Low‐dose oral cadmium increases airway reactivity and lung neuronal gene expression in mice. Issue 13 (12th July 2016)

• Record Type: Journal Article
• 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.
• Is Part Of: Physiological reports. Volume 4:Issue 13(2016:Jul.)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2016-07-12
• Subjects: Airway resistance -- chemosensory function -- metabolomics -- metal toxicity -- transcriptomics; Physiology -- Periodicals; 571
• DOI: 10.14814/phy2.12821
• Languages: English
• ISSNs: 2051-817X

Abstract

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. Abstract : Mice were exposed to cadmium (Cd) in drinking water for 20 weeks at a dose that resulted in lung tissue burden comparable to levels in adult lung transplant recipients. Cd exposure was associated with increased airway hyperresponsiveness and increased lung tissue gene expression in neuronal pathways, especially olfactory and glutamatergic pathways. We confirmed protein increase of the NMDA receptor gene GRIN2A, increased glutamate and other lung tissue metabolites which may have contributed to the increased airway resistance, suggesting that the public health risks of oral Cd may need to be more closely evaluated with respect to lung diseases.