Diphenyl Phosphate-Induced Toxicity During Embryonic Development

Diphenyl phosphate (DPHP) is an aryl
phosphate ester (APE) used
as an industrial catalyst and chemical additive and is the primary
metabolite of flame retardant APEs, including triphenyl phosphate
(TPHP). Minimal DPHP-specific toxicity studies have been published
despite ubiquitous exposure within human populations following metabolism
of TPHP and other APEs. Therefore, the objective of this study was
to determine the potential for DPHP-induced toxicity during embryonic
development. Using zebrafish as a model, we found that DPHP significantly
increased the distance between the sinus venosus and bulbus arteriosis
(SV-BA) at 72 h postfertilization (hpf) following initiation of exposure
before and after cardiac looping. Interestingly, pretreatment with d-mannitol mitigated DPHP-induced effects on SV-BA length despite
the absence of DPHP effects on pericardial area, suggesting that DPHP-induced
cardiac defects are independent of pericardial edema formation. Using
mRNA-sequencing, we found that DPHP disrupts pathways related to mitochondrial
function and heme biosynthesis; indeed, DPHP significantly decreased
hemoglobin levels in situ at 72 hpf following exposure from 24 to
72 hpf. Overall, our findings suggest that, similar to TPHP, DPHP
impacts cardiac development, albeit the potency of DPHP is significantly
less than TPHP within developing zebrafish.