Ibrahim Baher A, Louie Jeremy, Shinagawa Yoshitaka, Xiao Gang, Asilador Alexander R, Sable Helen J K, Schantz Susan L, Llano Daniel A
Department of Molecular & Integrative Physiology, the University of Illinois Urbana-Champaign, Urbana, IL 61801, USA.
Beckman Institute for Advanced Science & Technology, the University of Illinois Urbana-Champaign, Urbana, IL 61801, USA.
bioRxiv. 2023 Mar 25:2023.03.23.534008. doi: 10.1101/2023.03.23.534008.
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 if 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 minutes 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. In vivo two-photon imaging of the inferior colliculus 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 pre-and postnatal developmental changes induced by polychlorinated biphenyls could negatively impact the resilience of the brain to noise-induced hearing loss later in adulthood. The use of state-of-the-art tools, including in vivo 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.
环境毒素组合的暴露情况在人群中日益普遍，因此了解它们之间的相互作用对社会的重要性与日俱增。在此，我们研究了两种环境毒素——多氯联苯（PCBs）和高强度噪声——相互作用导致中枢听觉处理功能障碍的机制。多氯联苯对听力发育具有负面影响已得到充分证实。然而，尚不清楚发育过程中接触这种耳毒素是否会改变个体在生命后期对其他耳毒性暴露的敏感性。在此，雄性小鼠在子宫内接触多氯联苯，成年后再暴露于45分钟的高强度噪声中。然后，我们使用双光子成像和氧化应激介质表达分析，研究了这两种暴露对听力以及听觉中脑组织结构的影响。我们观察到，发育过程中接触多氯联苯会阻碍听力从声创伤中恢复。对下丘进行的体内双光子成像显示，这种恢复受阻与音调组织的破坏以及听觉中脑抑制作用的减弱有关。此外，在下丘进行的表达分析表明，在减轻氧化应激能力较低的动物中，γ-氨基丁酸能抑制作用的降低更为明显。这些数据表明，多氯联苯和噪声联合暴露以非线性方式损害听力，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，用以理解环境毒素组合之间的非线性相互作用。
接触常见环境毒素在人群中是一个日益严重且不断扩大的问题。这项工作提供了一种新的机制理解，即多氯联苯引起的产前和产后发育变化如何在成年后期对大脑抵抗噪声诱导的听力损失的恢复能力产生负面影响。使用包括中脑体内多光子显微镜在内的先进工具，有助于识别此类环境毒素引起外周听力损伤后听觉系统的长期中枢变化。此外，本研究采用的新颖方法组合将推动我们在其他情况下对中枢性听力损失机制的理解取得进一步进展。
