Our work provides preliminary evidence for significant interactions between a metal ion (Ni) and CAPs in terms of metabolic function. There are several important findings in this study. First, exposure to the combination of CAPs and Ni resulted in an increase in fasting glucose levels and a higher HOMA-IR index than exposure to CAPs alone. These changes were associated with decreased AMPK activity in the liver. Second, Ni exposure was equipotent to CAPs in terms of inflammatory cell infiltration in peripheral tissues, including the lung. Third, Ni co-exposure with CAPs synergized an induction of significant leukocyte adhesion and microcirculatory dysfunction. Finally, exposure to CAPs and Ni induced changes that are highly consistent with mitochondrial dysfunction.
Air pollution is a heterogeneous and complex mixture of compounds in gases, liquid droplets and solid particulate matter. Thus, the heterogeneous composition of the droplets and solid particles indicates that PM exposure may contribute to cellular and molecular toxicity through various pathways. Particle size, surface area, and chemical composition influence the health risk posed by PM. Exposure to ambient PM air pollution is associated with increased mortality and morbidity in susceptible populations. A number of studies have revealed that exposure to CAPs is related to acute and chronic effects on cardiac function, increased amounts of more invasive aortic plaque, inflammation, and insulin resistance, as well as adiposity
[9, 10, 19–22]. It has been reported that soluble transition metals, such as iron (Fe), Ni, and vanadium (V), are responsible for the majority of residual oil fly ash toxicity
[23, 24]. Lippmann et al.
 have demonstrated that Ni is significantly associated with acute changes in heart rate and its variability in CAPs-exposed and sham-exposed ApoE knockout mice. In this study, we used the whole body exposure system and exposed the same strain of the animal to CAPs and/or NiSO4 for 3 months. The concentration of Ni was expressed in terms of ng/m3, and it was much lower than the concentrations in any of the studies in which pure Ni compounds were used. We found that exposure to CAPs+Ni significantly induced inflammation in lung and adipose tissue, and enhanced the fasting glucose level and insulin resistance, although there was no significant difference in the intraperitoneal glucose tolerance test. In addition, exposure to NiSO4 exacerbated the microcirculatory dysfunction resulting from CAPs exposure. These findings suggest that Ni, together with the much larger mass concentration of the CAPs, has synergistic effects on these adverse health conditions.
Recent data in adult humans suggest an important link between BAT-mediated thermogenesis and obesity
. We have previously shown that long-term exposure to similar CAPs concentrations (for 10 months) induced a visible decrease in the iBAT and mitochondrial sizes
. These changes were accompanied by an increase in excess oxidative and nitrosative stress in BAT, coordinate with Phase II antioxidant gene induction including NF-E2-related factor 2 (Nrf2), NAD(P)H quinone oxidoreductase 1 (Nqo1) and glutamate-cysteine ligase modifier subunit (Gclm). BAT expressions of Ucp1 and Pgc-1α were decreased with CAPs exposure, while Prdm16, Pgc-1α, and Pparg2 were significantly decreased in the WAT, suggestive of downregulation of pathways that modulate insulin sensitivity in adipose
. Similar results were seen with the ApoE−/− model used in this study
. UCP1, which is specifically expressed in BAT mitochondria, is largely responsible for the uncoupling of respiration from ATP synthesis, resulting in dissipation of energy as heat
. In addition to UCP1, proteins such as Dio2 and PGC-1α have also been shown to be highly enriched in BAT, but low in WAT
[27, 28]. Furthermore, PGC-1α has been shown to coordinate multiple physiological cues for mitochondrial biogenesis and activity
. In this study, we demonstrated that exposure to CAPs and Ni reduces the brown adipocyte-specific gene expression in the BAT as well as WAT, suggesting that exposure to CAPs and Ni may induce important alteration in BAT and/or BAT-like phenotypic changes in WAT.
AMPK activity, measured as Thr172 phosphorylation, was reduced in the metabolically active tissues of the mice exposed to CAPs+Ni. AMPK, an enzyme central to cellular bioenergetics, is considered a major metabolic regulator at both cellular and whole-body levels
, and may regulate energy expenditure by modulating NAD+ metabolism and SIRT1 activity
. Activation of AMPK in the liver, skeletal muscle, and adipose tissue improves the status of type 2 diabetes
. AMP binds and activates AMPK, primarily by causing conformational changes that allow Thr172 phosphorylation to occur by upstream kinases. Yuan et al.
 reported that second-hand smoke inhibits AMPK and ACC phosphorylation, suggesting AMPK is critically involved in the adverse effects of smoking.
Characterization of the effects of inhalation exposures, and zeroing in on the PM2.5 sources, is challenging for a variety of reasons. First of all, ambient PM2.5 is intrinsically complex, with thousands of chemical components. Second, studies of inhalation exposures that mimic the real world scenarios in a laboratory environment require technical sophistication. Third, the data previously generated by exposing animal models to single metals have been either largely negative or hard to relate to data generated in in vitro experiments. In addition, a “knockout” design involving the elimination of certain metals from ambient air for an inhalation exposure is technically infeasible. To address those issues, we proposed an “overexpression” design by adding Ni to CAPs in comparison with CAPs alone, Ni alone, or FA. This design not only enabled us to address the differences among those groups, especially in indicating if Ni played a significant role in the development of the disorders that have been associated with ambient air PM2.5 exposures, but also reflected the real situations in some regions/countries of the world where the Ni levels in the ambient air are relatively high
[1, 33, 34].
In summary, our data suggest that Ni at a much lower concentration than that of CAPs (at a realistic level of CAPs exposure), can enhance metabolic disorders, mitochondrial dysfunction, and the monocytic cell infiltration into lung and adipose tissue. Therefore, they may explain an important role for co-exposure to Ni and CAPs in the development of metabolic disorders, and suggest an important public health impact of combined Ni and PM2.5 air pollution. Further understanding of the mechanism by which exposure to Ni and CAPs causes these adverse effects may provide novel prevention and therapeutic strategies for better control and treatment of metabolic disorders such as obesity, type 2 diabetes, and insulin resistance. The clinical implications of our results would be strengthened by further elucidation of the detailed mechanisms, and by alteration of the signaling pathways in exposed mice to assess possible improvement of mitochondrial biogenesis and reduction of the adverse health effects.