Volatile Organic Compounds as Biomarkers of Oxidative Stress in Childhood Obesity

Abstract

Childhood obesity is associated with increased oxidative stress and systemic inflammation, both of which contribute to the development of obesity-related comorbidities. Notably, obesity disproportionately affects certain racial and ethnic minority populations. While excess body fat is known to drive these complications, abdominal and visceral fat contribute significantly by promoting the release of pro-oxidants, reactive oxygen species (ROS), and pro-inflammatory mediators. This oxidative stress (OS) disrupts the balance between free radical generation and antioxidant defenses, leading to damage at the molecular level, including protein oxidation, lipid peroxidation, and DNA damage. One consequence of these oxidative processes is the production and release of volatile organic compounds (VOCs), which are detectable in various biological matrices such as urine, breath, skin, and feces. This dissertation focuses on VOCs as biomarkers of oxidative stress in childhood obesity. Through this research, we explored VOCs as noninvasive biomarkers of obesity and OS. In vitro models using differentiated 3T3-L1 adipocytes treated with hydrogen peroxide (H₂O₂) revealed that OS induced significant metabolic shifts and cell apoptosis, with altered VOC profiles. VOCs such as diphenyl ether, 1,3,5-trioxane, 5-methyl tridecane, 2-ethyl-1-hexanol, and 2,4-di-tert-butyl phenol were upregulated and identified as potential markers of oxidative damage. Furthermore, human studies supported the clinical relevance of VOCs. In a cross-sectional study of 159 children (ages 6–10 years), urinary VOC profiling using solid-phase microextraction gas chromatography–mass spectrometry (SPME-GC-MS) identified sixty-five VOCs differentiating overweight/obese from normal-weight children, with ten VOCs remaining significant predictors of obesity after adjusting for racial and socioeconomic status disparities. Key VOCs such as benzaldehyde, hexanal, furan, 4-heptanone, and 2-pentylfuran emerged as potential biomarkers of obesity. Additionally, urinary 8-isoprostane was significantly elevated in OW/OB children of EA and AA ethnicity. Inflammatory markers AGP and IL-6 were elevated in OW/OB children, especially among AA participants. Multivariable regression showed positive associations of 2-pentylfuran and 4-heptanone with 8-OHdG, and a negative association of furan with 8-OHdG. This study indicated that urinary VOCs, particularly 2-pentylfuran and 4-heptanone, may serve as early non-invasive biomarkers of oxidative and inflammatory stress in childhood obesity. In conclusion, these results suggest the potential of VOCs as early, noninvasive biomarkers for monitoring oxidative and inflammatory stress in childhood obesity. The differential expression patterns of VOCs and biomarkers across racial/ethnic subgroups further emphasize the importance of considering sociodemographic factors in obesity-related biomarker research. These findings show that urinary VOCs could play a crucial role in advancing our understanding of the pathogenesis of childhood obesity and its associated metabolic complications.