Developmental circulatory failure caused by metabolites of organophosphorus flame retardants in zebrafish, Danio rerio.

Organophosphate triesters are used worldwide as additives in flame retardants and plasticizer as a replacement of polybrominated diphenyl ethers. Increasing evidence on human exposure to and environmental contamination with organophosphorus flame retardants (OPFRs) requires an adequate toxicity assessment for this class of chemicals. While developmental toxicity of several OPFRs has been reported, developmental effects of OPFR metabolites have still to be understood. The present study aimed at characterizing developmental effects of OPFR metabolites using zebrafish embryos (Danio rerio). Triphenyl phosphate (TPHP) and two of its metabolites, 3-hydroxylphenyl diphenyl phosphate and 4-hydroxylphenyl diphenyl phosphate, were most potent for inducing pericardial edema and reduction in blood flow in trunk vessels. Other TPHP metabolites, such as diphenyl phosphate and 4-hydroxylphenyl phenyl phosphate, showed no substantial increase in circulatory failure at concentrations up to 30 µM. Tris (1,3-dichloro-2-propyl) phosphate showed circulatory failure at 30 µM, but its metabolite bis(1,3-dichloro-2-propyl) phosphate did not. Neither tris(2-chloroethyl) phosphate nor its metabolite bis(2-chloroethyl) phosphate, induced circulatory failure. The circulatory failure appeared to be enhanced with the increase in the octanol-water partition coefficients of OPFRs and their metabolites, suggesting that developmental circulatory failure posed by these chemicals could be estimated by their bioaccumulative potential. The present study demonstrated developmental circulatory failure of hydroxylated TPHP metabolites, which was almost equipotent to TPHP. Diester OPFR metabolites showed no major developmental toxicity at the concentrations used in this study. The current results establish the foundation for further understanding the similarities and differences in the toxic mechanisms between OPFRs and their metabolites.