Executive function deficits and social-behavioral abnormality in mice exposed to a low dose of dioxin in utero and via lactation.
Executive function deficits and social-behavioral abnormality in mice exposed to a low dose of dioxin in utero and via lactation.
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DOI：
10.1371/journal.pone.0050741
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Tohyama C
中科院分区：
文献类型：
--
作者：
Endo T;Kakeyama M;Uemura Y;Haijima A;Okuno H;Bito H;Tohyama C
心理健康问题日益普遍，部分原因是暴露于环境化学品后引起的大脑发育异常。然而，特别是在低接触水平下，很难发现和评估这种因果关系。为了解决这个问题，我们在这里调查了较高的大脑功能暴露于二恶英在子宫内和通过哺乳期使用我们最近开发的自动化行为灵活性测试和免疫组织化学的神经元激活标记弧，在14个大脑区域。妊娠C57 BL/6小鼠在妊娠第12.5天口服低剂量的2，3，7，8-四氯二苯并-对-二恶英（TCDD），剂量为0、0.6或3.0 µg/kg。当幼崽成年后，它们被分组圈养在IntelliCage中，以评估它们的行为。结果，暴露于0.6微克/千克TCDD的母鼠所生的后代表现出行为不稳定、强迫性重复行为和竞争优势显著降低。在这些小鼠中，Arc的免疫组织化学显示内侧前额叶皮质（mPFC）的低激活和杏仁核的过度激活的迹象。有趣的是，暴露于3.0 µg/kg的小鼠在行为和神经元激活指数方面几乎没有受到影响，这表明存在稳健的非单调剂量-反应关系。总之，这项研究首次表明，围产期暴露于低剂量的TCDD小鼠的执行功能缺陷和社会行为异常伴随着不平衡的mPFC-杏仁核激活的迹象。
An increasing prevalence of mental health problems has been partly ascribed to abnormal brain development that is induced upon exposure to environmental chemicals. However, it has been extremely difficult to detect and assess such causality particularly at low exposure levels. To address this question, we here investigated higher brain function in mice exposed to dioxin in utero and via lactation by using our recently developed automated behavioral flexibility test and immunohistochemistry of neuronal activation markers Arc, at the 14 brain areas. Pregnant C57BL/6 mice were given orally a low dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at a dose of either 0, 0.6 or 3.0 µg/kg on gestation day 12.5. When the pups reached adulthood, they were group-housed in IntelliCage to assess their behavior. As a result, the offspring born to dams exposed to 0.6 µg TCDD/kg were shown to have behavioral inflexibility, compulsive repetitive behavior, and dramatically lowered competitive dominance. In these mice, immunohistochemistry of Arc exhibited the signs of hypoactivation of the medial prefrontal cortex (mPFC) and hyperactivation of the amygdala. Intriguingly, mice exposed to 3.0 µg/kg were hardly affected in both the behavioral and neuronal activation indices, indicating that the robust, non-monotonic dose-response relationship. In conclusion, this study showed for the first time that perinatal exposure to a low dose of TCDD in mice develops executive function deficits and social behavioral abnormality accompanied with the signs of imbalanced mPFC-amygdala activation.