Insights Into the Separate and Joint Effects of Cadmium and Cesium on the Risk of Circadian Syndrome and the Underlying Mechanism: An Integrated Epidemiological and Network Toxicological Study.

The uncharted effects of cadmium and cesium on circadian syndrome (CircS), an emerging circadian rhythm disorder drawing considerable attention, and underlying mechanisms warrant exigent elaboration. Data of 11141 subjects from National Health and Nutrition Examination Survey 2005-2018 were incorporated to investigate separate-, joint-/interaction-, and mixture-effects of urinary cadmium and cesium on prevalent CircS risk exploiting survey weight regression and quantile g-computation. The underlying mechanisms were probed by network toxicological analysis. Separately, elevated cadmium or cesium was related to elevated (odds ratio = 1.32; 95% confidence interval: 1.15 ~ 1.52) or decreased (0.74; 0.58 ~ 0.94) CircS risk. Jointly, the effect of elevated cadmium on CircS was interactively (P_interaction = 0.002) exacerbated by decreased cesium with participants with high-cadmium and low-cesium manifested the highest CircS risk (1.71; 1.27 ~ 2.34), and mixture of cadmium and cesium was related to elevated CircS risk (1.30; 1.21 ~ 1.40). Hypoxia-inducible factor-1 (HIF-1), phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt), and mitogen-activated protein kinases (MAPK) signaling pathways were enriched and common (tumor necrosis factor [TNF], interleukin-6 [IL-6], tumor protein-53 [TP53]) and unique (HIF1A for cadmium, albumin [ALB] for cesium) targets were identified in linking cadmium and cesium with CircS. Separate exposure to cadmium or cesium was associated with increased or decreased CircS risk, while joint exposure to mixture of cadmium and cesium was interactively related to elevated CircS risk. Cadmium and cesium might affect CircS through mechanisms of modulating HIF-1, MAPK, and PI3K-Akt signaling pathways and shared (TNF, IL-6, and TP53) and unique (HIF1A for cadmium while ALB for cesium) targets.