Serrano-Civantos M, Beraza E, Álvarez-Erviti L, de Cerain A López, Vettorazzi A
Department of Pharmaceutical Sciences, MITOX Research Group, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain.
Laboratory of Molecular Neurobiology, Center for Biomedical Research of La Rioja (CIBIR), Piqueras 98, 26006, Logroño, Spain.
Arch Toxicol. 2025 May;99(5):1769-1790. doi: 10.1007/s00204-025-03994-5. Epub 2025 Mar 6.
Ochratoxin A (OTA) is a mycotoxin produced by Aspergillus and Penicillium species that contaminates various food and feed products, presenting potential risks to human health. While OTA is well-known for its nephrotoxic effects, emerging evidence highlights its neurotoxic potential. Parkinson's disease (PD) is a neurodegenerative disorder with both genetic and environmental aetiologies. Emerging lines of investigation have focused their research on the role of environmental toxins, including mycotoxins, in PD pathogenesis. However, the specific involvement of OTA in PD-related pathways still needs to be unravelled. This systematic review compiles and evaluates OTA neurotoxicity studies according to the adverse outcome pathway (AOP) for PD, established by the Organisation for Economic Cooperation and Development (OECD). The AOP framework outlines a series of key event (KEs) beginning with mitochondrial Complex I (CI) inhibition and progressing through mitochondrial dysfunction, impaired proteostasis, dopaminergic neuron degeneration, neuroinflammation, and resulting in parkinsonian motor deficits. In this systematic review, a comprehensive literature search was conducted in PubMed, to identify studies evaluating OTA neurotoxic effects. Using a search strategy of 19 terms and following a two-phased study selection, 30 relevant studies were retrieved, of which 16 dealt with in vitro adult neurotoxicity (ANT), 13 focused on in vivo ANT, and 1 gave both in vitro and in vivo approaches. Authors agree that in vitro and in vivo exposure to OTA causes mitochondrial dysfunction, impaired proteostasis, degeneration of dopaminergic (DA) neurons, and neuroinflammation. However, a notable absence of research remains on the molecular initiating event (MIE), binding to CI, and on KE1, inhibition of CI. This review identifies critical research gaps and highlights the need for further mechanistic studies on the impact of OTA on neurodegenerative pathways, particularly its binding and inhibition of CI, as well as mechanisms related to KE3: impaired proteostasis. Addressing these gaps may provide valuable insights into OTA neurotoxic potential and its relevance in PD-like neurodegeneration.
赭曲霉毒素A（OTA）是一种由曲霉属和青霉属产生的霉菌毒素，可污染各种食品和饲料产品，对人类健康构成潜在风险。虽然OTA以其肾毒性作用而闻名，但新出现的证据凸显了其神经毒性潜力。帕金森病（PD）是一种具有遗传和环境病因的神经退行性疾病。新的研究方向将研究重点放在了环境毒素（包括霉菌毒素）在PD发病机制中的作用上。然而，OTA在PD相关通路中的具体作用仍有待阐明。本系统综述根据经济合作与发展组织（OECD）建立的PD不良结局途径（AOP），汇编并评估了OTA神经毒性研究。AOP框架概述了一系列关键事件（KEs），从线粒体复合体I（CI）抑制开始，经过线粒体功能障碍、蛋白稳态受损、多巴胺能神经元变性、神经炎症，最终导致帕金森运动功能障碍。在本系统综述中，我们在PubMed中进行了全面的文献检索，以识别评估OTA神经毒性作用的研究。采用19个检索词的检索策略并经过两阶段的研究筛选，共检索到30项相关研究，其中16项涉及体外成人神经毒性（ANT），13项聚焦于体内ANT，1项同时采用了体外和体内研究方法。作者一致认为，体外和体内暴露于OTA会导致线粒体功能障碍、蛋白稳态受损、多巴胺能（DA）神经元变性和神经炎症。然而，关于分子起始事件（MIE）、与CI的结合以及KE1（CI抑制）的研究仍然明显缺乏。本综述确定了关键的研究空白，并强调需要进一步开展关于OTA对神经退行性通路影响的机制研究，特别是其与CI的结合和抑制，以及与KE3（蛋白稳态受损）相关的机制。填补这些空白可能会为OTA的神经毒性潜力及其在PD样神经退行性变中的相关性提供有价值的见解。
