Cadmium Exposure and Osteoporosis: A Spatially Contextualized Adverse Outcome Pathway Integrating Epidemiology, Toxicogenomics and Transcriptomics.

Abstract

Cadmium is an environmentally relevant metal toxicant associated with impaired bone health, but the mechanistic architecture linking cadmium exposure to osteoporosis remains insufficiently organized. We developed a cadmium-centered, adverse outcome pathway (AOP)-guided framework by integrating population epidemiology, toxicogenomics, bulk and single-cell transcriptomics, inferred myeloid pseudotime, and spatial transcriptomics. Survey-weighted analyses of NHANES 2013-2014 and 2017-2018 showed that whole-blood cadmium was positively associated with osteoporosis (odds ratio, 1.43; 95% confidence interval, 1.05-1.95), with an increasing exposure-response pattern. In quantile g-computation using total femur bone mineral density as the outcome, cadmium contributed the largest negative-direction weight. Cadmium-related toxicogenomic evidence from the Comparative Toxicogenomics Database was organized into six biologically interpretable key-event modules. Bulk transcriptomic analyses revealed compartment-skewed module representation in femoral tissue and peripheral monocytes, whereas single-cell analysis localized module scores mainly to stromal and myeloid populations. Myeloid pseudotime analysis identified three associated gene programs reflecting innate defense, interferon activation, and remodeling/lipid handling. Spatial transcriptomics further revealed niche-associated module distributions, trabecula-related gradients, and nonrandom spatial clustering, particularly for bone-remodeling, inflammation/cell-fate, and oxidative stress/mitochondrial modules. These findings provide a spatially contextualized, hypothesis-generating AOP framework that organizes cadmium-osteoporosis association evidence with osteoporosis-relevant molecular and spatial patterns. The proposed relationships require validation in longitudinal exposure studies and experimental models.