Organophosphate Ester, 2-Ethylhexyl Diphenyl Phosphate (EHDPP), Elicits Cytotoxic and Transcriptomic Effects in Chicken Embryonic Hepatocytes and Its Biotransformation Profile Compared to Humans

Biphenyl Compounds Chick Embryo 01 natural sciences Organophosphates Phosphates 3. Good health Hepatocytes Animals Humans Transcriptome Chickens Biotransformation Flame Retardants 0105 earth and related environmental sciences
DOI: 10.1021/acs.est.8b06246 Publication Date: 2019-01-17T10:53:40Z
ABSTRACT
The effects of 2-ethylhexyl diphenyl phosphate (EHDPP) on cytotoxicity and mRNA expression, as well as its metabolism, were investigated using a chicken embryonic hepatocyte (CEH) assay. After incubation for 36 h, the lethal concentration 50 (LC50) was 50 ± 11 μM, suggesting that EHDPP is one of a small cohort of highly toxic organophosphate esters (OPEs). By use of a ToxChip polymerase chain reaction (PCR) array, we report modulation of 6, 11, or 16/43 genes in CEH following exposure to 0.1, 1, or 10 μM EHDPP, respectively. The altered genes were from all nine biological pathways represented on the ToxChip including bile acids/cholesterol regulation, glucose metabolism, lipid homeostasis, and the thyroid hormone pathway. After incubation for 36 h, 92.5% of EHDPP was transformed, and one of its presumed metabolites, diphenyl phosphate (DPHP), only accounted for 12% of the original EHDPP concentration. Further screening by use of high-resolution mass spectrometry revealed a novel EHDPP metabolite, hydroxylated 2-ethylhexyl monophenyl phosphate (OH-EHMPP), which was also detected in a human blood pool. Additional EHDPP metabolites detected in the human blood pool included EHMPP and DPHP. Overall, this study provided novel information regarding the toxicity of EHDPP and identified a potential EHDPP metabolite, OH-EHMPP, in both avian species and humans.
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