title: 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.
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Emory University, Atlanta, Georgia.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Chandler
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Emory University, Atlanta, Georgia Atlanta VA Medical Center, Decatur, Georgia.
authors.forename: Cherry
authors.initials: C
authors.lastname: Wongtrakool
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Emory University, Atlanta, Georgia.
authors.forename: Sophia A
authors.initials: SA
authors.lastname: Banton
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Emory University, Atlanta, Georgia.
authors.forename: Shuzhao
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Emory University, Atlanta, Georgia.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Orr
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, Georgia.
authors.forename: Dana Boyd
authors.initials: DB
authors.lastname: Barr
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Emory University, Atlanta, Georgia.
authors.forename: David C
authors.initials: DC
authors.lastname: Neujahr
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Emory University, Atlanta, Georgia Atlanta VA Medical Center, Decatur, Georgia.
authors.forename: Roy L
authors.initials: RL
authors.lastname: Sutliff
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Emory University, Atlanta, Georgia.
authors.forename: Young-Mi
authors.initials: YM
authors.lastname: Go
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Emory University, Atlanta, Georgia dpjones@emory.edu.
authors.forename: Dean P
authors.initials: DP
authors.lastname: Jones
mesh_terms: D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001822:Body Burden; D016535:Bronchial Hyperreactivity / Q000139:chemically induced* / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects*; D019256:Cadmium Chloride / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D059329:Cholinergic Neurons / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D018698:Glutamic Acid / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018034:Olfactory Receptor Neurons / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018570:Risk Assessment; D059326:Serotonergic Neurons / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
chemical_list: D019256:Cadmium Chloride; D018698:Glutamic Acid; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate
keywords: Airway resistance; chemosensory function; metabolomics; metal toxicity; transcriptomics