低剂量甲状腺素可减轻胎儿酒精暴露对雄性后代社交行为和海马基因表达的自闭症相关不良影响。
Low-dose thyroxine attenuates autism-associated adverse effects of fetal alcohol in male offspring's social behavior and hippocampal gene expression.
机构信息
Department of Psychiatry and Behavioral Sciences, The Asher Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
出版信息
Alcohol Clin Exp Res. 2013 Nov;37(11):1986-95. doi: 10.1111/acer.12183. Epub 2013 Jun 13.
BACKGROUND
Fetal alcohol spectrum disorder (FASD) is characterized by neurodevelopmental anomalies manifesting in cognitive and behavioral deficits in the offspring with diverse severities. Social behavior is affected in FASD, and these deficits overlap with those of autism spectrum disorder (ASD). Identifying some of the molecular characteristics related to ASD in an animal model of FASD could ultimately provide details on the underlying molecular mechanisms of both disorders that could lead to novel treatments.
METHODS
Pregnant Sprague-Dawley rats received the following diets: control (C; ad libitum standard laboratory chow), nutritional control pair-fed (PF), ethanol (EtOH), or an EtOH diet supplemented with 0.3, 1.5, or 7.5 mg thyroxine (T4)/l in the diet. Social behavior and memory were tested in the adult offspring. Plasma total T4, free T3 (fT3), and thyroid-stimulating hormone (TSH) levels were measured. Hippocampal expression of Gabrb3, Ube3a, Nr2b, Rasgrf1, and Dio3 were measured by RT-qPCR and protein levels of Mecp2 and Slc25a12 by Western blotting.
RESULTS
Adult male offspring of EtOH dams showed elevated fT3 and low TSH levels. Adult male, but not female, offspring of EtOH dams exhibited social behavior and memory deficits. Expression of autism candidates, Gabrb3, Ube3a, Mecp2, and Slc25a12, was significantly increased in the hippocampus of male offspring of EtOH dams. Hippocampal Nr2b and Dio3 were also increased, while Rasgrf1 was decreased in the same population. Peripheral thyroid function, social behavioral deficits, and altered expression of the above genes were normalized by simultaneous administration of 0.3 mg/l T4 in the EtOH diet.
CONCLUSIONS
Our data suggest that social interaction deficits of FASD share molecular mechanism with ASD by showing altered hippocampal expression of several ASD candidate genes. Social interaction deficits as well as the gene expression changes in the offspring of EtOH-consuming dams can be reversed by low dose of thyroid hormone supplementation to the mothers.
背景
胎儿酒精谱系障碍（FASD）的特征是神经发育异常，表现为后代认知和行为缺陷，严重程度不一。社交行为受到 FASD 的影响，这些缺陷与自闭症谱系障碍（ASD）重叠。在 FASD 的动物模型中确定一些与 ASD 相关的分子特征，最终可以提供这两种疾病潜在分子机制的详细信息，从而为新的治疗方法提供依据。
方法
怀孕的 Sprague-Dawley 大鼠接受以下饮食：对照（C；自由摄取标准实验室饲料）、营养对照（PF）、乙醇（EtOH）或 EtOH 饮食补充 0.3、1.5 或 7.5mg 甲状腺素（T4）/l。在成年后代中测试社交行为和记忆。测量血浆总 T4、游离 T3（fT3）和促甲状腺激素（TSH）水平。通过 RT-qPCR 测量海马 Gabrb3、Ube3a、Nr2b、Rasgrf1 和 Dio3 的表达，通过 Western blot 测量 Mecp2 和 Slc25a12 的蛋白水平。
结果
EtOH 母鼠的成年雄性后代表现出 fT3 升高和 TSH 降低。EtOH 母鼠的成年雄性后代表现出社交行为和记忆缺陷，但雌性后代没有。EtOH 母鼠的雄性后代海马中自闭症候选基因 Gabrb3、Ube3a、Mecp2 和 Slc25a12 的表达显著增加。同样的人群中海马 Nr2b 和 Dio3 也增加，而 Rasgrf1 减少。同时在 EtOH 饮食中添加 0.3mg/l T4 可使外周甲状腺功能、社交行为缺陷和上述基因表达改变正常化。
结论
我们的数据表明，FASD 的社交互动缺陷与 ASD 具有相同的分子机制，表现为几个 ASD 候选基因的海马表达改变。通过对母鼠补充低剂量甲状腺激素，可以逆转 EtOH 消耗母鼠后代的社交互动缺陷和基因表达变化。
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