Gericke G S
Genetics Division, Ampath National Pathology Laboratories, P.O. Box 2040, Brooklyn Square, 0075 Pretoria, Gauteng, South Africa.
Med Hypotheses. 2006;66(1):92-9. doi: 10.1016/j.mehy.2005.07.031. Epub 2005 Sep 22.
The neuroendocrine response to stress utilizes several bio-communicative pathways which also play a role in neurodevelopmental plasticity. The mechanism of action of steroidal compounds includes DNA alteration by reactive oxygen species (ROS) arising through redox cycling of reactive hormone derivatives. ROS and reactive nitrogen species play a significant role in signaling networks affecting gene transcriptional regulation during normal as well as stress-induced responses. ROS-associated synaptic and regulatory region plasticity may have been important for normal brain evolution, but probably simultaneously lowered the threshold for inducing neuropathology. A shift from 'plasticity' to 'instability' is likely to be associated with the emergence of complex effects depending on the timing, duration and intensity of the ROS insult, and is suggested to include heritable epigenetic chromatin/regulatory region remodeling differentially influencing expression levels of significant neuropsychiatric genes and their variant alleles. Neurobehavioural disorder clinical manifestations have been linked with ROS effects. The concepts discussed here relate to ROS-associated instability of DNA regulatory region sequences and a proposal that it may play an important modifying role in brain and neuro-behaviourally related gene expression. Genes encoding key steps in mitochondrial, haem, iron and bilirubin ROS metabolic pathways have been used as examples to illustrate how ROS-modified regulatory networks could possibly alter the context within which (even ostensibly unrelated) neuropsychiatric gene candidates may sometimes be recruited. Furthermore, reactions of certain radicals release sufficient energy to generate UV-photons. DNA conformational changes accompanied by changes in photon emission suggest that functional neuroimaging findings probably reflect interaction on the level of ROS/biophoton/genome regulatory region domains rather than the signatures of individual neurobehavioural disorder candidate genes.
对压力的神经内分泌反应利用了几种生物通讯途径，这些途径在神经发育可塑性中也发挥着作用。甾体化合物的作用机制包括活性激素衍生物的氧化还原循环产生的活性氧（ROS）导致的DNA改变。ROS和活性氮物质在正常以及应激诱导反应期间影响基因转录调控的信号网络中发挥着重要作用。与ROS相关的突触和调节区域可塑性可能对正常大脑进化很重要，但可能同时降低了诱发神经病理学的阈值。从“可塑性”到“不稳定性”的转变可能与复杂效应的出现有关，这取决于ROS损伤的时间、持续时间和强度，并被认为包括可遗传的表观遗传染色质/调节区域重塑，其对重要神经精神基因及其变异等位基因的表达水平有不同影响。神经行为障碍的临床表现与ROS效应有关。这里讨论的概念涉及与ROS相关的DNA调节区域序列的不稳定性，以及它可能在大脑和神经行为相关基因表达中发挥重要修饰作用的提议。编码线粒体、血红素、铁和胆红素ROS代谢途径关键步骤的基因已被用作例子来说明ROS修饰的调节网络如何可能改变（即使表面上不相关的）神经精神基因候选者有时可能被招募的背景。此外，某些自由基的反应释放出足够的能量来产生紫外线光子。伴随光子发射变化的DNA构象变化表明，功能性神经影像学发现可能反映了ROS/生物光子/基因组调节区域域水平上的相互作用，而不是单个神经行为障碍候选基因的特征。
