Studies on the pleiotropic effects of gaseous chemical compound on the function of the central nervous system.

在本研究中，我们研究了1-溴丙烷(1-BP)对中枢神经系统(CNS)功能的影响。在非洲爪哇卵母细胞表达系统的实验中，我们发现1-BP直接增强了GABA_A受体的功能，而抑制了神经元烟碱型乙酰胆碱受体的功能。在使用大鼠海马片的研究中，1-BP还增强了群体峰电位(PS)幅度的成对脉冲抑制(PPI)，表明1-BP具有麻醉作用。然而，亚慢性暴露于1-BP蒸气时，可在海马区观察到PS波幅PPI的降低，即与上述1-BP的直接作用相反的去抑制作用，这种去抑制作用主要发生在齿状回，而不是CA1区。逆转录聚合酶链式反应分析显示，1-BP暴露的大鼠海马区GABAA受体β3和δ亚单位-突触外GABAA受体的组成成分-的基因表达水平降低。此外，体外和体内实验均表明，1-BP可改变神经营养因子BDNFmRNA和抗细胞凋亡分子BclxLmRNA的表达，其机制可能分别与抑制CREB和NF-κB的激活有关。这些结果表明，1-BP可能通过不同的机制改变神经元的兴奋性，这需要进一步的研究。另一方面，我们检测了1-BP暴露大鼠脑内的溴(BR-)浓度，以确定1-BP吸入引起的BR-浓度随时间变化的单室模型。因此，这个模型结合我们的实验观察，将描述1-BP暴露引起的中枢神经毒性的风险评估，这也表明血液和/或尿样中的BR-浓度将是1-BP吸入的有用的化学指标。

In this research, we investigated the effects of 1-bromopropane (1-BP), a substitute for chlorofluorocarbons, on the function of the central nervous system (CNS). We found that 1-BP directly potentiated the function of GABA_A receptors, but inhibited neuronal nicotinic acetylcholine receptors, respectively, from the experiments using Xenopus oocytes expression system. 1-BP also enhanced paired-pulse inhibition (PPI) of population spike (PS) amplitudes in the study using rat hippocampal slice preparations, suggesting an anesthetic effect of 1-BP. However, when the rats were exposed to 1-BP vapor subchronically, the decrease in PPI of PS amplitudes, i.e.disinhibition which was opposite to the direct effect of 1-BP mentioned above, was observed in the hippocampus, and this disinhibition occurred in the dentate gyrus more predominantly than CA1 area. RT-PCR analysis indicated decreased mRNA levels of GABA_A receptor β3 and δ subunits - the components of extrasynaptic GABA_A receptors - in the hippocampus of 1-BP-exposed rats. Moreover, both in vitro and in vivo experiments revealed that 1-BP altered mRNA levels of BDNF, a neurotrophic factor and Bcl-xL, an anti-apoptotic molecule, which was probably due to the inhibition of CREB and NF-κB activation, respectively. These results demonstrate that 1-BP may alter neuronal excitability via different mechanisms, which requires further investigation to be clarified.On the other hand, we examined bromide (Br-) concentrations in the brain obtained from 1-BP-exposed rats, to determine the one compartment model for time-dependent changes of Br- concentrations caused by 1-BP inhalation. In consequence, this model, together with our experimental observations, would describe a risk assessment for the CNS neurotoxicity induced by 1-BP exposure, which also suggests that Br- concentration in the blood and/or urine sample would be a useful chemical-indicator of 1-BP inhalation.