Dodecamethylcyclohexasiloxane (D6) modulates Ca-Cd homeostasis and metabolic-mitochondrial functions to attenuate cadmium-induced toxicity in Caenorhabditis elegans

Dodecamethylcyclohexasiloxane (D6) is a cyclic organosilicon monomer widely used in consumer and industrial products and is increasingly detected in environmental and biological systems. Previous studies have shown that D6 modulates the ecological behavior of the heavy metal cadmium (Cd) in soil and reduces Cd accumulation in plants; however, D6-mediated stress responses to Cd in animals and their underlying mechanisms remain inadequately explored. This study reveals that D6 exerts multi-layered protective effects against Cd toxicity in Caenorhabditis elegans. Cd exposure significantly reduced lifespan, brood size, locomotion, and growth, whereas D6 co-treatment (Cd_D6) improved survival by 20%, increased brood size from 64 ± 4.37-90 ± 1.53 eggs, and partially restored locomotor activity. D6 also reduced germline apoptosis and decreased internal Cd accumulation by more than 30%, while stabilizing Ca homeostasis. Biochemically, D6 reversed Cd-induced declines in glucose, pyruvate, and ATP levels, restored mitochondrial ultrastructure, and lowered ROS and MDA accumulation, alongside partial recovery of antioxidant enzyme activities (SOD, CAT, POD, HK, ATPase). Transcriptomic profiling revealed that D6 counteracted Cd-driven repression of metabolic and mitochondrial pathways, including peroxisomal β-oxidation, ubiquinone biosynthesis, and genes essential for lipid catabolism (e.g., acs-7, acox-3, nkat-1). Weighted gene co-expression network analysis identified a D6-responsive module enriched with regulatory genes associated with metabolic repair and stress resilience. Collectively, these findings identify D6 as a previously unrecognized organosilicon compound that reduces Cd accumulation and reprograms metabolic and mitochondrial functions, thereby improving organismal homeostasis and enhancing resilience to Cd stress.