Fox D A, Srivastava D, Hurwitz R L
College of Optometry, University of Houston, Texas 77204-6052.
Neurotoxicology. 1994 Fall;15(3):503-12.
Long-term scotopic (rod-mediated) visual deficits following developmental lead exposure occur in monkeys and hooded rats. This report describes and summarizes previous ERG and biochemical findings, presents new biochemical data aimed at determining the mechanism of inhibition of lead on rod cGMP-PDE, presents an integratory framework for understanding the ERG and cGMP results and speculates on the implications of the present data. A- and b-wave voltage-log intensity and latency-log intensity functions, generated from single-flash ERGs in fully dark-adapted rats, revealed that low and moderate level lead exposure caused decreases in absolute sensitivity and amplitude, and increases in latency. Rod- and cone-mediated flicker fusion frequency measures revealed selective rod deficits in temporal resolution. In addition, the slope of the increment threshold function was decreased, but only at scotopic adapting backgrounds, and dark adaptation was delayed. Prior exposure to lead produced a dose-response inhibition of retinal cGMP-phosphodiesterase (PDE) resulting in an increase in cGMP in dark-adapted and light-adapted states and an increase in the calcium content of rods. In vitro experiments with adult rat retinas incubated with 10(-9) to 10(-4) M Pb2+ revealed a concentration-dependent inhibition of cGMP-PDE which suggested that Pb2+ directly inhibited the rod cGMP-PDE. This was confirmed in experiments conducted with isolated, purified, trypsin-activated bovine rod cGMP-specific PDE exposed to 5 x 10(-8) to 10(-4) M Pb2+. The cGMP data are entirely consistent with the observed ERG changes. The ERG data is relevant to low level pediatric lead poisoning since rat rods are similar to human rods. Finally, since a lesion in the gene that codes for a cAMP-PDE leads to defective learning and memory in the Drosophila dunce flies, it is possible that lead-induced alterations in cyclic nucleotide phosphodiesterases contribute to the long-term CNS deficits produced by developmental lead exposure.
发育过程中铅暴露后，猴子和长爪沙鼠会出现长期暗视（视杆介导）视觉缺陷。本报告描述并总结了先前的视网膜电图（ERG）和生化研究结果，提供了旨在确定铅对视杆细胞环磷酸鸟苷磷酸二酯酶（cGMP-PDE）抑制机制的新生化数据，提出了一个综合框架以理解ERG和cGMP结果，并对当前数据的意义进行了推测。从完全暗适应的大鼠单次闪光ERG产生的a波和b波电压-对数强度以及潜伏期-对数强度函数显示，低水平和中等水平的铅暴露会导致绝对敏感性和振幅降低，潜伏期增加。视杆和视锥介导的闪烁融合频率测量显示在时间分辨率上存在选择性视杆缺陷。此外，增量阈值函数的斜率降低，但仅在暗视适应背景下，并且暗适应延迟。先前的铅暴露对视网膜cGMP-磷酸二酯酶（PDE）产生剂量反应性抑制，导致暗适应和明适应状态下cGMP增加以及视杆细胞钙含量增加。用10^(-9)至10^(-4) M Pb2+孵育成年大鼠视网膜的体外实验显示cGMP-PDE受到浓度依赖性抑制，这表明Pb2+直接抑制视杆细胞cGMP-PDE。在分离、纯化、胰蛋白酶激活的牛视杆细胞特异性cGMP-PDE暴露于5×10^(-8)至10^(-4) M Pb2+的实验中得到了证实。cGMP数据与观察到的ERG变化完全一致。由于大鼠视杆细胞与人视杆细胞相似，ERG数据与低水平儿童铅中毒相关。最后，由于编码cAMP-PDE的基因损伤会导致果蝇“笨蛋”果蝇学习和记忆缺陷，铅诱导的环核苷酸磷酸二酯酶改变可能导致发育过程中铅暴露产生的长期中枢神经系统缺陷。
