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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年7月20日

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  • Ye Tong,
  • Baicheng Wan,
  • Gaofeng Zeng,
  • Shaohui Zong

摘要

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.