Low-Level Prenatal Lead Exposure and Retinal Toxicity

描述(申请人提供)：铅是一种普遍而有效的神经毒物，在发育和成年期暴露于铅后，会对人和动物产生持续性的、浓度依赖的视网膜、视觉运动、听觉和认知障碍。在美国，大约有200万儿童的血铅水平等于或等于10微克/分升，这是目前公认的“安全”水平，还有数百万儿童的血铅水平为2.5-10微克/分升，这使他们面临这些不利健康影响的风险。出生后血[铅]等于或&gt；20mUg/dL会产生低于正常的视杆细胞介导的视网膜电信号(ERG)。相比之下，最近的结果显示，孕期和出生后持续铅暴露的7-10岁儿童(血铅水平从4-14微克/分升)具有独特的超常视杆介导的ERG，其特征是a波振幅、b波振幅和灵敏度增加。 这项研究的总体目标是确定孕期接触低水平铅的儿童ERG异常的部位和分子机制。我们建立了一种新的低水平孕期铅暴露大鼠模型(血铅浓度为8-12mU/dL)，在成年大鼠中产生类似持续超常的视杆介导的ERG。这项拟议的研究旨在通过改变视杆光感受器a波视杆cGMP水解的主要机制以及改变b波幅度和敏感度背后的多巴胺能调制输入，来检验围产期暴露于铅会导致ERG异常的假说。具体地说，我们将确定围产期铅暴露是否：1)通过视杆细胞和视网膜内神经元的独立变化分别导致持续异常的ERGa波和b波；2)通过抑制任何关键转录因子与视杆cGMP磷酸二酯酶β亚单位启动子的结合而降低视杆cGMP水解率；以及3)导致肿瘤坏死因子-α介导的细胞凋亡和视网膜多巴胺能神经元功能障碍，从而导致围产期低水平铅暴露后视网膜组织中肿瘤坏死因子-α水平的升高。 这些功能(ERG)、生化、分子和免疫细胞化学研究的结果将：1)确定视杆介导的ERG异常的机制；2)确定妊娠发育期间视网膜(神经)脆弱的关键期；3)提供有关低水平铅暴露的基本神经毒性数据，这是科学和监管日益关注的问题。

DESCRIPTION (provided by applicant): Lead is a pervasive and potent neurotoxicant that produces persistent, concentration-dependent retinal, visual-motor, auditory and cognitive deficits in man and animals following exposure during development and adulthood. Approximately 2 million young children in the USA have blood [Pb] equal to or >10 mu g/dL, the currently accepted "safe" level, and millions more have levels of 2.5-10 mu g/dL, which place them at risk for these adverse health effects. Postnatal blood [Pb] equal to or >20 mu g/dL produce SUBNORMAL rod-mediated electroretinograms (ERGs). In contrast, recent results reveal that 7-10 year old children with low-level (blood [Pb] from 4-14 mu g/dL) gestational and continuous postnatal lead exposure have unique SUPERNORMAL rodmediated ERGs characterized by increases in a-wave amplitude, b-wave amplitude and sensitivity. The overall objective of this research is to determine the sites and molecular mechanisms underlying ERG supernormality in children exposed to low-level lead during gestation. We developed a new rat model of lowlevel gestational lead exposure (blood [Pb] of 8-12 mu g/dL) that produces similar persistent supernormal rodmediated ERGs in adult rats. The proposed studies are designed to test the hypothesis that lead exposure during perinatal development produces ERG supernormality by altering the primary mechanism underlying the rod photoreceptor a-wave rod cGMP hydrolysis - and by altering the dopaminergic-modulated input underlying the b-wave amplitude and sensitivity. Specifically, we will determine whether perinatal lead exposure: 1) causes persistent supernormal ERG a- and b-waves by independent changes in rods and inner retinal neurons, respectively, 2) decreases the steady-state rate of rod cGMP hydrolysis by inhibiting the binding of any of the critical transcription factors to the rod cGMP phosphodiesterase beta-subunit promoter, and 3) produces TNF-alpha-mediated apoptotic cell death and dysfunction of dopaminergic retinal neurons resulting from the elevated retinal TNF-alpha levels measured following low-level perinatal lead exposure in rats. The results from these functional (ERG), biochemical, molecular and immunocytochemical studies will: 1) determine the mechanisms underlying the rod-mediated ERG supernormality, 2) establish the critical period of retinal (neural) vulnerability during gestational development and 3) provide essential neurotoxicity data on low-levels of lead exposure that is of increasing scientific and regulatory concern.