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 non-alcoholic fatty liver disease (NAFLD), common in US 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.

Influenza is a significant health concern worldwide. Viral infection induces local and systemic activation of the immune system causing attendant changes in metabolism. High-resolution metabolomics (HRM) uses advanced mass spectrometry and computational methods to measure thousands of metabolites inclusive of most metabolic pathways. We used HRM to identify metabolic pathways and clusters of association related to inflammatory cytokines in lungs of mice with H1N1 influenza virus infection. Infected mice showed progressive weight loss, decreased lung function, and severe lung inflammation with elevated cytokines [interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ] and increased oxidative stress via cysteine oxidation. HRM showed prominent effects of influenza virus infection on tryptophan and other amino acids, and widespread effects on pathways including purines, pyrimidines, fatty acids, and glycerophospholipids. A metabolome-wide association study (MWAS) of the aforementioned inflammatory cytokines was used to determine the relationship of metabolic responses to inflammation during infection. This cytokine-MWAS (cMWAS) showed that metabolic associations consisted of distinct and shared clusters of 396 metabolites highly correlated with inflammatory cytokines. Strong negative associations of selected glycosphingolipid, linoleate, and tryptophan metabolites with IFN-γ contrasted strong positive associations of glycosphingolipid and bile acid metabolites with IL-1β, TNF-α, and IL-10. Anti-inflammatory cytokine IL-10 had strong positive associations with vitamin D, purine, and vitamin E metabolism. The detailed metabolic interactions with cytokines indicate that targeted metabolic interventions may be useful during life-threatening crises related to severe acute infection and inflammation.

Acylcarnitines transport fatty acids into mitochondria and are essential for β-oxidation and energy metabolism. Decreased mitochondrial activity results in increased plasma acylcarnitines, and increased acylcarnitines activate proinflammatory signaling and associate with age-related disease. Changes in acylcarnitines associated with healthy aging, however, are not well characterized. In the present study, we examined the associations of plasma acylcarnitines with age (range: 20-90) in 163 healthy, non-diseased individuals from the predictive medicine research cohort (NCT00336570) and tested for gender-specific differences. The results show that long-chain and very long-chain acylcarnitines increased with age, while many odd-chain acylcarnitines decreased with age. Gender-specific differences were observed for several acylcarnitines, e.g., eicosadienoylcarnitine varied with age in males, and hydroxystearoylcarnitine varied in females. Metabolome-wide association study (MWAS) of age-associated acylcarnitines with all untargeted metabolic features showed little overlap between genders. These results show that plasma concentrations of acylcarnitines vary with age and gender in individuals selected for criteria of health. Whether these variations reflect mitochondrial dysfunction with aging, mitochondrial reprogramming in response to chronic environmental exposures, early pre-disease change, or an adaptive response to healthy aging, is unclear. The results highlight a potential utility for untargeted metabolomics research to elucidate gender-specific mechanisms of aging and age-related disease.