谢组,通过核磁共振测量出生时的脐带血和1年时的儿童血浆。我们使用小分子途径数据库和主成分分析来构建反映代谢途径的复合代谢物评分。通过儿童行为清单和优势和困难问卷的子量表，在596和674名儿童中测量了2年和4年的ASD症状，分别。多变量线性回归分析（i）较高的产前邻苯二甲酸二（2-乙基己基）酯（DEHP）水平与母体非氧化能量代谢途径上调之间的前瞻性关联，(ii)这些途径的上调与2岁和4岁时后代ASD症状增加之间的前瞻性关联。反事实调解分析表明，较高的产前DEHP暴露影响儿童早期ASD症状发展的部分机制是通过母亲在怀孕期间向非氧化能量途径的代谢转变。与氧化代谢相比效率低下。这些结果突出了产前时期的重要性，并表明有必要进一步研究母体能量代谢作为产前环境暴露（例如邻苯二甲酸酯）的不利影响的分子介质。
