Abstract
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.
Highlights
Tris (1,3-dichloro-2-propyl) phosphate (TDCIPP) is an organophosphate flame retardant extensively used in polyurethane foam, acrylic latexes, plastics and resins (WHO, 1998)
TDCIPP disrupts biological processes specific to bone morphogenetic protein (BMP) signaling and dorsoventral patterning Based on transcriptome profiling using zebrafish-specific microarrays, initiation of TDCIPP exposure at 0.75 hpf resulted in no significant impacts on transcript levels at 2 hpf (Fig. S1)
Gene Ontology (GO) enrichment analysis based on 42 DAVID-identified transcripts with False Discovery Rates (FDR) p-values < 0.1 demonstrated that the three most significant biological processes affected by TDCIPP exposures were specific to BMP signaling and dorsoventral patterning (Table 1)
Summary
Tris (1,3-dichloro-2-propyl) phosphate (TDCIPP) is an organophosphate flame retardant extensively used in polyurethane foam, acrylic latexes, plastics and resins (WHO, 1998). TDCIPP has been detected at elevated levels within consumer products and indoor dust, resulting in TDCIPP exposure within pediatric populations (Butt et al, 2014; Stapleton et al, 2012). TDCIPP was detected in 100% of residential dust samples (mean concentration = 1,390 ng/g) and hand wipes (mean concentration = 84.1 ng/hand wipe) collected from children; TDCIPP concentrations were associated with levels of bis(1,3-dichloro-2-propyl) phosphate (BDCIPP, the primary metabolite of TDCIPP) in urine samples, suggesting that hand-to-mouth transfer and/or dermal absorption may be possible routes of exposure of TDCIPP within children (Hoffman et al, 2015). TDCIPP and/or BDCIPP has been detected within human populations around the world, our understanding about the potential effects of TDCIPP during early vertebrate development is relatively limited
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