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

Authors: Chandler, Joshua D; Wongtrakool, Cherry; Banton, Sophia A; Li, Shuzhao; Orr, Michael L; Barr, Dana Boyd; Neujahr, David C; Sutliff, Roy L; Go, Young-Mi; Jones, Dean P

Published In Physiol Rep, (2016 Jul)

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.

PubMed ID: 27401458 Exiting the NIEHS site

MeSH Terms: Airway Resistance/drug effects; Animals; Body Burden; Bronchial Hyperreactivity/chemically induced*; Bronchial Hyperreactivity/physiopathology; Bronchial Provocation Tests; Bronchoconstriction/drug effects*; Cadmium Chloride/administration & dosage; Cadmium Chloride/metabolism; Cadmium Chloride/toxicity*; Cholinergic Neurons/drug effects; Cholinergic Neurons/metabolism; Dose-Response Relationship, Drug; Gene Expression Profiling; Gene Expression Regulation/drug effects*; Glutamic Acid/metabolism; Lung/drug effects*; Lung/innervation; Lung/metabolism; Male; Mice, Inbred C57BL; Neurons/drug effects*; Neurons/metabolism; Olfactory Receptor Neurons/drug effects; Olfactory Receptor Neurons/metabolism; RNA, Messenger/genetics; RNA, Messenger/metabolism; Receptors, N-Methyl-D-Aspartate/drug effects; Receptors, N-Methyl-D-Aspartate/genetics; Receptors, N-Methyl-D-Aspartate/metabolism; Risk Assessment; Serotonergic Neurons/drug effects; Serotonergic Neurons/metabolism; Time Factors

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