Associations among exposure to methylmercury, reduced Reelin expression, and gender in the cerebellum of developing mice
Associations among exposure to methylmercury, reduced Reelin expression, and gender in the cerebellum of developing mice
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DOI：
10.1016/j.neuro.2014.09.006
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发表时间：
2014-12-01
期刊：
影响因子：
3.4
通讯作者：
Keller, Flavio
中科院分区：
文献类型：
--
作者：
Biamonte, Filippo;Latini, Laura;Keller, Flavio
在怀孕期间或出生后早期起作用的遗传风险因素被认为是过去20年来自闭症诊断指数增长的原因。特别是，有人提出与接触环境汞可能存在联系。男性是自闭症的第二个危险因素。第三个潜在的遗传风险因素是Reelin表达减少。雄性杂合reeler（rl（+/-））小鼠表现出自闭症样表型，包括浦肯野细胞（PC）丢失和行为僵硬。我们评估了rl（+/-）小鼠中3个风险因素（即遗传状态、性别和甲基汞（MeHg）暴露）之间的复杂相互作用。小鼠在产前和产后早期暴露于甲基汞，无论是在亚毒性剂量（在母鼠的饮用水中为2 ppm），或毒性剂量（6 ppm母鼠饮用水），结果表明：（a）2 ppm甲基汞不会引起不同动物组的PC丢失，也不会增加rl（+/-）雄性的PC丢失;与无明显神经毒性一致，2 ppm的甲基汞本身不会引起行为改变（新生儿分离引起的超声波呼叫，或成人的社交和社交偏好）;（B）与此形成鲜明对比的是，6 ppm的甲基汞会导致所有群体中的PC数量急剧减少，而与基因型和性别无关。细胞色素C从线粒体的PC释放增强在6 ppm的甲基汞暴露组，与μ-钙蛋白酶活性亚基的伴随增加。在行为层面，6 ppm甲基汞暴露强烈增加超声波发声在所有动物群体。值得注意的是，6 ppm甲基汞显著降低rl（+/-）雄性小鼠的社交能力，而2 ppm组没有显示出这种降低。在亚毒性剂量下，甲基汞不会增强rl（+/-）雄性小鼠的自闭症样表型，在较高剂量下，情况更加复杂，一些“自闭症样”特征（社交能力丧失、偏好相同）仅在rl（+/-）雄性小鼠中受到明显影响，而其他神经病理学和行为参数在所有组中均发生改变，与基因型和性别无关。线粒体异常似乎在观察到的效应中起着至关重要的作用。(C)2014爱思唯尔公司All rights reserved.
Genetic risk factors acting during pregnancy or early after birth have been proposed to account for the exponential increase of autism diagnoses in the past 20 years. In particular, a potential link with exposure to environmental mercury has been suggested. Male sex constitutes a second risk factor for autism. A third potential genetic risk factor is decreased Reelin expression. Male heterozygous reeler (rl(+/-)) mice show an autism-like phenotype, including Purkinje cells (PCs) loss and behavioral rigidity. We evaluated the complex interactions between 3 risk factors, i.e. genetic status, sex, and exposure to methylmercury (MeHg), in rl(+/-) mice. Mice were exposed to MeHg during the prenatal and early postnatal period, either at a subtoxic dose (2 ppm in Dams' drinking water), or at a toxic dose (6 ppm Dams' drinking water), based on observations in other rodent species and mice strains.We show that: (a) 2 ppm MeHg does not cause PCs loss in the different animal groups, and does not enhance PCs loss in rl(+/-) males; consistent with a lack of overt neurotoxicity, 2 ppm MeHg per se does not cause behavioral alterations (separation-induced ultrasonic calls in newborns, or sociability and social preference in adults); (b) in stark contrast, 6 ppm MeHg causes a dramatic reduction of PCs number in all groups, irrespective of genotype and sex. Cytochrome C release from mitochondria of PCs is enhanced in 6 ppm MeHg-exposed groups, with a concomitant increase of mu-calpain active subunit. At the behavioral level, 6 ppm MeHg exposure strongly increases ultrasonic vocalizations in all animal groups. Notably, 6 ppm MeHg significantly decreases sociability in rl(+/-) male mice, while the 2 ppm group does not show such as decrease. At a subtoxic dose, MeHg does not enhance the autism-like phenotype of male rl(+/-) mice.At the higher MeHg dose, the scenario is more complex, with some "autism-like" features (loss of sociability, preference for sameness) being evidently affected only in rl(+/-) males, while other neuropathological and behavioral parameters being altered in all groups, independently from genotype and sex. Mitochondrial abnormalities appear to play a crucial role in the observed effects. (C) 2014 Elsevier Inc. All rights reserved.