Depletion of Liver Glutathione Levels in Rats: A Potential Confound of Nose-Only Inhalation

Abstract

Nose-only inhalation exposure chambers offer key advantages to whole-body systems, particularly when aerosol or mixed aerosol-vapor exposures are used. Specifically, nose-only chambers provide enhanced control over the route of exposure and dose by minimizing the deposition of particles either on the subjects skin/fur or on surfaces of a whole-body exposure system. In the current series of experiments, liver, brain, and lung total glutathione (GSH) levels were assessed following either nose-only or whole-body exposures to either jet fuel or to clean, filtered air. The data were compared to untreated control subjects. Acute nose-only inhalation exposures of rats resulted in a significant depletion of liver GSH levels both in subjects that were exposed to clean, filtered air as well as those exposed to JP-8 jet fuel and to a synthetic jet fuel. Glutathione levels were not altered in lung or brain tissue. Whole-body inhalation exposure had no effect on GSH levels in any tissue for any of the treatment groups. A second experiment demonstrated that the loss of GSH did not occur if rats were anaesthetized prior to and during nose-only exposure to clean, filtered air or to mixed hydrocarbons. These data appear to be consistent with studies demonstrating depletion in liver GSH levels among rats subjected to restraint stress. Finally, the depletion of GSH that was observed in liver following a single acute exposure was reduced following five daily exposures to clean, filtered air, suggesting the possibility of habituation to restraint in the nose-only exposure chamber. The finding that placement in a nose-only exposure chamber per se yields liver GSH depletion raises the possibility of an interaction between this mode of toxicant exposure and the toxicological effects of certain inhaled test substances.Nose-only inhalation exposure chambers provide toxicologists with a convenient means of exposing laboratory animals to investigational compounds while minimizing the deposition of such compounds on the subjects' skin or fur from which it might be ingested. Nose-only exposure, then, is particularly useful when test compounds contain significant aerosol components and when the investigator either seeks to determine the effect of the test compound specifically on the lungs and conducting airways or wishes to model deposition of compounds in these airways.This investigation stems from the observation that nose-only inhalation exposure to JP-8 jet fuel yielded a significant deple-

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“…Superoxide Dismutase (SOD) activity was determined as previously described by some resesarchers [17,18].…”

“…This goes with a previous work by Raza et al, [20] that recorded decrease in brain GSH with concomitant increase in lipid peroxidation levels after gasoline exposure in plants. The decrease in glutathione levels due to inhalation of the organic chemicals is attributed to the oxidative stress induced by Fechter et al, [18].…”

l-Cysteine augments microtubule-associated protein 2 levels and enhances antioxidant activity in rats following traumatic brain injury

“…l-Cysteine is a well-known sulfur-containing non-essential amino acid that is oxidized to cysteine (Lee et al 2013), which exerts antioxidant activities (Lee et al 2013;Elias et al 2005;Miura et al 2014). l-Cysteine is also important for glutathione (GSH), which is a key antioxidant molecule in cellular systems (Fechter et al 2008); accordingly, Jain et al (2016) reported that oral supplementation with l-cysteine upregulates circulating levels of GSH.…”

Guidance Document 116 on the Conduct and Design of Chronic Toxicity and Carcinogenicity Studies, Supporting Test Guidelines 451, 452 and 453

“…These effects have been seen in animals exposed to clean air in nose-only exposure tubes for varying lengths (van Eijl et al, 2006;Narciso et al, 2003). There is the potential for stress experienced by animals in nose-only exposure studies to affect the results of the study by affecting immune competence (Bernet et al, 1998;Jakab and Hemenway 1989) or xenobiotic metabolism (Fechter et al, 2008), or by modulating gene expression in key organs (Thomson et al, 2009;Ha et al, 2003;Laconi et al, 2000;Panuganti et al, 2006;Sato et al, 2006;Yin et al, 2006), although some did not find confounding effects (Rothenberg et al, 2000). The duration of a chronic toxicity study by the inhalation route will normally be 12 months and that for a carcinogenicity study will be 18-24 months, dependent on the species used (see also Section 3.3.3 of this guidance).…”