Tris(1,3-dichloro-2-propyl) phosphate disrupts dorsoventral patterning in zebrafish embryos.
Tris(1,3-dichloro-2-propyl) phosphate disrupts dorsoventral patterning in zebrafish embryos.
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作者：
Dasgupta S;Vliet SM;Kupsco A;Leet JK;Altomare D;Volz DC
磷酸三（1，3-二氯-2-丙基）酯（TDCIPP）是一种在美国广泛使用的高产量有机磷酸酯阻燃剂。在斑马鱼内，在受精后0.75小时（hpf）开始TDCIPP暴露导致在卵裂期间（2 hpf）甲基化的全基因组改变，以及在囊胚晚期和原肠胚早期（4-6 hpf）期间的外包延迟或停滞（在较高浓度下）。为了确定这些TDCIPP诱导的效应是否与对转录组的影响相关，将胚胎从0.75 hpf至6 hpf暴露于媒介物（0.1%DMSO）或2 μM TDCIPP，并且从每次处理的一式三份胚胎池中提取总RNA，并将每个RNA样品杂交到一式两份的Affyclium斑马鱼基因1.0 ST阵列上。基于全转录组分析，TDCIPP对涉及背腹图案和骨形态发生蛋白（BMP）信号传导的生物过程产生了显着影响。与这些反应一致，TDCIPP暴露也导致了24 hpf-a表型的强烈背侧化胚胎，其模拟了dorsomorphin（一种有效的选择性BMP抑制剂）的作用。此外，大多数背侧化的胚胎在6 hpf时发生外包停滞。我们的微阵列数据还显示，sizzled（szl）的表达-一个基因编码的分泌卷曲相关蛋白，限制BMP信号-显着减少了近4倍，在6 hpf。因此，我们使用剪接阻断吗啉代来检验szl表型TDCIPP的敲低诱导外延进展延迟的假设。有趣的是，与我们的假设相反，注射szl MO不影响外延进展，但类似于脊索蛋白（chd）变形，导致24 hpf的轻度腹侧化胚胎。总体而言，我们的研究结果表明，TDCIPP诱导的epiboly延迟可能不是由szl表达减少驱动的，TDCIPP诱导的背侧化可能是由于干扰BMP信号在早期斑马鱼发育过程中类似dorsomorphin。
Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) is a high-production volume organophosphate flame retardant widely used within the United States. Within zebrafish, initiation of TDCIPP exposure at 0.75 h post-fertilization (hpf) results in genome-wide alterations in methylation during cleavage (2 hpf) as well as epiboly delay or arrest (at higher concentrations) during late-blastula and early-gastrula (4–6 hpf). To determine whether these TDCIPP-induced effects were associated with impacts on the transcriptome, embryos were exposed to vehicle (0.1% DMSO) or 2 µM TDCIPP from 0.75 hpf to 6 hpf, and total RNA was extracted from triplicate embryo pools per treatment and hybridized onto duplicate Affymetrix Zebrafish Gene 1.0 ST Arrays per RNA sample. Based on transcriptome-wide profiling, TDCIPP resulted in a significant impact on biological processes involved in dorsoventral patterning and bone morphogenetic protein (BMP) signaling. Consistent with these responses, TDCIPP exposure also resulted in strongly dorsalized embryos by 24 hpf—a phenotype that mimicked the effects of dorsomorphin, a potent and selective BMP inhibitor. Moreover, the majority of dorsalized embryos were preceded by epiboly arrest at 6 hpf. Our microarray data also revealed that the expression of sizzled (szl)—a gene encoding a secreted Frizzled-related protein that limits BMP signaling—was significantly decreased by nearly 4-fold at 6 hpf. Therefore, we used a splice-blocking morpholino to test the hypothesis that knockdown of szl phenocopies TDCIPP-induced delays in epiboly progression. Interestingly, contrary to our hypothesis, injection of szl MOs did not affect epiboly progression but, similar to chordin (chd) morphants, resulted in mildly ventralized embryos by 24 hpf. Overall, our findings suggest that TDCIPP-induced epiboly delay may not be driven by decreased szl expression, and that TDCIPP-induced dorsalization may—similar to dorsomorphin—be due to interference with BMP signaling during early zebrafish development.
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