Low-Level Prenatal Lead Exposure and Retinal Toxicity

低水平的产前铅暴露和视网膜毒性

• 批准号: 6675071
• 负责人: DONALD A FOX
• 金额: $ 30.59万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-07 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6675071
• 关键词: cyclic GMP; electroretinography; embryo /fetus toxicology; environmental exposure; enzyme linked immunosorbent assay; gel mobility shift assay; high performance liquid chromatography; hydrolysis; immunocytochemistry; laboratory rat; lead poisoning; neurotoxicology; perinatal; phosphodiesterases; prenatal stress; retinal ganglion; rod cell; transcription factor; tumor necrosis factor alpha; western blottings

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.

描述（由申请人提供）：铅是一种普遍存在的强效神经毒物，在人类和动物发育和成年期间接触铅后，会产生持续的、浓度依赖性的视网膜、视觉运动、听觉和认知缺陷。在美国，大约 200 万幼儿的血液 [Pb] 等于或 >10 μg/dL（目前公认的“安全”水平），还有数百万人的血液 [Pb] 水平为 2.5-10 μg/dL，这使他们面临这些不利健康影响的风险。出生后血液 [Pb] 等于或 >20 mu g/dL 会产生低于正常的视杆介导的视网膜电图 (ERG)。相比之下，最近的结果表明，妊娠期低水平（血液[Pb]为4-14μg/dL）和连续产后铅暴露的7-10岁儿童具有独特的超正常杆介导ERG，其特征是a波幅度、b波幅度和敏感性增加。 本研究的总体目标是确定妊娠期间接触低水平铅的儿童 ERG 超正常的位点和分子机制。我们开发了一种新的低水平妊娠铅暴露大鼠模型（血液[Pb]为8-12μg/dL），该模型在成年大鼠中产生类似的持续超正常杆介导的ERG。拟议的研究旨在检验以下假设：围产期发育期间的铅暴露通过改变视杆光感受器 a 波视杆 cGMP 水解的主要机制以及通过改变 b 波幅度和敏感性下的多巴胺能调制输入来产生 ERG 超常性。具体来说，我们将确定围产期铅暴露是否：1）分别通过视杆细胞和视网膜内神经元的独立变化引起持续超正常的ERG a波和b波，2）通过抑制任何关键转录因子与视杆细胞cGMP磷酸二酯酶β亚基启动子的结合，降低视杆细胞cGMP水解的稳态速率，以及3）产生 大鼠围产期低水平铅暴露后测得的视网膜 TNF-α 水平升高，导致 TNF-α 介导的细胞凋亡和多巴胺能视网膜神经元功能障碍。 这些功能性（ERG）、生物化学、分子和免疫细胞化学研究的结果将：1）确定视杆介导的ERG超常性的潜在机制，2）确定妊娠发育过程中视网膜（神经）脆弱性的关键时期，3）提供关于低水平铅暴露的重要神经毒性数据，这引起了越来越多的科学和监管关注。