Reddam Aalekhya, Mitchell Constance A, Dasgupta Subham, Kirkwood Jay S, Vollaro Alyssa, Hur Manhoi, Volz David C
Environmental Toxicology Graduate Program.
Department of Environmental Sciences.
Toxicol Sci. 2019 Nov 1;172(1):51-62. doi: 10.1093/toxsci/kfz169.
Triphenyl phosphate (TPHP) is a commonly used organophosphate flame retardant and plasticizer in the United States. Using zebrafish as a model, the overall objective of this study was to identify potential organs that might be targeted by TPHP during embryonic development. Based on mRNA-sequencing, TPHP exposure from 24 to 30 h post fertilization (hpf) and 24 to 48 hpf significantly affected the abundance of 305 and 274 transcripts, respectively, relative to vehicle (0.1% DMSO) controls. In addition to minor effects on cardiotoxicity- and nephrotoxicity-related pathways, ingenuity pathway analysis (IPA) of significantly affected transcripts within 30- and 48-hpf embryos revealed that hepatotoxicity-related pathways were strongly affected following exposure to TPHP-alone. Moreover, although pretreatment with fenretinide (a retinoic acid receptor agonist) mitigated TPHP-induced pericardial edema and liver enlargement at 72 and 128 hpf, respectively, IPA revealed that fenretinide was unable to block TPHP-induced effects on cardiotoxicity-, nephrotoxicity-, and hepatotoxicity-related pathways at 48 hpf, suggesting that TPHP-induced effects on the transcriptome were not associated with toxicity later in development. In addition, based on Oil Red O staining, we found that exposure to TPHP nearly abolished neutral lipids from the embryonic head and trunk and, based on metabolomics, significantly decreased the total abundance of metabolites-including betaine, a known osmoprotectant-at 48 and 72 hpf. Overall, our data suggest that, in addition to the heart, TPHP exposure during early development results in adverse effects on the liver, lipid utilization, and osmoregulation within embryonic zebrafish.
磷酸三苯酯（TPHP）是美国一种常用的有机磷酸酯类阻燃剂和增塑剂。本研究以斑马鱼为模型，总体目标是确定胚胎发育过程中可能受到TPHP影响的潜在器官。基于mRNA测序，相对于载体（0.1%二甲亚砜）对照组，受精后24至30小时（hpf）和24至48 hpf暴露于TPHP分别显著影响了305和274个转录本的丰度。除了对心脏毒性和肾毒性相关途径有轻微影响外，对30 hpf和48 hpf胚胎中受显著影响的转录本进行的 Ingenuity 通路分析（IPA）显示，单独暴露于TPHP后，肝毒性相关途径受到强烈影响。此外，尽管用阿维A（一种视黄酸受体激动剂）预处理分别减轻了TPHP在72 hpf和128 hpf时诱导的心包水肿和肝脏肿大，但IPA显示阿维A在48 hpf时无法阻断TPHP对心脏毒性、肾毒性和肝毒性相关途径的影响，这表明TPHP对转录组的影响与发育后期的毒性无关。此外，基于油红O染色，我们发现暴露于TPHP几乎消除了胚胎头部和躯干中的中性脂质，并且基于代谢组学，在48 hpf和72 hpf时显著降低了包括甜菜碱（一种已知的渗透保护剂）在内的代谢物总丰度。总体而言，我们的数据表明，除了心脏外，早期发育过程中暴露于TPHP会对斑马鱼胚胎的肝脏、脂质利用和渗透调节产生不利影响。
