title: Low-Dose Cadmium Causes Metabolic and Genetic Dysregulation Associated With Fatty Liver Disease in Mice.
abstract: Cadmium (Cd) is present in food at low levels and accumulates in humans throughout life because it is not effectively excreted. Cd from smoking or occupational exposure shows adverse effects on health, but the mechanistic effect of Cd at low dietary intake levels is poorly studied. Epidemiology studies found that nonalcoholic fatty liver disease (NAFLD), common in U.S. adults, is associated with Cd burden. In cell studies, we found that environmental low-dose Cd oxidized proteins and stimulated inflammatory signaling. However, little is known about low-dose Cd effects on liver function and associated metabolic pathways in vivo. We investigated effects of low-level Cd exposure on liver gene transcripts, metabolites, and associated metabolic pathways and function after challenging mice with Cd (10 mg/l) by drinking water. Results showed liver Cd in treated mice was similar to adult humans without occupational or smoking exposures and 10-fold higher than control mouse values. Pathway analysis of significantly altered liver genes and metabolites mapped to functional pathways of lipid metabolism, cell death and mitochondrial oxidative phosphorylation. These are well-recognized pathways associated with NAFLD. Cd-treated mice had higher liver enzymes in plasma and a trend toward fat accumulation in liver. To verify low-dose Cd-induced stimulation of cell death pathways, phosphorylation of c-Jun N-terminal kinase (JNK) was examined in cultured hepatic cells. Consistent with mouse liver data, low-dose Cd stimulated JNK activation. Together, the results show that low-dose Cd exposure causes liver function changes consistent with a role in NAFLD and possibly also nonalcoholic steatohepatitis.
authors.affiliation: *Division of Pulmonary, Allergy and Critical Care Medicine, and.
authors.forename: Young-Mi
authors.initials: YM
authors.lastname: Go
authors.affiliation: *Division of Pulmonary, Allergy and Critical Care Medicine, and.
authors.forename: Roy L
authors.initials: RL
authors.lastname: Sutliff
authors.affiliation: *Division of Pulmonary, Allergy and Critical Care Medicine, and.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Chandler
authors.affiliation: Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia 30322.
authors.forename: Rahman
authors.initials: R
authors.lastname: Khalidur
authors.affiliation: *Division of Pulmonary, Allergy and Critical Care Medicine, and.
authors.forename: Bum-Yong
authors.initials: BY
authors.lastname: Kang
authors.affiliation: Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia 30322.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Anania
authors.affiliation: *Division of Pulmonary, Allergy and Critical Care Medicine, and.
authors.forename: Michael
authors.initials: M
authors.lastname: Orr
authors.affiliation: *Division of Pulmonary, Allergy and Critical Care Medicine, and.
authors.forename: Li
authors.initials: L
authors.lastname: Hao
authors.affiliation: *Division of Pulmonary, Allergy and Critical Care Medicine, and.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Fowler
authors.affiliation: *Division of Pulmonary, Allergy and Critical Care Medicine, and dpjones@emory.edu.
authors.forename: Dean P
authors.initials: DP
authors.lastname: Jones
mesh_terms: D000818:Animals; D002104:Cadmium / Q000008:administration & dosage / Q000032:analysis / Q000633:toxicity*; D005234:Fatty Liver / Q000139:chemically induced* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008562:Membrane Glycoproteins; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D017472:Receptors, Interleukin-1
chemical_list: D008562:Membrane Glycoproteins; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; D002104:Cadmium
keywords: apoptosis; environmental toxicant; metabolomics; nonalcoholic fatty liver disease; transcriptomics