3,3′,5.5′-Tetrabromobisphenol A (TBBPA) is a widely used brominated flame-retardant. The objective of this study is to use zebrafish as a model and determine the effects of TBBPA exposure on early embryogenesis. We initiated TBBPA exposures at 0.75 h post fertilization (hpf) and showed that TBBPA induced developmental delays during maternal-to-zygotic transition (MZT) and zygotic genome activation (ZGA). To examine the genetic basis of TBBPA-induced delays, we conducted mRNA-sequencing on embryos exposed to 0 or 40 μM TBBPA from 0.75 hpf to 2, 3.5 or 4.5 hpf. Read count data showed that while TBBPA exposures had no overall impacts on maternal or maternal-zygotic genes, collective read counts for zygotically activated genes were lower in TBBPA treatment at 4.5 hpf compared to time-matched controls, suggesting that TBBPA delays ZGA. Gene ontology assessments for both time- and stage-matched differentially expressed genes revealed TBBPA-induced inhibition of chromatin assembly- a process regulated by histone modifications. Immunostaining and in vitro experiments showed inhibition of histone H3 lysine 27 acetylation (H3K27Ac) as well as its catalyzing enzyme, p300. Finally, co-exposure with a p300 activator showed partial mitigation of effects, demonstrating that inhibition of histone acetylation drives TBBPA-induced developmental delays.

中文翻译：

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阻燃剂四溴双酚 A （TBBPA） 在斑马鱼母体向合子转变过程中破坏组蛋白乙酰化


3,3′，5.5′-四溴双酚 A （TBBPA） 是一种广泛使用的溴化阻燃剂。本研究的目的是以斑马鱼为模型，确定 TBBPA 暴露对早期胚胎发生的影响。我们在受精后 0.75 小时 （hpf） 开始 TBBPA 暴露，并表明 TBBPA 在母体到合子过渡 （MZT） 和合子基因组激活 （ZGA） 期间诱导发育延迟。为了检查 TBBPA 诱导延迟的遗传基础，我们对暴露于 0 或 40 μM TBBPA 的胚胎进行了 mRNA 测序，从 0.75 hpf 到 2、3.5 或 4.5 hpf。读取计数数据显示，虽然 TBBPA 暴露对母体或母体合子基因没有总体影响，但与时间匹配的对照相比，在 4.5 hpf 的 TBBPA 处理中，合子激活基因的集体读取计数较低，表明 TBBPA 延迟了 ZGA。时间和阶段匹配的差异表达基因的基因本体论评估揭示了 TBBPA 诱导的染色质组装抑制——一个由组蛋白修饰调节的过程。免疫染色和体外实验显示，组蛋白 H3 赖氨酸 27 乙酰化 （H3K27Ac） 及其催化酶 p300 受到抑制。最后，与 p300 激活剂的共暴露显示部分减轻了作用，表明组蛋白乙酰化的抑制驱动了 TBBPA 诱导的发育迟缓。