Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, Illinois 61801.
Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, Illinois 61801.
J Neurosci. 2023 Jun 21;43(25):4580-4597. doi: 10.1523/JNEUROSCI.0030-23.2023. Epub 2023 May 5.
Exposure to combinations of environmental toxins is growing in prevalence; and therefore, understanding their interactions is of increasing societal importance. Here, we examined the mechanisms by which two environmental toxins, polychlorinated biphenyls (PCBs) and high-amplitude acoustic noise, interact to produce dysfunction in central auditory processing. PCBs are well established to impose negative developmental impacts on hearing. However, it is not known whether developmental exposure to this ototoxin alters the sensitivity to other ototoxic exposures later in life. Here, male mice were exposed to PCBs in utero, and later as adults were exposed to 45 min of high-intensity noise. We then examined the impacts of the two exposures on hearing and the organization of the auditory midbrain using two-photon imaging and analysis of the expression of mediators of oxidative stress. We observed that developmental exposure to PCBs blocked hearing recovery from acoustic trauma. two-photon imaging of the inferior colliculus (IC) revealed that this lack of recovery was associated with disruption of the tonotopic organization and reduction of inhibition in the auditory midbrain. In addition, expression analysis in the inferior colliculus revealed that reduced GABAergic inhibition was more prominent in animals with a lower capacity to mitigate oxidative stress. These data suggest that combined PCBs and noise exposure act nonlinearly to damage hearing and that this damage is associated with synaptic reorganization, and reduced capacity to limit oxidative stress. In addition, this work provides a new paradigm by which to understand nonlinear interactions between combinations of environmental toxins. Exposure to common environmental toxins is a large and growing problem in the population. This work provides a new mechanistic understanding of how the prenatal and postnatal developmental changes induced by polychlorinated biphenyls (PCBs) could negatively impact the resilience of the brain to noise-induced hearing loss (NIHL) later in adulthood. The use of state-of-the-art tools, including multiphoton microscopy of the midbrain helped in identifying the long-term central changes in the auditory system after the peripheral hearing damage induced by such environmental toxins. In addition, the novel combination of methods employed in this study will lead to additional advances in our understanding of mechanisms of central hearing loss in other contexts.
暴露于多种环境毒素的情况日益普遍，因此，了解它们的相互作用对社会具有越来越重要的意义。在这里，我们研究了两种环境毒素，多氯联苯（PCBs）和高声强噪声，相互作用导致中枢听觉处理功能障碍的机制。PCBs 已被证实对听力产生负面影响。然而，尚不清楚在发育过程中接触这种耳毒素是否会改变成年后对其他耳毒性暴露的敏感性。在这里，雄性小鼠在子宫内接触 PCBs，然后在成年后暴露于 45 分钟的高强度噪声。然后，我们使用双光子成像和氧化应激介质表达分析来检查两种暴露对听力和听觉中脑组织的影响。我们观察到，发育过程中接触 PCBs 会阻止声创伤后的听力恢复。对下丘脑中脑（IC）的双光子成像显示，这种恢复的缺失与听觉中脑的调谐组织破坏和抑制减少有关。此外，下丘脑中的表达分析表明，GABA 能抑制减少在氧化应激缓解能力较低的动物中更为明显。这些数据表明，PCBs 和噪声联合暴露以非线性方式损害听力，并且这种损害与突触重组以及限制氧化应激的能力降低有关。此外，这项工作提供了一个新的范例，用于理解环境毒素组合之间的非线性相互作用。暴露于常见环境毒素是人群中一个庞大且日益严重的问题。这项工作提供了一个新的机制理解，多氯联苯（PCBs）引起的产前和产后发育变化如何对成年后因噪声引起的听力损失（NIHL）的大脑弹性产生负面影响。使用最先进的工具，包括中脑的多光子显微镜，有助于确定由这种环境毒素引起的外周听力损伤后听觉系统的长期中枢变化。此外，本研究中采用的新颖组合方法将导致我们在其他情况下对中枢听力损失机制的理解的进一步进展。
