Life Cycle Exposure to Environmentally Relevant Concentrations of Diphenyl Phosphate (DPhP) Inhibits Growth and Energy Metabolism of Zebrafish in a Sex-Specific Manner

Abstract

Due to commercial uses and environmental degradation of aryl phosphate esters, diphenyl phosphate (DPhP) is frequently detected in environmental matrices and is thus of growing concern worldwide. However, information on potential adverse effects of chronic exposure to DPhP at environmentally realistic concentrations was lacking. Here, we investigated the effects of life cycle exposure to DPhP on zebrafish at environmentally relevant concentrations of 0.8, 3.9, or 35.6 μg/L and employed a dual-omics approach (metabolomics and transcriptomics) to characterize potential modes of action. Exposure to DPhP at 35.6 μg/L for 120 days resulted in significant reductions in body mass and length of male zebrafish, but did not cause those same effects to females. Predominant toxicological mechanisms, including inhibition of oxidative phosphorylation, down-regulation of fatty acid oxidation, and up-regulation of phosphatidylcholine degradation, were revealed by integrated dual-omics analysis and successfully linked to adverse outcomes. Activity of succinate dehydrogenase and protein content of carnitine O-palmitoyltransferase 1 were significantly decreased in livers of male fish exposed to DPhP, which further confirmed the proposed toxicological mechanisms. This study is the first to demonstrate that chronic, low-level exposure to DPhP can retard growth via inhibiting energy output in male zebrafish.

Carcinogenic Risk of 2,6-Di-tert-Butylphenol and Its Quinone Metabolite 2,6-DTBQ Through Their Interruption of RARβ: In Vivo, In Vitro, and In Silico Investigations

“…More details of exposure design and all sequences data have been described in our previous work . The quantification method and measured concentrations of 2,6-DTBP and 2,6-DTBQ in mice livers and serums are provided in Text S1 and Table S1. − Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed based on differential expressed genes (DEGs) induced by 2,6-DTBP and 2,6-DTBQ.…”

Biotransformation, Physico-Chemical Properties and Environmental Fate of Bisphenol A Bis(Diphenyl Phosphate): In Slico, In Vitro and Non-Target Metabolites using a Wister-Han Rat Liver Microsomal Model

“…Aquatic toxicity of diphenyl phosphate (DPHP) (the diester of TPHP) is known (Choi et al, 2020;Chen et al, 2021). Long-range transport (LRT) as well as persistence were suggested for TBOEP and TEHP in a study of arctic fox from Svalbard, Norway (Hallanger et al, 2015).…”

“…Aquatic toxicity of novel OPEs is widely reported, partly because most publications concerning these compounds to date focus on aquatic taxa. Most toxicity studies of novel OPEs use zebrafish as the model species, and a range of toxic effects have been reported including developmental changes and acute embryonic and larval toxicity (Zhang et al, 2020;Chen et al, 2021). Screening of groups of OPEs has been conducted in avian embryonic hepatocytes, mostly chicken and double crested cormorant, identifying multiple novel OPEs to pose potent cytotoxicity and transcriptomic effects (Pagé-Larivière et al, 2018).…”

“…DPHP has been found to pose a risk of aquatic toxicity, though studies of acute effects do not often consider environmentally relevant concentrations. Chronic, more environmentally relevant doses (1-100 µg/L) of DPHP have recently been studied and found to inhibit zebrafish growth and metabolism (Chen et al, 2021).…”

“…Data is limited concerning chronic aquatic toxicity of phenol, though acute effects have been studied in multiple taxa, with toxicity ranging widely from slight to high (10 < EC50 < 100 and 0.1 < EC50 <1, respectively) (Duan et al, 2018). Developmental, behavioural and reproductive effects have been reported in several aquatic and avian species following exposure to BPA (Naveira et al, 2021;Wu & Seebacher, 2020;Cetin & Ozaydin, 2021) and zebrafish growth was found to be inhibited by exposure to DPHP (Zhang et al, 2020;Chen et al, 2021).…”