Oxidative Damage Induced by Daily Exposure to Primary and Emerging Aromatic Amines: Insights from Large Scale Biomonitoring and Cell-based High-Throughput PCR Array Analysis

Abstract

Aromatic amines are a group of compounds with industrial and environmental significance. The oxidative damage induced by large scale residential exposure to aromatic amines remains poorly characterized, necessitating comprehensive biomonitoring and mechanistic investigations. Herein, this study integrates large scale biomonitoring and cell-based high-throughput PCR array analysis to evaluate the oxidative damage induced by daily exposure to primary aromatic amines (PAAs), emerging aromatic amines (AAs), and their quinone derivatives (PPD-Qs) in the Chinese population. Urinary concentrations of 11 PAAs, 20 AAs, and 6 PPD-Qs were quantified (ΣPAAs > ΣAAs > ΣPPD-Qs) in 397 samples across 31 provinces/municipalities in China, uncovering significant regional variations. Advanced statistical regression analyses (multiple linear regression, weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR)) identified key chemical contributors, correlating with oxidative stress biomarkers (8-oxo-7,8-dihydro-2′-deoxyguanosine (8-OHdG), 8-hydroxyguanosine (8-OHG), dityrosine (di-Y), and malondialdehyde (MDA)), indicative of DNA, RNA, protein, and lipid damage. The WQS model identified several key chemicals driving oxidative stress, including 1,3-Diphenylguanidine (DPG), 1,2,3-Triphenylguanidine(TPG), 1,3-Di-o-tolyguanidine(DTG), 4-Phenylaminodiphenylamine quinone (DPPD-Q), 4-(Cyclohexyl amino) diphenylamine quinone (CPPD-Q), and 2-naphthylamine (2-NA). In vitro experiments demonstrated that these prioritized chemicals elevated reactive oxygen species production by 118%–241% and dysregulated 11 oxidative stress-related genes, implicating pathways linked to superoxide metabolism and ferroptosis. This multi-faceted approach advances the understanding of aromatic amine-induced oxidative damage, offering critical insights to support chemical prioritization and regulatory measures to mitigate associated health risks.