Low-dose oral cadmium increases airway reactivity and lung neuronal gene expression in mice

Abstract

Inhalation of cadmium (Cd) is associated with lung diseases, but less is known concerning pulmonary effects of Cd found in the diet. Cd has a decades‐long half‐life in humans and significant bioaccumulation occurs with chronic dietary intake. We exposed mice to low‐dose CdCl2 (10 mg/L in drinking water) for 20 weeks, which increased lung Cd to a level similar to that of nonoccupationally exposed adult humans. Cd‐treated mice had increased airway hyperresponsiveness to methacholine challenge, and gene expression array showed that Cd altered the abundance of 443 mRNA transcripts in mouse lung. In contrast to higher doses, low‐dose Cd did not elicit increased metallothionein transcripts in lung. To identify pathways most affected by Cd, gene set enrichment of transcripts was analyzed. Results showed that major inducible targets of low‐dose Cd were neuronal receptors represented by enriched olfactory, glutamatergic, cholinergic, and serotonergic gene sets. Olfactory receptors regulate chemosensory function and airway hypersensitivity, and these gene sets were the most enriched. Targeted metabolomics analysis showed that Cd treatment also increased metabolites in pathways of glutamatergic (glutamate), serotonergic (tryptophan), cholinergic (choline), and catecholaminergic (tyrosine) receptors in the lung tissue. Protein abundance measurements showed that the glutamate receptor GRIN2A was increased in mouse lung tissue. Together, these results show that in mice, oral low‐dose Cd increased lung Cd to levels comparable to humans, increased airway hyperresponsiveness and disrupted neuronal pathways regulating bronchial tone. Therefore, dietary Cd may promote or worsen airway hyperresponsiveness in multiple lung diseases including asthma.

Cadmium stimulates myofibroblast differentiation and mouse lung fibrosis

“…For these studies, the mouse food was nominally Cd-free, equivalent to intake of 0.04 mg/L in the drinking water (Chandler et al 2016). Lung samples were harvested from the mice at the end of 16 weeks and the left lobes of lung tissues treated with 10% neutral formalin for fixation.…”

“…We use 1 μM as our in vitro reference dose (Go et al 2013a, b) because this is similar to the concentration found in human lung (Chandler et al 2016), does not cause cell death, and activates proinflammatory signaling similarly to that observed with mouse models in which oral Cd is provided to raise lung Cd to values similar to human lung Cd content (Chandler et al 2016). Our previous study of Cd in this range showed that Cd disrupts actin cytoskeleton regulation in lung fibroblast by stimulating actin polymerization (Go et al 2013a).…”

Low-dose cadmium potentiates lung inflammatory response to 2009 pandemic H1N1 influenza virus in mice

“…Male C57BL6 mice (n = 11 -13 per group) aged 8 weeks (Jackson Labs, Bar Harbor, ME, USA) were maintained in clean facilities and given sterile-filtered drinking water with 1 mg/L CdCl 2 (Sigma-Aldrich, St. Louis, MO, USA) or vehicle for 16 weeks. Food content of Cd (62 ± 1 ng/g food) was negligible compared to the Cd derived from water (1). Ten days prior to study completion, mice were inoculated with H1N1 (A/California/04/2009; dose of 0.6 x 10 3 pfu) under isoflurane anesthesia.…”

“…Lung tissue 114 Cd was assayed as previously described (1). ICP-MS procedures conformed to accuracy (100 ± 10%) and precision standards (relative standard deviation < 12%).…”

“…Recent studies of the environmental toxic metal cadmium (Cd) show that Cd at levels found in human lungs potentiates pro-inflammatory signaling by the redox-sensitive transcription factor NF-κB (1,2). Cd is a commercially important metal used in NiCd batteries, plating, pigments and plastics (3)(4)(5).…”