Ross J F, Broadwell R D, Poston M R, Lawhorn G T
Human and Environmental Safety Division, Procter and Gamble Company, Miami Valley Laboratories, Cincinnati, Ohio 45239-8707.
Toxicol Appl Pharmacol. 1994 Feb;124(2):191-200. doi: 10.1006/taap.1994.1023.
A small fraction of humans ingesting bismuth (Bi)-containing medications develops neurotoxicity in which neuropsychiatric signs precede motor dysfunction. Large ip doses of Bi subnitrate (BSN) produce similar signs in mice, but little is known about the pathogenesis of neurotoxicity in either species. Adult female Swiss-Webster mice received a neurotoxic dose (2500 mg/kg ip) of BSN. Bi distribution and neuropathology were determined as follows: (1) Regions of central and peripheral nervous system were assayed for Bi by atomic absorption spectrometry (AAS) 28 days after dosing, (2) regional brain Bi distribution was demonstrated in histologic sections by autometallography 28 days after dosing, and (3) blood/brain barrier status and neuropathologic effects were evaluated by light and electron microscopic techniques 1, 3, and 7 days and 2, 3, 4, and 5 weeks after dosing. By AAS, Bi levels were highest in olfactory bulb (approximately 7 ppm), hypothalamus (approximately 7 ppm), septum (approximately 3 ppm), and brain stem (approximately 3 ppm). Striatum and cerebral cortex had the least Bi (approximately 1 ppm). Regional distribution by autometallography showed that high Bi levels were associated with diffusion of Bi from fenestrated blood vessels of circumventricular organs and olfactory epithelium. All treated mice had hydrocephalus, but no other pathology was demonstrable by light microscopy. By electron microscopy, dramatic expansion of the extracellular space between choroid plexus epithelial cells was observed. Dendrites in the neuropil of the hypothalamus and septum exhibited vacuoles and membranous debris. Based on the Bi distribution and lesions, we propose that diffusion of Bi from fenestrated blood vessels contributes to pathogenesis of neurotoxicity in mice. This proposal is consistent with the clinical features of Bi-related neurotoxicity in humans.
一小部分摄入含铋（Bi）药物的人会出现神经毒性，其中神经精神症状先于运动功能障碍出现。大剂量腹腔注射硝酸铋（BSN）会在小鼠身上产生类似症状，但对于这两个物种中神经毒性的发病机制知之甚少。成年雌性瑞士韦伯斯特小鼠接受了神经毒性剂量（2500 mg/kg腹腔注射）的BSN。铋的分布和神经病理学检测如下：（1）给药28天后，通过原子吸收光谱法（AAS）检测中枢和外周神经系统区域的铋含量；（2）给药28天后，通过自动金相显微镜在组织切片中显示脑内铋的区域分布；（3）给药后1天、3天、7天以及2周、3周、4周和5周，通过光镜和电镜技术评估血脑屏障状态和神经病理学效应。通过AAS检测，嗅球（约7 ppm）、下丘脑（约7 ppm）、隔区（约3 ppm）和脑干（约3 ppm）中的铋含量最高。纹状体和大脑皮层中的铋含量最少（约1 ppm）。自动金相显微镜的区域分布显示，高铋含量与铋从室周器官和嗅上皮的有窗孔血管扩散有关。所有接受治疗的小鼠都有脑积水，但光镜下未发现其他病变。通过电镜观察，脉络丛上皮细胞之间的细胞外间隙显著扩大。下丘脑和隔区神经毡中的树突出现空泡和膜性碎片。基于铋的分布和病变情况，我们认为铋从有窗孔血管的扩散是小鼠神经毒性发病机制的原因。这一观点与人类铋相关神经毒性的临床特征相符。
