Relationship between cadmium exposure in metal mixtures and preserved ratio impaired spirometry: A combined cohort and experimental study

The health implications of widespread heavy metal pollution are of growing concern, particularly for respiratory diseases like Chronic Obstructive Pulmonary Disease (COPD). Preserved ratio impaired spirometry (PRISm) is an early abnormal phenotype in COPD development, yet its connection to environmental heavy metal mixtures is unestablished. Our research aimed to bridge this gap by analyzing data from 6585 U.S. adults in the 2007-2012 NHANES. Multivariable logistic regression showed elevated cadmium (Cd) increased PRISm risk (OR:1.35, 95% CI: 1.10 ∼ 1.65, P for trend < 0.05, per unit increase in log₁₀-transformed Cd, logCd). WQS (OR:1.40, 95% CI: 1.09 ∼ 1.81, per quartile increase in the mixture index of log₁₀-transformed metals), Qgcomp (OR:1.30, 95% CI: 1.05 ∼ 1.61, per quartile increase in all log₁₀-transformed metals) and BKMR (OR=1.079, 95% CI: 1.009-1.153, for increasing all log₁₀-transformed metals from the 50th to the 75th percentile) models consistently demonstrated a significant adverse effect of the metal mixture on PRISm incidence in females, with Cd identified as the primary contributor (PIP = 0.9996). A nonlinear relationship was observed for blood Cd, with a risk threshold of logCd = -0.673 (Cd = 0.510 μg/L). Mediation analysis revealed that albumin, HRR, and RAR mediated 5.06%, 3.59%, and 11.11% of the logCd-PRISm association, respectively. These findings were corroborated in two mouse models of CdCl₂ exposure (via drinking water or inhalation), which demonstrated robust lung inflammation (elevated IL-17, TNF-α, IL-13, IL-4), histopathological damage, increased EMT-related (N-cadherin, Tgf-β) and matrix degradation-related (Mmp8) mRNA expression. RNA-seq KEGG pathway analysis enriched four pathways (ECM-receptor interaction, IL-17, TNF, hematopoietic cell lineage) consistent with the phenotypic and mediation data. Collectively, these results highlight a critical role for Cd exposure in PRISm pathogenesis, warranting further prospective and mechanistic investigation.