Dataset Information

Complex Interplay Among Nuclear Receptor Ligands, Cytosine Methylation, and the Metabolome in Driving Tris(1,3-dichloro-2-propyl)phosphate-Induced Epiboly Defects in Zebrafish.

ABSTRACT: Tris(1,3-dichloro-2-propyl)phosphate (TDCIPP) is a high-production-volume organophosphate flame retardant (OPFR) that induces epiboly defects during zebrafish embryogenesis, leading to the disruption of dorsoventral patterning. Therefore, the objectives of this study were to (1) identify the potential mechanisms involved in TDCIPP-induced epiboly defects and (2) determine whether coexposure to triphenyl phosphate (TPHP)-an OPFR commonly detected with TDCIPP-enhances or mitigates epiboly defects. Although TDCIPP-induced epiboly defects were not associated with adverse impacts on cytoskeletal protein abundance in situ, the coexposure of embryos to TPHP partially blocked TDCIPP-induced epiboly defects. As nuclear receptors are targets for both TPHP and TDCIPP, we exposed the embryos to TDCIPP in the presence or absence of 69 nuclear receptor ligands and, similar to TPHP, found that ciglitazone (a peroxisome proliferator-activated receptor ? agonist) and 17?-estradiol (E2; an estrogen receptor ? agonist) nearly abolished TDCIPP-induced epiboly defects. Moreover, E2 and ciglitazone mitigated TDCIPP-induced effects on CpG hypomethylation within the target loci prior to epiboly, and ciglitazone altered TDCIPP-induced effects on the abundance of two polar metabolites (acetylcarnitine and cytidine-5-diphosphocholine) during epiboly. Overall, our results point to a complex interplay among nuclear receptor ligands, cytosine methylation, and the metabolome in both the induction and mitigation of epiboly defects induced by TDCIPP.

SUBMITTER: Dasgupta S

PROVIDER: S-EPMC6721996 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Complex Interplay Among Nuclear Receptor Ligands, Cytosine Methylation, and the Metabolome in Driving Tris(1,3-dichloro-2-propyl)phosphate-Induced Epiboly Defects in Zebrafish.

Dasgupta Subham S Vliet Sara M F SMF Cheng Vanessa V Mitchell Constance A CA Kirkwood Jay J Vollaro Alyssa A Hur Manhoi M Mehdizadeh Chris C Volz David C DC

Environmental science & technology 20190820 17

Tris(1,3-dichloro-2-propyl)phosphate (TDCIPP) is a high-production-volume organophosphate flame retardant (OPFR) that induces epiboly defects during zebrafish embryogenesis, leading to the disruption of dorsoventral patterning. Therefore, the objectives of this study were to (1) identify the potential mechanisms involved in TDCIPP-induced epiboly defects and (2) determine whether coexposure to triphenyl phosphate (TPHP)-an OPFR commonly detected with TDCIPP-enhances or mitigates epiboly defects. ...[more]

PMID: 31385694

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Project description: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.

Project description:Organophosphate esters (OPEs) are a class of semi-volatile organic compounds (SVOCs) used as flame retardants, plasticizers, and anti-foaming agents. Due to stringent flammability standards in vehicles and the ability of OPEs to migrate out of end-use products, elevated concentrations of OPEs have been found in car dust samples around the world. As many residents of Southern California spend a significant amount of time in their vehicles, there is potential for increased exposure to OPEs associated with longer commute times. As approximately 70% of the University of California, Riverside's undergraduate population commutes, the objective of this study was to use silicone wristbands to monitor personal exposure to OPEs and determine if exposure was associated with commute time in a subset of these students. Participants were asked to wear wristbands for five continuous days and complete daily surveys about the amount of time spent commuting. Data were then used to calculate a participant-specific total commute score. Components of Firemaster 550 (triphenyl phosphate, or TPHP, and isopropylated triaryl phosphate isomers) and Firemaster 600 (TPHP and tert-butylated triaryl phosphate isomers) - both widely used commercial flame retardant formulations - were strongly correlated with other OPEs detected within participant wristbands. Moreover, the concentration of tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) was significantly correlated with the concentration of several Firemaster 500 components and tris(2-chloroisopropyl) phosphate (TCIPP). Finally, out of all OPEs measured, TDCIPP was significantly and positively correlated with total commute score, indicating that longer commutes are associated with increased human exposure to TDCIPP. Overall, our findings raise concerns about the potential for chronic TDCIPP exposure within vehicles and other forms of transportation, particularly within densely populated and traffic-congested areas such as Southern California.

Dataset Information

Complex Interplay Among Nuclear Receptor Ligands, Cytosine Methylation, and the Metabolome in Driving Tris(1,3-dichloro-2-propyl)phosphate-Induced Epiboly Defects in Zebrafish.

Publications

Complex Interplay Among Nuclear Receptor Ligands, Cytosine Methylation, and the Metabolome in Driving Tris(1,3-dichloro-2-propyl)phosphate-Induced Epiboly Defects in Zebrafish.

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