Emergence of More Potent PPD-Qs beyond 6PPD-Q in Human Blood and Cerebrospinal Fluid

Abstract

N-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine-quinone (6PPD-Q) has been detected in human body fluids, with uncertainty about the occurrence of other p-phenylenediamine quinones (PPD-Qs) and their potential toxicities. In this study, following detection of PPD-Qs in human blood and cerebrospinal fluid (CSF), we investigated their toxicities to the blood–brain barrier (BBB). After ethical approval and signed informed consent, 27 participants were enrolled, and 20 blood and 20 CSF samples were collected. High-performance liquid chromatography coupled with triple quadrupole mass spectrometry (HPLC-3Q-MS) was used to detect the PPD-Qs in the samples. Cell biology and molecular biology technologies were applied to investigate the toxicological effects and the mechanisms of PPD-Qs on the BBB model by using human cerebral microvascular endothelial cell line (hCMEC-D3). PPD-Qs were frequently detected in both extracts of serum and CSF samples, with 6PPD-Q, N-isopropyl-N′-phenyl-1,4-phenylenediamine-quinone (IPPD-Q), and N,N′-bis(1,4-dimethylpentyl)-p-phenylenediamine-quinone (77PD-Q) being the most abundant. 77PD-Q and IPPD-Q exhibited greater toxicity compared with 6PPD-Q. 6PPD-Q, IPPD-Q, and 77PD-Q led to endothelial-to-mesenchymal transition (EndMT) of cerebral microvascular endothelial cells by upregulating PAI-1, resulting in BBB dysfunction. However, atorvastatin reversed this process and reduced their toxicities.

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