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: 7239661
• 负责人: DONALD A FOX
• 金额: $ 30.1万
• 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 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7239661
• 关键词: 10 year old; Adult; Adverse effects; Affect; Age; Animals; Apoptosis; Apoptotic; Auditory; Binding; Biochemical; Cell Death; Centers for Disease Control and Prevention (U.S.); Child; Cognitive deficits; Cyclic GMP; Data; Development; Dopamine; Dose; Electroretinography; First Pregnancy Trimester; Functional disorder; Gene Expression; Genes; Goals; Health; Human; Hydrolysis; Impairment; Kinetics; Lead; Leucine; Ligands; Light; Long-Term Effects; Measures; Mediating; Messenger RNA; Modeling; Molecular; Neonatal; Neurons; Neurotoxins; Nuclear Extract; Numbers; Perinatal; Photoreceptors; Pregnancy; Proteins; Rate; Rattus; Receptor Signaling; Reporting; Research; Research Design; Retina; Retinal; Retinal Cone; Risk; Signal Pathway; Staging; TNFRSF1B gene; Testing; Toxic effect; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-Beta; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Tyrosine 3-Monooxygenase; Vision; blood Pb concentration; blood lead; cognitive function; critical developmental period; day; dopaminergic neuron; enzyme activity; fetal lead exposure; human TNF protein; immunoreactivity; lead exposure; lead retinotoxic effect; mRNA Expression; man; molecular site; neurotoxicity; phosphoric diester hydrolase; postnatal; prenatal; promoter; protein expression; relating to nervous system; research study; response; retinal neuron; retinal rods; transcription factor; visual motor; visual-motor integration

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（由申请方提供）：铅是一种普遍存在的强效神经毒物，在人类和动物发育期和成年期暴露于铅后，会导致持续性、浓度依赖性视网膜、视觉运动、听觉和认知缺陷。在美国，大约有200万幼儿的血液[Pb]等于或大于10 μ g/dL，这是目前公认的“安全”水平，还有数百万儿童的血液[Pb]水平为2.5-10 μ g/dL，这使他们面临这些不良健康影响的风险。出生后血[Pb]等于或>20 μ g/dL产生亚正常视杆细胞介导的视网膜电图（ERG）。相反，最近的研究结果表明，7-10岁的儿童与低水平（血[铅]从4-14微克/分升）妊娠期和连续出生后铅暴露具有独特的超常杆介导的ERG，其特征是增加a波振幅，b波振幅和敏感性。 本研究的总体目标是确定在怀孕期间暴露于低水平铅的儿童的视网膜电图超常的位点和分子机制。我们开发了一种新的低水平妊娠期铅暴露大鼠模型（血液[Pb]为8-12 μ g/dL），在成年大鼠中产生类似的持续性超常视杆细胞介导的ERG。拟议的研究旨在验证以下假设：围产期发育期间铅暴露通过改变视杆细胞a波视杆cGMP水解的主要机制以及通过改变b波振幅和敏感性的多巴胺能调制输入来产生ERG超正常。具体而言，我们将确定围产期铅暴露是否：1）分别通过视杆细胞和内部视网膜神经元的独立变化引起持续性超常ERG a-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-亚基启动子的结合来降低视杆细胞cGMP水解的稳态速率，和3）产生TNF-α介导的凋亡性细胞死亡和多巴胺能视网膜神经元的功能障碍，这是由大鼠低水平围产期铅暴露后测量的视网膜TNF-α水平升高引起的。 这些功能（ERG）、生物化学、分子和免疫细胞化学研究的结果将：1）确定视杆细胞介导的ERG超常的机制，2）确定妊娠发育期间视网膜（神经）脆弱性的关键期，3）提供关于低水平铅暴露的基本神经毒性数据，这越来越受到科学和监管的关注。