Connecting volatile organic compounds exposure to osteoporosis risk via oxidative stress based on adverse outcome pathway methodology.

Existing evidence has demonstrated the association between exposure to volatile organic compounds (VOCs) and osteoporosis (OP) risk, but the underlying mechanistic framework remains unclear. This study aimed to explore potential pathways using adverse outcome pathway (AOP) analysis, and evidence this association in middle-to-old-aged American adults using the updated National Health and Nutrition Examination Survey data. Multivariable-adjusted general linear and weighted quantile sum models were employed to analyze associations of VOC metabolites (VOCMs), representing internal VOCs exposure levels, with OP-related phenotypes. An AOP framework based on network analysis was developed by extracting target genes and phenotypes. Among 3555 American adults aged ≥ 40 years (539 OP participants), we found that increasing urinary 3- and 4-methylhippuric acid, N-acetyl-S-(n-propyl)-l-cysteine (BPMA), and N-acetyl-S-(3-hydroxypropyl)-l-cysteine were associated with elevated OP odds with odds ratios (ORs) (95 % confidence intervals, 95 % CIs) being 1.254 (1.016 to 1.548), 1.182 (1.014 to 1.377), and 1.244 (1.029 to 1.505), respectively, per standard deviation. Urinary BPMA and N-acetyl-S-(2-cyanoethyl)-l-cysteine were inversely associated with lumbar spine bone mineral density (BMD), while urinary N-acetyl-S-(2-hydroxypropyl)-l-cysteine was positively associated with hip BMD. Additionally, OP odds increased by 46.0 % (95 % CI: 3.9 % to 105.1 %) per quartile increment in the VOC mixture. AOP analysis identified 53 target genes and 9 target phenotypes, and 5 of 9 target phenotypes were oxidative stress (OS)-related. Literature and the "AOP 482″ framework implied the core role of OS in the VOC exposure and prevalent OP association, with the interleukin-6 as the molecular initiating event. Our findings provided a theoretical basis for further investigation.