State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Toxicol Sci. 2014 Jun;139(2):452-65. doi: 10.1093/toxsci/kfu049. Epub 2014 Mar 27.
Thimerosal is a vaccine antimicrobial preservative which has long been suspected an iatrogenic factor possibly contributing to neurodevelopmental disorders including autism. The association between infant vaccine thimerosal exposure and autism remains an open question. Although thimerosal has been removed from mandatory childhood vaccines in the United States, thimerosal-preserved vaccines are still widely used outside of the United States especially in developing countries. Notably, thimerosal-containing vaccines are being given to the newborns within the first 12-24 h after birth in some countries. To examine the possible neurotoxic effects of early neonatal exposure to a higher level of thimerosal, FVB mice were subcutaneously injected with thimerosal-mercury at a dose which is 20× higher than that used for regular Chinese infant immunization during the first 4 months of life. Thimerosal-treated mice exhibited neural development delay, social interaction deficiency, and inclination of depression. Apparent neuropathological changes were also observed in adult mice neonatally treated with thimerosal. High-throughput RNA sequencing of autistic-behaved mice brains revealed the alternation of a number of canonical pathways involving neuronal development, neuronal synaptic function, and the dysregulation of endocrine system. Intriguingly, the elevation of anterior pituitary secreting hormones occurred exclusively in male but not in female thimerosal-treated mice, demonstrating for the first time the gender bias of thimerosal-mercury toxicity with regard to endocrine system. Our results indicate that higher dose of neonatal thimerosal-mercury (20× higher than that used in human) is capable of inducing long-lasting substantial dysregulation of neurodevelopment, synaptic function, and endocrine system, which could be the causal involvements of autistic-like behavior in mice.
硫柳汞是一种疫苗抗菌防腐剂，长期以来一直被怀疑是一种医源性因素，可能导致神经发育障碍，包括自闭症。婴儿疫苗中硫柳汞暴露与自闭症之间的关系仍然是一个悬而未决的问题。尽管在美国，硫柳汞已从强制性儿童疫苗中去除，但在美国以外的国家，特别是在发展中国家，仍广泛使用硫柳汞保存的疫苗。值得注意的是，一些国家在新生儿出生后 12-24 小时内给予含硫柳汞的疫苗。为了研究早期新生儿接触更高水平硫柳汞的可能神经毒性作用，FVB 小鼠在生命的前 4 个月内，通过皮下注射比中国常规婴儿免疫剂量高 20 倍的硫柳汞-汞。接受硫柳汞治疗的小鼠表现出神经发育延迟、社交互动缺陷和抑郁倾向。在新生儿期接受硫柳汞治疗的成年小鼠中也观察到明显的神经病理学变化。对具有自闭症行为的小鼠大脑进行高通量 RNA 测序显示，涉及神经元发育、神经元突触功能和内分泌系统失调的一些典型途径发生改变。有趣的是，仅在雄性而非雌性接受硫柳汞治疗的小鼠中观察到前垂体分泌激素的升高，首次证明了硫柳汞-汞毒性在内分泌系统方面存在性别偏见。我们的结果表明，更高剂量的新生儿硫柳汞-汞（比人类使用的高 20 倍）能够诱导神经发育、突触功能和内分泌系统的持久、实质性失调，这可能是小鼠自闭症样行为的因果关系。
