Department of Psychiatry and Behavioral Sciences, University of Louisville, Louisville, KY, USA.
Med Hypotheses. 2010 Jul;75(1):53-8. doi: 10.1016/j.mehy.2010.01.027. Epub 2010 Feb 9.
The phenotypic expression of autism, according to the Triple Hit Hypothesis, is determined by three factors: a developmental time window of vulnerability, genetic susceptibility, and environmental stressors. In utero exposure to thalidomide, valproic acid, and maternal infections are examples of some of the teratogenic agents which increase the risk of developing autism and define a time window of vulnerability. An additional stressor to genetically susceptible individuals during this time window of vulnerability may be prenatal ultrasound. Ultrasound enhances the genesis and differentiation of progenitor cells by activating the nitric oxide (NO) pathway and related neurotrophins. The effects of this pathway activation, however, are determined by the stage of development of the target cells, local concentrations of NO, and the position of nuclei (basal versus apical), causing consequent proliferation at some stages while driving differentiation and migration at others. Ill-timed activation or overactivation of this pathway by ultrasound may extend proliferation, increasing total cell number, and/or may trigger precipitous migration, causing maldistribution of neurons amongst cortical lamina, ganglia, white matter, and germinal zones. The rising rates of autism coincident with the increased use of ultrasound in obstetrics and its teratogenic/toxic effects on the CNS demand further research regarding a putative correlation.
根据三重打击假说，自闭症的表型表达由三个因素决定：易损性的发育时间窗、遗传易感性和环境应激源。在子宫内接触沙利度胺、丙戊酸和母体感染是一些增加自闭症发病风险并定义易损性时间窗的致畸剂的例子。在这个易损性时间窗期间，对遗传易感个体的另一个应激源可能是产前超声。超声通过激活一氧化氮 (NO) 途径和相关神经营养因子来增强祖细胞的发生和分化。然而，该途径激活的效果取决于靶细胞的发育阶段、NO 的局部浓度以及核的位置（基底对顶），导致在某些阶段增殖，而在其他阶段驱动分化和迁移。超声对该途径的时机不当或过度激活可能会延长增殖，增加总细胞数量，和/或可能引发急剧迁移，导致神经元在皮质层、神经节、白质和生发区之间分布不良。自闭症的发病率上升与妇产科中超声使用的增加以及其对中枢神经系统的致畸/毒性作用相吻合，这需要进一步研究两者之间可能存在的相关性。
