Abstract

Background:

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent and toxic environmental pollutant. Gestational exposure to TCDD has been linked to cognitive and motor deficits, and increased incidence of autism spectrum disorder (ASD) traits in children. Most animal studies of these neurodevelopmental effects involve acute TCDD exposure, which does not model typical exposure in humans.

Objectives:

The aim of the study was to establish a dietary low-dose gestational TCDD exposure protocol and performed an initial characterization of the effects on offspring behavior, neurodevelopmental phenotypes, and gene expression.

Methods:

Throughout gestation, pregnant C57BL/6J mice were fed a diet containing a low dose of TCDD ($9\text{\hspace{0.17em}ng}$ TCDD/kg body weight per day) or a control diet. The offspring were tested in a battery of behavioral tests, and structural brain alterations were investigated by magnetic resonance imaging. The dendritic morphology of pyramidal neurons in the hippocampal Cornu Ammonis (CA)1 area was analyzed. RNA sequencing was performed on hippocampi of postnatal day 14 TCDD-exposed and control offspring.

Results:

TCDD-exposed females displayed subtle deficits in motor coordination and reversal learning. Volumetric difference between diet groups were observed in regions of the hippocampal formation, mammillary bodies, and cerebellum, alongside higher dendritic arborization of pyramidal neurons in the hippocampal CA1 region of TCDD-exposed females. RNA-seq analysis identified 405 differentially expressed genes in the hippocampus, enriched for genes with functions in regulation of microtubules, axon guidance, extracellular matrix, and genes regulated by SMAD3.

Discussion:

Exposure to $9\text{\hspace{0.17em}ng}$ TCDD/kg body weight per day throughout gestation was sufficient to cause specific behavioral and structural brain phenotypes in offspring. Our data suggest that alterations in SMAD3-regulated microtubule polymerization in the developing postnatal hippocampus may lead to an abnormal morphology of neuronal dendrites that persists into adulthood. These findings show that environmental low-dose gestational exposure to TCDD can have significant, long-term impacts on brain development and function. https://doi.org/10.1289/EHP7352

中文翻译：

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低剂量妊娠期 TCDD 暴露对小鼠行为、海马神经元形态和基因表达的影响

 抽象的

 背景：

2,3,7,8-四氯二苯并-对-二恶英（TCDD）是一种持久性有毒环境污染物。妊娠期接触 TCDD 与认知和运动缺陷以及儿童自闭症谱系障碍 (ASD) 特征的发生率增加有关。大多数对这些神经发育影响的动物研究都涉及急性 TCDD 暴露，这并不能模拟人类的典型暴露。

 目标：

该研究的目的是建立饮食低剂量妊娠期 TCDD 暴露方案，并初步表征其对后代行为、神经发育表型和基因表达的影响。

 方法：

在整个妊娠过程中，怀孕的 C57BL/6J 小鼠被喂食含有低剂量 TCDD 的饮食（$\mathrm{<span\; data-immersive-translate-walked="6d8ab2ae-6a86-4735-9f2c-17c0de30381f">9</span>}\text{<span data-immersive-translate-walked="6d8ab2ae-6a86-4735-9f2c-17c0de30381f">吴</span>}$TCDD/每天公斤体重）或对照饮食。后代接受了一系列行为测试，并通过磁共振成像研究了大脑结构的改变。分析海马 Cornu Ammonis (CA)1 区域锥体神经元的树突形态。对出生后第 14 天接触 TCDD 的后代和对照后代的海马进行 RNA 测序。

 结果：

暴露于 TCDD 的女性在运动协调和逆向学习方面表现出微妙的缺陷。在暴露于 TCDD 的雌性海马结构、乳头体和小脑的区域中观察到饮食组之间的体积差异，同时海马 CA1 区域锥体神经元的树突状神经元更高。 RNA-seq分析鉴定出海马体中405个差异表达基因，其中富含具有调节微管、轴突导向、细胞外基质和SMAD3调节功能的基因。

 讨论：

接触$\mathrm{<span\; data-immersive-translate-walked="6d8ab2ae-6a86-4735-9f2c-17c0de30381f">9</span>}\text{<span data-immersive-translate-walked="6d8ab2ae-6a86-4735-9f2c-17c0de30381f">吴</span>}$整个妊娠期间每天 TCDD/kg 体重足以引起后代特定的行为和结构性大脑表型。我们的数据表明，发育中的产后海马中 SMAD3 调节的微管聚合的改变可能导致神经元树突的异常形态，并持续到成年期。这些发现表明，妊娠期环境中低剂量的 TCDD 暴露会对大脑发育和功能产生显着的长期影响。 https://doi.org/10.1289/EHP7352