Chlorinated Organophosphate Flame Retardants Impair the Lung Function via the IL-6/JAK/STAT Signaling Pathway

• Published in: Environmental science & technology 2022-12, Vol.56 (24), p.17858-17869
• Main Authors: Zhu, Huanhuan, Zhang, Huilin, Lu, Kai, Yang, Sheng, Tang, Xiying, Zhou, Meiyu, Sun, Guanting, Zhang, Zhengdong, Chu, Haiyan
• Format: Article
• Language: English
• Subjects: Chlorination; Ecotoxicology and Public Health; Epidemiology; Flame Retardants; Flow velocity; Interleukin 6; Interleukin-6 - metabolism; Janus kinase; Janus Kinases - metabolism; Kinases; Lung; Lungs; Metabolites; Nutrition; Nutrition Surveys; Organophosphates; Phosphates; Regression models; Respiratory function; Respiratory system; Risk assessment; Signal Transduction; STAT Transcription Factors - metabolism; Tobacco; Toxicity; Toxicity testing
• ISSN: 0013-936X; 1520-5851
• DOI: 10.1021/acs.est.2c05357

Toxicological studies have revealed the adverse impacts of organophosphate flame retardants (OPFRs) on the respiratory system, while there is a lack of epidemiological evidence, and information for risk assessment remains insufficient. Herein, we investigated the associations of urinary metabolites of OPFRs with the lung function in 987 adults participating in the U.S. National Health and Nutrition Examination Survey 2011–2012. The elevation of three primary metabolites of chlorinated OPFRs [bis­(1,3-dichloro-2-propyl) phosphate (BDCIPP), bis­(2-chloroethyl) phosphate (BCEP), and bis­(1-chloro-2-propyl) phosphate (BCIPP)] was related to pulmonary dysfunction in a sample-weighted regression model. Each one-unit increase in the log-transformed levels of BDCIPP and BCEP was related to 91.52 and 79.34 mL reductions in the forced vital capacity (FVC). Each one-unit elevation in BCIPP was correlated with 130.86, 153.56, 302.26, and 148.24 mL reductions in forced expiratory volume 1st second (FEV1), FVC, peak expiratory flow rate (PEF), and forced expiratory flow at 25-75% of FVC (FEF25–75%), respectively. Then, an adverse outcome pathway (AOP) framework was constructed using the Comparative Toxicogenomics Database, the Toxicity Forecaster, and the GeneCards database. Based on the weight of the evidence, BDCIPP, BCEP, BCIPP, and their parent compounds (TDCIPP, TCEP, and TCIPP) may affect the IL-6/Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, induce airway remodeling, and impair the lung function. Additionally, tobacco smoke exposure may modify the effects of BDCIPP on the lung function (P int < 0.05) and affect the IL-6-mediated AOP. These results suggested that chlorinated OPFRs were associated with pulmonary dysfunction via the IL-6/JAK/STAT pathway.