Enantioselective Induction of Cytotoxicity by <i>o</i>,<i>p</i>′‑DDD in PC12 Cells: Implications of Chirality in Risk Assessment of POPs Metabolites

Abstract

The increased release of chiral persistent organic pollutants (POPs) into the environment has resulted in more attention to the role of enantioselectivity in the fate and ecotoxicological effects of these compounds. Although the enantioselectivity of chiral POPs has been considered in previous studies, little effort has been expended to discern the enantiospecific effects of chiral POPs metabolites, which may impede comprehensive risk assessments of these chemicals. In the present study, <i>o</i>,<i>p</i>′-DDD, the chiral metabolite of <i>o</i>,<i>p</i>′-DDT, was used as a model chiral metabolite. First, a preferential chiral separation at 100% ethanol was employed to obtain a pure enantiomer. The enantioselective cytotoxicity of <i>o</i>,<i>p</i>′-DDD in rat cells (PC12) was evaluated by detecting activation of the cellular apoptosis and oxidative stress systems and microarray analysis. We have documented for the first time that <i>R</i>-(+)-<i>o</i>,<i>p</i>′-DDD increases apoptosis by selectively disturbing the oxidative system (enzymes and molecules) and regulating the transcription of Aven, Bid, Cideb and Tp53. By comparing the data from the present study to data derived from the parent compound, we concluded that the <i>R</i>-enantiomer is the more detrimental stereostructure for both <i>o</i>,<i>p</i>′-DDT and <i>o</i>,<i>p</i>′-DDD. This observed stereostructural effect is in line with the structure–activity relationship formulated at other structural levels. Biological activities of the chiral metabolites are likely to occur in the same absolute configuration between chiral POPs and their metabolites provided that they have the similar stereostructures