Pilot assessment of the effects of noise, lead, and cadmium on hearing in mice

描述（由申请人提供）：听力损失是影响全球数亿人的一种非常常见的疾病，对人类健康和生活质量产生重大不利影响，并与各种不利的社会、心理和职业后果相关。它还对儿童的学习成果和智力发展产生重大影响。听力损失的一个潜在重要但尚未得到充分研究的原因是暴露于环境污染物，特别是重金属。一项有限但极具启发性的研究表明，接触铅（Pb）和镉（Cd）——这两种在美国和世界范围内都是常见的环境污染物——可能与听力损失的风险增加有关。然而，目前还没有发现重金属暴露与听力损失之间的因果关系。此外，环境污染物（例如有机溶剂）的不利影响可能会因同时暴露于许多被重金属污染的环境中存在的噪音而加剧。目前还没有研究过铅和镉之间的相互作用。该研究将在一个已知的动物模型（CBA/J小鼠）中评估和量化铅和镉暴露与听力损伤之间的关系。第一种假设是，接触铅和镉会有听力和前庭损伤的风险。为了评估这一假设，我们将几组幼鼠暴露于饮用水中不同剂量的铅或镉，持续8周，达到污染地区人类血清中常见的水平。我们将通过听觉脑干反应（ABR）和畸变产物耳声发射（dpoae）定量评估动物在基线、中点和暴露期结束时的听觉阈值。我们还将在同一时间点评估前庭功能。在研究结束时，我们将进行耳蜗毛细胞计数，以列举耳蜗损伤，并将分析听骨和其他选定骨骼中的铅水平，作为铅暴露的额外措施。第二个假设是，噪音和铅或镉的结合比单独暴露在噪音或金属环境中会导致更严重的听力损失。为了评估这些物质的协同效应或叠加效应，我们将测量单独暴露于噪音或与铅或镉结合造成的听觉缺陷。该项目涉及NIDCD的两个重点领域（听力损失和平衡）；改善这些领域的健康状况，例如可能最终从拟议的工作中获得的健康状况，也是“健康人2020”方案的目标。在建议的研究中成功收集试验数据，将导致随后向NIDCD申请R01。这项研究的结果可能有助于指导未来旨在通过减少重金属环境暴露来减轻听力损失负担的公共卫生干预措施。

DESCRIPTION (provided by applicant): Hearing loss - a very common condition affecting hundreds of millions of people globally - has substantial adverse impact on human health and quality of life, and is associated with a wide variety of adverse social, psychological, and occupational consequences. It also has a substantial impact on learning outcomes and intellectual development in children. A potentially important but not well-researched cause of hearing loss is exposure to environmental contaminants, and in particular heavy metals. A limited but highly suggestive body of research suggests that exposures to lead (Pb) and cadmium (Cd) - both common environmental contaminants in the United States and worldwide - may be associated with an increased risk of hearing loss. However, no causal link has yet been established between exposure to heavy metals and hearing loss. Moreover, adverse effects of environmental contaminants (e.g., organic solvents) can be aggravated by concurrent exposure to noise which is present in many environments contaminated with heavy metals. Such interactions have not been explored for Pb or Cd. The proposed study will evaluate and quantify, in a well- understood animal model (CBA/J mice), the relationship between Pb and Cd exposure and hearing damage. The first hypothesis is that exposure to Pb and Cd will be associated with a risk of hearing and vestibular damage. To evaluate this hypothesis we will expose groups of young mice to varying doses of Pb or Cd in their drinking water for a period of 8 weeks, achieving serum levels commonly found in humans in contaminated areas. We will quantitatively evaluate animals' auditory thresholds at baseline and at the midpoint and end of the exposure period via Auditory Brainstem Response (ABR) and Distortion Product Otoacoustic Emissions (DPOAEs). We will also evaluate vestibular function at the same time points. At the conclusion of the study we will conduct cochlear hair cell counts to enumerate cochlear damage, and will analyze Pb levels in the ossicles and other selected bones as an additional measure of Pb exposure. The second hypothesis is that a combination of noise and Pb or Cd will result in a greater hearing loss than exposure to noise or metals alone. To evaluate synergistic or additive effects of these agents we will measure auditory deficits resulting from noise exposure alone or in combinations with Pb or Cd. This project addresses two of NIDCD's focus areas (hearing loss and balance); improvements in health in these areas, such as those that might ultimately results from the proposed work, are also goals of the Healthy People 2020 program. Successful collection of pilot data in the proposed study will result in a subsequent R01 application to NIDCD. The results of this study may help guide future public health interventions designed to reduce the burden of hearing loss through reductions in environmental exposures to heavy metals.