Background

Prenatal phthalate exposure has been linked with altered neurodevelopment, including externalizing behaviors and attention-deficit hyperactivity disorder (ADHD). However, the implicated metabolite, neurobehavioral endpoint, and child sex have not always been consistent across studies, possibly due to heterogeneity in neurodevelopmental instruments. The complex set of findings may be synthesized using executive function (EF), a construct of complex cognitive processes that facilitate ongoing goal-directed behaviors. Impaired EF can be presented with various phenotypes of poor neurodevelopment, differently across structured conditions, home/community, or preschool/school. We evaluated the relationship between prenatal phthalate exposure and comprehensive assessment of preschool EF.

Methods

Our study comprised 262 children with clinically significant/subthreshold ADHD symptoms and 78 typically developing children who were born between 2003 and 2008 and participated in the Preschool ADHD Substudy, which is nested within a population-based prospective cohort study, the Norwegian Mother, Father, and Child Cohort (MoBa). Twelve phthalate metabolites were measured from urine samples that their mothers had provided during pregnancy, at 17 weeks’ gestation. All children, at approximately 3.5-years, took part in a detailed clinical assessment that included parent-and teacher-rated inventories and administered tests. We used instruments that measured constructs related to EF, which include a parent-and teacher-reported Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P) and three performance-based tests: A Developmental NEuroPSYchological Assessment (NEPSY), Stanford-Binet intelligence test V (SB5), and the cookie delay task (CDT). The standard deviation change in test score per interquartile range (IQR) increase in phthalate metabolite was estimated with multivariable linear regression. We applied weighting in all models to account for the oversampling of children with clinically significant or subthreshold symptoms of ADHD. Additionally, we assessed modification by child sex and potential co-pollutant confounding.

Results

Elevated exposure to mono-benzyl phthalate (MBzP) during pregnancy was associated with poorer EF, across all domains and instruments, in both sex. For example, an IQR increase in MBzP was associated with poorer working memory rated by parent (1.23 [95% CI: 0.20, 2.26]) and teacher (1.13 [0.14, 2.13]) using BRIEF-P, and administered tests such as SB5 (no-verbal: 0.19 [0.09, 0.28]; verbal: 0.13 [0.01, 0.25]). Adverse associations were also observed for mono-n-butyl phthalate (MnBP) and mono-iso-butyl phthalate (MiBP), although results varied by instruments. EF domains reported by parents using BRIEF-P were most apparently implicated, with stronger associations among boys (e.g., MnBP and inhibition: 2.74 [1.77, 3.72]; MiBP and inhibition: 1.88 [0.84, 2.92]) than among girls (e.g., MnBP and inhibition: −0.63 [−2.08, 0.83], interaction p-value: 0.04; MiBP and inhibition: −0.15 [−1.04, 0.74], interaction p-value: 0.3). Differences by sex, however, were not found for the teacher-rated BRIEF-P or administered tests including NEPSY, SB5, and CDT.

Conclusion and relevance

Elevated mid-pregnancy MBzP, MiBP, and MnBP were associated with more adverse profiles of EF among preschool-aged children across a range of instruments and raters, with some associations found only among boys. Given our findings and accumulating evidence of the prenatal period as a critical window for phthalate exposure, there is a timely need to expand the current phthalate regulations focused on baby products to include pregnancy exposures.

中文翻译：

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学龄前儿童的产前邻苯二甲酸酯暴露和执行功能

背景

产前邻苯二甲酸酯暴露与神经发育改变有关，包括外化行为和注意力缺陷多动障碍 (ADHD)。然而，涉及的代谢物、神经行为终点和儿童性别在研究中并不总是一致的，这可能是由于神经发育工具的异质性。可以使用执行功能 (EF) 来综合复杂的研究结果，执行功能是一种复杂的认知过程，可促进持续的目标导向行为。EF 受损可以表现为神经发育不良的各种表型，在结构化条件、家庭/社区或学前班/学校中有所不同。我们评估了产前邻苯二甲酸酯暴露与学龄前 EF 综合评估之间的关系。

方法

我们的研究包括 262 名具有临床显着/亚阈值 ADHD 症状的儿童和 78 名在 2003 年至 2008 年间出生并参加学龄前 ADHD 子研究的儿童，该子研究嵌套在一项基于人群的前瞻性队列研究中，挪威母亲、父亲、和儿童队列 (MoBa)。在怀孕 17 周时，他们的母亲在怀孕期间提供的尿液样本中测量了 12 种邻苯二甲酸酯代谢物。所有大约 3.5 岁的儿童都参加了详细的临床评估，其中包括家长和教师评定的清单和管理测试。我们使用了测量与 EF 相关的结构的工具，其中包括家长和教师报告的执行功能-学前教育行为评定量表 (BRIEF-P) 和三个基于表现的测试：发展性神经心理学评估 (NEPSY)、Stanford-Binet 智力测试 V (SB5) 和 cookie 延迟任务 (CDT)。使用多变量线性回归估计邻苯二甲酸酯代谢物每四分位间距 (IQR) 增加的测试分数的标准差变化。我们在所有模型中应用加权来解释对具有临床显着性或亚阈值多动症症状的儿童的过度抽样。此外，我们评估了儿童性别和潜在的共同污染物混杂因素的修改。我们在所有模型中应用加权来解释对具有临床显着性或亚阈值多动症症状的儿童的过度抽样。此外，我们评估了儿童性别和潜在的共同污染物混杂因素的修改。我们在所有模型中应用加权来解释对具有临床显着性或亚阈值多动症症状的儿童的过度抽样。此外，我们评估了儿童性别和潜在的共同污染物混杂因素的修改。

结果

怀孕期间邻苯二甲酸单苄酯 (MBzP) 暴露量增加与所有领域和仪器的 EF 较差有关，无论男女。例如，MBzP 的 IQR 增加与父母 (1.23 [95% CI: 0.20, 2.26]) 和老师 (1.13 [0.14, 2.13]) 使用 Brief-P 和管理测试（如 SB5）评定的较差工作记忆相关（非语言：0.19 [0.09, 0.28]；语言：0.13 [0.01, 0.25]）。邻苯二甲酸单正丁酯 (MnBP) 和单异- 邻苯二甲酸丁酯 (MiBP)，尽管结果因仪器而异。父母使用 BRIEF-P 报告的 EF 域最为明显，男孩之间的关联性更强（例如，MnBP 和抑制：2.74 [1.77, 3.72]；MiBP 和抑制：1.88 [0.84, 2.92]）比女孩（例如， MnBP 和抑制：-0.63 [-2.08, 0.83]，相互作用 p 值：0.04；MiBP 和抑制：-0.15 [-1.04, 0.74]，相互作用 p 值：0.3）。然而，在教师评分的 Brief-P 或包括 NEPSY、SB5 和 CDT 在内的管理测试中没有发现性别差异。

结论和相关性

在一系列仪器和评估者中，妊娠中期 MBzP、MiBP 和 MnBP 升高与学龄前儿童 EF 的不良特征相关，其中一些关联仅在男孩中发现。鉴于我们的研究结果和越来越多的证据表明，产前时期是邻苯二甲酸酯暴露的关键窗口，因此需要及时扩大当前针对婴儿产品的邻苯二甲酸酯法规，将妊娠暴露纳入其中。