Bioactivity assessment of organophosphate flame retardants via a dose-dependent yeast functional genomics approach

Abstract

Organophosphate flame retardants (OPFRs) have been widely detected in multiple environment media and have many adverse effects with complex toxicity mechanisms. However, the early molecular responses to OPFRs have not been fully elucidated, thereby making it difficult to assess their risks accurately. In this work, we systematically explored the point of departure (POD) of biological pathways at genome-wide level perturbed by 14 OPFRs with three substituents (alkyl, halogen, and aryl) using a dose-dependent functional genomics approach in Saccharomyces cerevisiae at 24 h exposure. Firstly, our results demonstrated that the overall biological potency at gene level (POD_DRG20) ranged from 0.013 to 35.079 μM for 14 OPFRs, especially the tributyl phosphate (TnBP) exhibited the strongest biological potency with the least POD_DRG20. Secondly, we found that structural characteristics of carbon number and logK_ow were significantly negatively correlated with POD, and carbon number and logK_ow also significantly affected lipid metabolism associated processes. Thirdly, these early biological pathways of OPFRs toxification were found to be involved in lipid metabolism, oxidative stress, DNA damage, MAPK signaling pathway, and amino acid and carbohydrate metabolism, among which the lipid metabolism was the most sensitive molecular response perturbed by most OPFRs. More importantly, we identified one resistant mutant strain with knockout of ERG2 (YMR202W) gene participated in steroid biosynthesis pathway, which can serve as a key yeast strain of OPFRs toxification. Overall, our study demonstrated an effective platform for accurately assessing OPFRs risks and provided a basis for further green OPFRs development.

Keywords: Dose-dependent functional genomics; ERG2 (YMR202W); Lipid metabolism; Molecular initiating event (MIE); Organophosphate flame retardants (OPFRs); Point of departure (POD).