Centre for Craniofacial and Regenerative Biology, King's College London, London, UK.
Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
Environ Health Perspect. 2021 May;129(5):57002. doi: 10.1289/EHP7352. Epub 2021 May 6.
2,3,7,8-tetrachlorodibenzo--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.
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.
Throughout gestation, pregnant C57BL/6J mice were fed a diet containing a low dose of TCDD ( 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.
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.
Exposure to 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.
2,3,7,8-四氯二苯并对二恶英（TCDD）是一种持久性有毒的环境污染物。妊娠暴露于 TCDD 与儿童的认知和运动缺陷以及自闭症谱系障碍（ASD）特征的发生率增加有关。大多数关于这些神经发育影响的动物研究涉及急性 TCDD 暴露，而这种暴露不能模拟人类的典型暴露。
本研究旨在建立一种饮食性低剂量妊娠期 TCDD 暴露方案，并初步研究其对后代行为、神经发育表型和基因表达的影响。
在整个妊娠期，给予 C57BL/6J 孕鼠含低剂量 TCDD（TCDD/公斤体重/天）的饮食或对照饮食。通过一系列行为测试对后代进行测试，并通过磁共振成像研究结构脑改变。分析海马角 CA1 区锥体神经元的树突形态。对 TCDD 暴露和对照后代出生后第 14 天的海马进行 RNA 测序。
TCDD 暴露的雌性表现出轻微的运动协调和反转学习缺陷。在海马结构、乳突体和小脑的区域观察到饮食组之间的体积差异，TCDD 暴露雌性的海马 CA1 区锥体神经元的树突分支更多。RNA-seq 分析鉴定了海马中 405 个差异表达的基因，这些基因富集了微管、轴突导向、细胞外基质以及 SMAD3 调节的基因的功能。
整个妊娠期暴露于 TCDD/公斤体重/天足以引起后代特定的行为和结构脑表型。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，这种形态持续到成年。这些发现表明，环境低剂量妊娠期 TCDD 暴露会对大脑发育和功能产生重大的、长期的影响。
