Takesono Aya, Kudoh Tetsuhiro, Tyler Charles R
Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom.
Front Pharmacol. 2022 Feb 11;13:718072. doi: 10.3389/fphar.2022.718072. eCollection 2022.
Endocrine disrupting chemicals (EDCs) are environmental pollutants that mimic hormones and/or disrupt their function. Estrogenic EDCs (eEDCs) interfere with endogenous estrogen signalling pathway(s) and laboratory animal and human epidemiological studies have provided evidence for a causal link between exposure to them during embryonic/early life and neurological impairments. However, our understanding of the molecular and cellular mechanism(s) underlying eEDCs exposure effects on brain development, tissue architecture and function and behaviour are limited. Transgenic (TG) zebrafish models offer new approach methodologies (NAMs) to help identify the modes of action (MoAs) of EDCs and their associated impacts on tissue development and function. Estrogen biosensor TG zebrafish models have been applied to study eEDC interactions and resulting transcriptional activation ( a fluorescent reporter expression) across the entire body of the developing zebrafish embryo, including in real time. These estrogen biosensor TG zebrafish models are starting to deepen our understanding of the spatiotemporal actions of eEDCs and their resulting impacts on neurological development, brain function and behaviour. In this review, we first investigate the links between early life exposure to eEDCs and neurodevelopmental alterations in model organisms (rodents and zebrafish) and humans. We then present examples of the application of estrogen biosensor and other TG zebrafish models for elucidating the mechanism(s) underlying neurodevelopmental toxicities of eEDCs. In particular we illustrate the utility of combining estrogen biosensor zebrafish models with other TG zebrafish models for understanding the effects of eEDCs on the brain, spanning cellular processes, brain circuitry, neurophysiology and behaviour. Finally, we discuss the future prospects of TG zebrafish models as experimental models for studying more complex scenarios for exposure to contaminant mixtures on neurological development and function.
内分泌干扰化学物质（EDCs）是一类环境污染物，它们能够模拟激素和/或干扰激素的功能。具有雌激素活性的EDCs（eEDCs）会干扰内源性雌激素信号通路，实验室动物和人类流行病学研究已提供证据，证明在胚胎期/生命早期接触这些物质与神经损伤之间存在因果关系。然而，我们对eEDCs暴露影响大脑发育、组织结构和功能以及行为的分子和细胞机制的了解有限。转基因（TG）斑马鱼模型提供了新的方法学（NAMs），有助于确定EDCs的作用模式（MoAs）及其对组织发育和功能的相关影响。雌激素生物传感器TG斑马鱼模型已被用于研究eEDCs在发育中的斑马鱼胚胎全身的相互作用以及由此产生的转录激活（荧光报告基因表达），包括实时监测。这些雌激素生物传感器TG斑马鱼模型开始加深我们对eEDCs的时空作用及其对神经发育、脑功能和行为的影响的理解。在这篇综述中，我们首先研究了在模型生物（啮齿动物和斑马鱼）以及人类中，生命早期接触eEDCs与神经发育改变之间的联系。然后，我们列举了雌激素生物传感器和其他TG斑马鱼模型在阐明eEDCs神经发育毒性潜在机制方面的应用实例。特别是，我们阐述了将雌激素生物传感器斑马鱼模型与其他TG斑马鱼模型相结合，对于理解eEDCs对大脑的影响（涵盖细胞过程、脑回路、神经生理学和行为）的实用性。最后，我们讨论了TG斑马鱼模型作为实验模型在研究更复杂的污染物混合物暴露对神经发育和功能影响场景方面的未来前景。
