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

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 γ agonist) and
17β-estradiol (E2; an estrogen receptor α 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.