Acute Exposure to Ozone Exacerbates Acetaminophen-Induced Liver Injury in Mice

Abstract

Ozone (O(3)), an oxidant air pollutant in photochemical smog, principally targets epithelial cells lining the respiratory tract. However, changes in gene expression have also been reported in livers of O(3)-exposed mice. The principal aim of the present study was to determine if acute exposure to environmentally relevant concentrations of O(3) could cause exacerbation of drug-induced liver injury in mice. Overdose with acetaminophen (APAP) is the most common cause of drug-induced liver injury in developed countries. In the present study, we examined the hepatic effects of acute O(3) exposure in mice pretreated with a hepatotoxic dose of APAP. C57BL/6 male mice were fasted overnight and then given APAP (300 mg/kg ip) or saline vehicle (0 mg/kg APAP). Two hours later, mice were exposed to 0, 0.25, or 0.5 ppm O(3) for 6 h and then sacrificed 9 or 32 h after APAP administration (1 or 24 h after O(3) exposure, respectively). Animals euthanized at 32 h were given 5-bromo-2-deoxyuridine 2 h before sacrifice to identify hepatocytes undergoing reparative DNA synthesis. Saline-treated mice exposed to either air or O(3) had no liver injury. All APAP-treated mice developed marked centrilobular hepatocellular necrosis that increased in severity with time after APAP exposure. O(3) exposure increased the severity of APAP-induced liver injury as indicated by an increase in necrotic hepatic tissue and plasma alanine aminotransferase activity. O(3) also caused an increase in neutrophil accumulation in livers of APAP-treated animals. APAP induced a 10-fold increase in the number of bromodeoxyuridine-labeled hepatocytes that was markedly attenuated by O(3) exposure. Gene expression analysis 9 h after APAP revealed differential expression of genes involved in inflammation, oxidative stress, and cellular regeneration in mice treated with APAP and O(3) compared to APAP or O(3) alone, providing some indications of the mechanisms behind the APAP and O(3) potentiation. These results suggest that acute exposure to near ambient concentrations of this oxidant air pollutant may exacerbate drug-induced liver injury by delaying hepatic repair.

Mapping Acute Systemic Effects of Inhaled Particulate Matter and Ozone: Multiorgan Gene Expression and Glucocorticoid Activity

“…Ozone increased CYP1A1 mRNA in the heart, an effect generally considered cardiotoxic although the actual function of CYP1A1 in either a harmful or protective capacity is not well understood (Korashy and El-Kadi, 2006). Impacts of ozone inhalation on the liver have been noted previously, including exacerbation of acetaminophen-induced toxicity that correlated with reduced expression of inflammation and xenobiotic metabolism pathway genes (Aibo et al ., 2010), but the factor(s) responsible for these effects are not known. Given the recent report that pretreatment with glucocorticoid receptor inhibitors protects mice from acetaminophen-induced liver injury (Masson et al ., 2010), it is possible that ozone-induced corticosterone is at least partly responsible for the acetaminophen-ozone interactions observed in previous studies.…”

Ozone inhalation modifies the rat liver proteome

“…For example, animals predisposed to heart disease display greater vascular injury when exposed to O 3 [10] . In addition, rodents administered acetaminophen, a known hepatotoxicant, have increased liver injury following O 3 exposure [54] . Also, genetic predisposition to obesity in multiple animal models modulates airway hypersensitivity and inflammatory cytokines as compared to unexposed obese controls [55–57] .…”

Environmental exposure as a risk-modifying factor in liver diseases: Knowns and unknowns

“…In contrast, several studies in preclinical models support at least the notion of such a potential interaction. For example, APAP toxicity is enhanced by coexposure to several environmental chemicals in animal models 33 , 34 , 35 . Interestingly, the finding that respiratory ozone exposure enhances experimental APAP-induced liver injury suggests the potential for organ–organ interactions in this process 33 .…”

“…For example, APAP toxicity is enhanced by coexposure to several environmental chemicals in animal models 33 , 34 , 35 . Interestingly, the finding that respiratory ozone exposure enhances experimental APAP-induced liver injury suggests the potential for organ–organ interactions in this process 33 . The mechanisms by which environmental chemicals may enhance dDILI focus largely on increased metabolic intoxication ( e.g ., the interaction between alcohol exposure and acetaminophen), enhanced response to injury ( e.g ., inflammation), as well as impaired regeneration/recovery (see Section 9 ).…”

“…This famous quote by the astrophysicist Neil deGrasse Tyson highlights the difficulty in making conclusions on what is known when all data are not available. This review will highlight the knowledgebase of environmental exposure as a potential risk-modifying agent for the development of liver disease by other causes ( Table 1 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 ). We will focus on what is known, as well as prospects for better understanding ( i.e ., unknowns).…”