Metabolic perturbations underlying the associations of endocrine-disrupting chemical mixtures with muscle mass and strength in adults: A repeated-measures study

Introduction: Adult exposure to endocrine-disrupting chemicals (EDCs) may reduce muscle mass and strength; however, few studies considered EDC mixtures and their potential mechanisms. Objectives: We aimed to explore associations of EDC mixtures with adult muscle mass and strength, the modifying effects of diet and exercise, as well as the potential metabolic perturbations through plasma metabolome. Methods: We included 127 adults from a panel study that repeated measures across 3 seasons. We measured 110 EDCs spanning 12 groups in plasma and urine, along with the plasma metabolome. Bayesian kernel machine regression (BKMR), Bayesian weighted quantile sum regression, and quantile-based g-computation were employed to assess the mixture effects and relative contributions. Key EDCs were defined as those with weights exceeding the group average in at least two models. Stratified analyses were employed to investigate the modifying effects of diet and exercise. A meet-in-the-middle (MITM) approach was applied to characterize the underlying mechanisms. Results: BKMR results revealed significant negative associations between 7 EDC groups and both appendicular skeletal muscle mass (ASM) and hand-grip strength (HGS), namely per- and polyfluoroalkyl substances, polycyclic aromatic hydrocarbons, organophosphate pesticides, bisphenols, neonicotinoids, atrazine, and parabens. Three multi-exposure models identified 22 and 17 key EDCs linked to decreased ASM and HGS, respectively. Mixtures of these key EDCs were associated with decreases in both ASM and HGS, with significantly attenuated effects observed among participants with healthy diets or regular exercise. MITM approach identified overlapping pathways linking key EDC mixtures to ASM, including arachidonic acid, linoleic acid, and alpha-linolenic acid metabolism. Key EDC Mixtures were negatively associated with glycocyamine, which was positively associated with ASM. Conclusions: Adult exposure to EDC mixtures was linked to reduced ASM and HGS, whereas healthy diets and regular exercise mitigated such impairment. Downregulated glycocyamine and altered fatty acid metabolism were potential mechanisms underlying the decreased ASM.