钟基因在双酚A所致斑马鱼发育毒性中的作用及机制研究

BPA is one of the most important EDCs, possibly inducing the developmental toxicity through multi-mechanisms. Circadian rhythms are the approximate 24-hour oscillations in behavioural or physiological processes that allow organisms to anticipate routine environmental changes and prepare for the appropriate alignment in order to adapt. Our previous study had shown that circadian clocks could be disturbed by EDCs. To explore the role of circadian clocks in BPA-induced the developmental toxicity, circadian clocks knockout zebrafish will be constructed. The spatial and temporal expression of circadian clocks will be investigated using this model. In addition, the relationship between developmental toxity phenotype in zebrafish and window period of BPA exposure will be explored. The methylation of circadian genes will be analyzed to reveal the underlying molecular mechanism. The purpose of this study is to explore the role of circadian clocks in BPA induced developmental toxity and possible epigenetic mechanisms. The results will help provide insights into the metabolism of BPA and the subsequent developmental toxicity, and give novel clues to the prevention and control of environmental pollutant-induced biological damages as well.

双酚A（BPA）是一种常见的环境内分泌干扰物， 可能通过多种机制导致发育毒性。从简单的单细胞细菌到复杂的人都呈现以大约24 小时为周期的生物节律, 即生物钟，它在维持各种基本的生命过程中发挥重要的作用。我们前期研究发现钟基因易受环境内分泌干扰物的调控。为此，本研究在构建斑马鱼钟基因敲除模型的基础上，通过研究钟基因的时空表达谱、BPA暴露窗口期与斑马鱼发育毒性的表型、钟基因甲基化状态及调控靶点，以新的视角系统审视钟基因在BPA引起发育毒性的作用及机制，为预防BPA的生殖发育危害、保护人群健康提供重要参考。

双酚A（BPA）是一种常见的环境内分泌干扰物，可能通过多种机制导致发育毒性。本研究在构建斑马鱼钟基因clock敲除模型的基础上揭示BPA可以通过ER介导作用，激活clock1a基因的表达，通过上调clock1a-PI3k/AKT-Nrf2/ARE通路诱导细胞的抗氧化、抗凋亡等保护机制，部分拮抗了BPA的毒性作用。此外还发现BPA对斑马鱼胚胎运动行为敏感期为卵裂期到体节期（1-24 hpf），BPA可以通过下调卵裂期到体节期（1-24 hpf）cypin mRNA的表达来介导神经毒性，并对斑马鱼的运动行为产生影响。BPA胚胎期暴露可以干扰斑马鱼自发运动节律，影响的敏感期为孵化期（48-72 hpf）。通钟基因NR1D1与氧化还原过程对斑马鱼孵化期（48-72 hpf）节律紊乱存在一定的联系。该研究，以新的视角系统审视钟基因在BPA引起发育毒性的作用及机制，为预防BPA的生殖发育危害、保护人群健康提供重要参考。