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

描述(申请人提供)：听力损失-一种影响全球数亿人的非常常见的疾病-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、心理和职业后果有关。它还对儿童的学习结果和智力发展产生重大影响。听力损失的一个潜在的重要原因是暴露在环境污染物中，特别是重金属。一项有限但极具启发性的研究表明，暴露于铅(Pb)和镉(Cd)--这两种在美国和世界各地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，目前还没有确定接触重金属和听力损失之间的因果联系。此外，环境污染物(如有机溶剂)的不利影响可能会因同时暴露在噪声中而加剧，而噪声存在于许多受重金属污染的环境中。对于铅和镉，这种相互作用还没有被探索过。这项拟议的研究将在一个广为人知的动物模型(CBA/J小鼠)中评估和量化铅和镉暴露与听力损害的关系。第一种假设是，铅和镉的暴露将与听力和前庭损伤的风险有关。为了评估这一假设，我们将把不同剂量的小鼠暴露在饮用水中，为期8周，达到污染地区人类常见的血清水平。我们将通过听性脑干反应(ABR)和失真产物耳声发射(DPOAEs)来定量评估动物在基线以及暴露期间的中点和末期的听阈。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，以计数耳蜗损伤，并将分析听骨和其他选定骨骼中的铅水平，作为铅暴露的额外衡量标准。第二个假设是，噪声和铅或镉的结合会导致比单独暴露在噪声或金属中更严重的听力损失。为了评估这些制剂的协同或相加效应，我们将测量单独或与铅或镉联合暴露所造成的听觉缺陷。该项目涉及NIDCD的两个重点领域(听力损失和平衡)；这些领域的健康改善，例如拟议中的工作最终可能产生的结果，也是健康人2020计划的目标。拟议研究中试点数据的成功收集将导致随后将R01应用于NIDCD。这项研究的结果可能有助于指导未来的公共卫生干预措施，旨在通过减少环境中的重金属暴露来减轻听力损失的负担。

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.