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.
3,3'-Dichlorobiphenyl (PCB 11) is a byproduct of industrial processes and detected in environmental samples. PCB 11 and its metabolites are present in human serum, and emerging evidence demonstrates that PCB 11 is a developmental neurotoxicant. However, little is known about the metabolism of PCB 11 in humans. Here we investigated the metabolism of PCB 11 and the associated metabolomics changes in HepG2 cells using untargeted high-resolution mass spectrometry. HepG2 cells were exposed for 24 h to PCB 11 in DMSO or DMSO alone. Cell culture media were analyzed with ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry. Thirty different metabolites were formed by HepG2 cells exposed to 10 μM PCB 11, including monohydroxylated, dihydroxylated, hydroxylatedmethoxylated, and methoxylated-di-hydroxylated metabolites, and the corresponding sulfo and glucuronide conjugates. The methoxylated PCB metabolites were observed for the first time in a human-relevant model. 4-OH-PCB 11 (3,3'-dichlorobiphenyl-4-ol) and the corresponding catechol metabolite, 4,5-di-OH-PCB 11 (3',5-dichloro-3,4-dihydroxybiphenyl), were unambiguously
Background The production ban of polychlorinated biphenyl (PCB) technical mixtures has left the erroneous impression that PCBs exist only as legacy pollutants. Some lower-chlorinated PCBs are still being produced and contaminate both indoor and ambient air. Objectives To inform PCB risk assessment, we characterized lung uptake, distribution, metabolism and excretion of PCB11 as a signature compound for these airborne non-legacy PCBs. Methods After delivering [14C]PCB11 to the lungs of male rats, radioactivity in 34 major tissues and 5 digestive matter compartments was measured at 12, 25, 50, 100, 200 and 720 min postexposure, during which time the excreta and exhaled air were also collected. [14C]PCB11 and metabolites in liver, blood, digestive matter, urine and adipose tissues were extracted separately to establish the metabolic profile of the disposition. Results [14C]PCB11 was distributed rapidly to all tissues after 99.8% pulmonary uptake and quickly underwent extensive metabolism. The major tissue deposition of [14C]PCB11 and metabolites translocated from liver, blood and muscle to skin and adipose tissue 200 min postexposure, while over 50% of administered dose was discharged via urine and feces within 12 h. Elimination of the [14C]PCB11 and metabolites consisted of an initial fast phase (t½ = 9-33 min) and a slower clearance phase to low concentrations. Phase II metabolites dominated in liver, blood and excreta after 25 min postexposure. Conclusions This study shows that PCB11 is completely absorbed after inhalation exposure and is rapidly eliminated from most tissues. Phase II metabolites dominated with a slower elimination rate than the PCB11 or phase I metabolites and thus can best serve as urine biomarkers of exposure.
Despite the continued presence of PCBs in indoor and ambient air, few studies have investigated the inhalation route of exposure. While dietary exposure has declined, inhalation of the semi-volatile, lower-chlorinated PCBs has risen in importance. We measured the uptake, distribution and time course of elimination of inhaled PCB congeners to characterize the pulmonary route after short-term exposure. Vapor-phase PCBs were generated from Aroclor 1242 to a nose-only exposure system and characterized for congener levels and profiles. Rats were exposed via inhalation acutely (2.4 mg/m3 for 2 hr) or subacutely (8.2 mg/m3, 2 hr × 10 days), after which pulmonary immune responses and PCB tissue levels were measured. Animals acutely exposed were euthanized at 0, 1, 3, 6 and 12 hr post exposure to assess the time course of PCB uptake and elimination. Following rapid absorption and distribution, PCBs accumulated in adipose tissue, but decayed in other tissues with half-lives increasing in liver (5.6 hr) < lung (8.2 hr) < brain (8.5 hr) < blood (9.7 hr). PCB levels were similar in lung, liver and adipose tissue, lower in brain and lowest in blood. Inhalation of the airborne PCB mixture contributed significantly to the body burden of lower chlorinated congeners. Congeners detected in tissue were mostly ortho-substituted ranging from mono- to pentachlorobiphenyls. Selective uptake and elimination led to accumulation of a distinct congener spectrum in tissue. Minimal evidence of toxicity was observed.
The recent discovery of 3,3′-dichlorobiphenyl (CB11) as a byproduct of pigment manufacturing underscores the urgency to investigate its biological fate. The high level and ubiquity of atmospheric CB11 indicates that inhalation is the major route of exposure. However, few data on its uptake and elimination exist. A time course study was performed exposing male Sprague-Dawley rats to CB11 via nose-only inhalation with necropsy at 0, 4 and 8 h post exposure. An analytical method for CB11 and mono-hydroxylated metabolites employing pressurized liquid extraction and gas chromatography-mass spectrometry yielded efficient recovery of CB11 (73±9%) and its metabolite 3,3′-dichlorobiphenyl-4-ol (4-OH-CB11) (82±12%). Each rat was exposed to 106 μg/m3 vapor-phase CB11 for 2 h and received an estimated dose of 1.8 μg. Rapid apparent first-order elimination of CB11 was found in lung, serum and liver with half-lives of 1.9, 1.8 and 2.1 h, respectively. 4-OH-CB11 was detected in the liver but not the lung or serum of exposed animals and displayed apparent first-order elimination with a 2.4 h half-life. This study demonstrates rapid metabolism of CB11 and elimination of 4-OH-CB11 and suggests that the metabolite is not retained in the body but is susceptible to further biotransformation.
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