Estrogenic and growth inhibitory responses to organophosphorus flame retardant metabolites in zebrafish embryos

Recent evidence has revealed that organophosphorus flame retardants (OPFRs) elicit a variety of toxic effects, including endocrine disruption. The present study examined estrogenic and growth inhibitory responses to OPFR metabolites in comparison to their parent compounds using zebrafish eleutheroembryos.1 Exposure to 4-hydroxylphenyl diphenyl phosphate (HO-p-TPHP) but not its parent compound triphenyl phosphate (TPHP) elicited upregulation of a marker gene of estrogenic responses, cytochrome P450 19A1b (CYP19A1b), and this upregulation was reversed by co-exposure to an estrogen receptor antagonist. Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), as well as 3-hydroxylphenyl diphenyl phosphate (HO-m-TPHP) and diphenyl phosphate (DPHP), did not elicit significant changes in the CYP19A1b expression. Reduction in body length was induced by TPHP and to a lesser extent by its hydroxylated metabolites. Altered expression of genes involved in the synthesis and action of thyroid hormones, including iodothyronine deiodinases 1 and 2, thyroid hormone receptor alpha, and transthyretin, were commonly observed for TPHP and its hydroxylated metabolites. Reduction in the body length was also seen in embryos exposed to TDCIPP but not BDCIPP. The transcriptional effect of TDCIPP was largely different from that of TPHP, with decreased expression of growth hormone and prolactin observed only in TDCIPP-exposed embryos. Considering the concentration-response relationships for the growth retardation and gene expression changes, together with existing evidence from other researchers, it is likely that prolactin is in part involved in the growth inhibition caused by TDCIPP. The present study showed similarities and differences in the endocrine disruptive effects of OPFRs and their metabolites.