Dataset Information

TPhP exposure disturbs carbohydrate metabolism, lipid metabolism, and the DNA damage repair system in zebrafish liver.

ABSTRACT: Triphenyl phosphate is a high production volume organophosphate flame retardant that has been detected in multiple environmental media at increasing concentrations. The environmental and health risks of triphenyl phosphate have drawn attention because of the multiplex toxicity of this chemical compound. However, few studies have paid close attention to the impacts of triphenyl phosphate on liver metabolism. We investigated hepatic histopathological, metabolomic and transcriptomic responses of zebrafish after exposure to 0.050?mg/L and 0.300?mg/L triphenyl phosphate for 7 days. Metabolomic analysis revealed significant changes in the contents of glucose, UDP-glucose, lactate, succinate, fumarate, choline, acetylcarnitine, and several fatty acids. Transcriptomic analysis revealed that related pathways, such as the glycosphingolipid biosynthesis, PPAR signaling pathway and fatty acid elongation, were significantly affected. These results suggest that triphenyl phosphate exposure markedly disturbs hepatic carbohydrate and lipid metabolism in zebrafish. Moreover, DNA replication, the cell cycle, and non-homologous end-joining and base excision repair were strongly affected, thus indicating that triphenyl phosphate hinders the DNA damage repair system in zebrafish liver cells. The present study provides a systematic analysis of the triphenyl phosphate-induced toxic effects in zebrafish liver and demonstrates that low concentrations of triphenyl phosphate affect normal metabolism and cell cycle.

SUBMITTER: Du Z

PROVIDER: S-EPMC4761896 | biostudies-other | 2016 Feb

REPOSITORIES: biostudies-other

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TPhP exposure disturbs carbohydrate metabolism, lipid metabolism, and the DNA damage repair system in zebrafish liver.

Du Zhongkun Z Zhang Yan Y Wang Guowei G Peng Jianbiao J Wang Zunyao Z Gao Shixiang S

Scientific reports 20160222

Triphenyl phosphate is a high production volume organophosphate flame retardant that has been detected in multiple environmental media at increasing concentrations. The environmental and health risks of triphenyl phosphate have drawn attention because of the multiplex toxicity of this chemical compound. However, few studies have paid close attention to the impacts of triphenyl phosphate on liver metabolism. We investigated hepatic histopathological, metabolomic and transcriptomic responses of ze ...[more]

PMID: 26898711

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Project description:In order to explore effects of low levels of continuous microcystin-LR (MC-LR) (a cyanotoxin) exposure on hepatic lipid metabolism on the basis of the endoplasmic reticulum stress (ERS) pathway, we exposed adult male zebrafish to MC-LR (0, 1, 5, and 25 μg/L) for 60 days, and hepatic histopathology as well as lipid metabolic parameters were determined with mRNA levels of ERS signal molecules and downstream factors, along with genes associated with lipid metabolism in zebrafish liver. The results revealed that prolonged exposure to MC-LR remarkably altered the levels of hepatic total cholesterol and triglyceride and led to hepatic steatosis, which was also confirmed by hepatic cytoplasmic vacuolization in Hematoxylin/eosin (H&E) stain and lipid droplet accumulation in Oil Red O stain. The severity of hepatic damage and lipidation was increased in a dose-related manner. MC-LR exposure significantly upregulated transcriptional levels of ERS markers including hspa5, mapk8, and chop, indicating the occurrence of ERS in the liver of zebrafish. Concurrently, MC-LR significantly improved mRNA expression of unfolded protein response (UPR) pathway-related genes including atf6, eif2ak3, ern1, and xbp1s, suggesting that all of the three UPR branches were activated by MC-LR. MC-LR also induced significant upregulation of downstream lipid metabolism-related factors and genes including srebf1, srebf2, fatty acid synthase (fasn), acetyl-CoA carboxylase (acaca), stearoyl-CoA desaturase (scd), HMG CoA reductase (hmgcra), and HMG CoA synthase (hmgcs1), and downregulation of genes associated with lipolysis such as triglyceride hydrolase gene (atgl), hormone-sensitive enzyme gene (hsla), and carnitine palmitoyltransferase gene (cpt1aa). Our present results indicated that the cause of hepatic lipid accumulation by MC-LR was mainly by upregulating lipogenic and cholesterol genes but downregulating the expression of lipolytic genes through the induction of srebf1 and srebf2, which were involved in the activation of ERS signal pathways.

Project description:BackgroundDNA damage repair (DDR) system is vital in maintaining genome stability and survival. DDR consists of over 160 genes in 7 different pathways to repair specific type of DNA damage caused by external and internal damaging factors. The functional importance of DDR system implies that evolution could play important roles in maintaining its functional intactness to perform its function. Indeed, it has been observed that positive selection is present in BRCA1 and BRCA2 (BRCA), which are key genes in homologous recombination pathway of DDR system, in the humans and its close relatives of chimpanzee and bonobos. Efforts have been made to investigate whether the same selection could exist for BRCA in other mammals but found no evidence so far. However, as most of the studies in non-human mammals analyzed only a single or few individuals in the studied species, the observation may not reflect the true status in the given species. Furthermore, few studies have studied evolution selection in other DDR genes except BRCA. In current study, we used laboratory mouse C57BL/6 J as a model to address evolution selection on DDR genes in non-primate mammals by dynamically monitoring genetic variation across 30 generations in C57BL/6 J.ResultsUsing exome sequencing, we collected coding sequences of 169 DDR genes from 44 C57BL/6 J individual genomes in 2018. We compared the coding sequences with the mouse reference genome sequences derived from 1998 C57BL/6 J DNA, and with the mouse Eve6B reference genome sequences derived from 2003 C57BL/6 J DNA, covering 30 generations of C57BL/6 J from 1998 to 2018. We didn't identify meaningful coding variation in either Brca1 or Brca2, or in 167 other DDR genes across the 30 generations. In the meantime, we did identify 812 coding variants in 116 non-DNA damage repair genes during the same period, which served as a quality control to validate the reliability of our analytic pipeline and the negative results in DDR genes.ConclusionsDDR genes in laboratory mouse strain C57BL/6 J were not under positive selection across its 30-generation period, highlighting the possibility that DDR system in rodents could be evolutionarily stable.

Dataset Information

TPhP exposure disturbs carbohydrate metabolism, lipid metabolism, and the DNA damage repair system in zebrafish liver.

Publications

TPhP exposure disturbs carbohydrate metabolism, lipid metabolism, and the DNA damage repair system in zebrafish liver.

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