Comparative toxicity evaluations for polybrominated diphenyl ethers (PBDEs) : investigation of developmental toxicity, uptake and mechanisms of action in embryonic zebrafish (Danio rerio)

Recently, polybrominated diphenyl ethers (PBDEs) were banned due to extensive environmental contamination and potential health effects. There is little understanding of the comparative toxicity of individual congeners. Seven congeners were selected over a wide-range of physical-chemical properties for investigation into relative toxicity, uptake, and mechanisms/modes of action. Based on the occurrences in environmental and human samples, BDE 28, 47, 99, 100, 153, 183, and 209 were chosen for evaluations, using embryonic zebrafish as the model organism. Exposure to PBDEs disrupted behavior during different windows of development, as well as induced curved body malformations and mortality over the exposure period from 6-168 hours post fertilization (hpf). There was a direct correlation between log Kow and the toxicity of the compounds as well as their subsequent uptake in embryos. In addition to uptake, metabolites and potential metabolic pathways were investigated. Several genes were assessed to elucidate the primary pathway of metabolism for different congeners. Several genes were significantly upregulated following exposure to most congeners (i.e. deiodinase 1 and 2, CYP1A1, CYP1B1, and CYP3A1), with the exception of BDE 153. Interestingly, BDE 153 also had the greatest amount of debromination. The analysis of phase II metabolism pathways demonstrated that UGT5g was significantly upregulated following exposure to all congeners. Two pathways were further investigated for BDE 28, 47, 99, and 100: oxidative stress and thyroid disruption. There was not a significant oxidative stress-related response for any of the treatments until 120 hpf, where we observed upregulation. We concluded that oxidative stress was not a primary pathway of toxicity for these congeners. Further analysis demonstrated that the adverse effects observed in zebrafish are most likely due to disruption of thyroid hormone homeostasis. In addition to metabolism, the toxicity of three hydroxylated metabolites was assessed, with very different responses to exposure than the parent congeners. Individual congeners did not appear to act through different mechanisms/modes of action; however the actual dose was a primary determinant in the toxicity of PBDEs.