Inhaled Furan Selectively Damages Club Cells in Lungs of A/J Mice

Abstract

Furan, a possible human carcinogen, is a product of incomplete combustion and is present in cigarette smoke, engine exhaust, and processed food. Oral administration induces liver toxicity and carcinogenesis in F344 rats and B6C3F1 mice. To assess possible adverse effects from inhalation, A/J mice were nose-only exposed for 3 hours to furan (0, 30, 75, 150, 300, or 600 ppmv) and euthanized after 24 hours, 48 hours, or 1 week. Histopathology evaluation revealed bronchiolar club cell necrosis (diffuse, marked) with airway denudation following exposure to 300 and 600 ppmv furan with evidence of club cell regeneration and partial repair after 1 week. Initial signs of hepatotoxicity were observed in the 150 ppmv furan-exposed group. Acute necrosis and mineralization were observed in livers at 24 and 48 hours with hepatocyte regeneration by 1-week postexposure in mice exposed to 300 and 600 ppmv furan; the 300 ppmv exposed group had multifocal mineralization that evoked a mild granulomatous response. Measurement of urinary furan metabolites confirmed that the mice metabolized furan to the toxic intermediate, cis-2-butene-1,4-dial. These observations indicate that inhaled furan is toxic to lungs with club cells as the target as well as liver.

Effect of Atmospheric Aging on Soot Particle Toxicity in Lung Cell Models at the Air–Liquid Interface: Differential Toxicological Impacts of Biogenic and Anthropogenic Secondary Organic Aerosols (SOAs)

“…( 2020 ) pointed out the importance of short-lived unsaturated carbonyls in aged naphthalene as the main toxic components at the posttranslational level. Furthermore, the oxidation of furan-containing compounds favored the formation of epoxides, which are associated with enhanced harmful cellular effects ( Peterson 2013 ; Tǎbǎran et al. 2019 ).…”

Small Airway Susceptibility to Chemical and Particle Injury

“…For example, cytochrome B5 in mice is restricted to the bronchiolar region and not expressed in larger bronchial or smaller alveolar structures [85]. The toxicity of the combustion product furan was found to have specific bronchiolar injury attributable to CYP2E1 expression in secretory club cells [86]. It has also long been recognized that chemicals such as styrene, permethrin, and fluensulfone among others [87-89] are specifically toxic to the TBs in mice, attributable to the high number of metabolically active secretory club cells in this region enriched for CYP2F2 activity [90].…”

Furan Metabolites Are Elevated in Users of Various Tobacco Products and Cannabis

“…Furan is a product of incomplete combustion and is present in mainstream tobacco smoke at concentrations (7–65 μg/cigarette) comparable to other toxic volatile organic compounds (VOCs) such as 1,3-butadiene (16–75 μg/cigarette) and benzene (6–73 μg/cigarette). − Furan is a liver and lung toxicant and a liver carcinogen in rodents. − Furan’s toxicity requires cytochrome P450 2E1 (CYP2E1) catalyzed oxidation; − the initial product of this oxidation is 2- cis -butene-1,4-dial (BDA, Scheme ). , Furan’s urinary metabolites result from the reaction of BDA with lysine (BDA- N α -acetyllysine, 1 ) and from cysteine-BDA-lysine cross-links ( N -acetylcysteine-BDA-lysine 2 , N -acetylcysteine-BDA- N α -acetyllysine 4 , and their sulfoxides 3 and 5 ) (Scheme ).…”

“…With oral administration, the liver is the primary site of toxicity ,,, because of the extensive first pass metabolism due to the high hepatic levels of CYP2E1 . Consequently, very little furan enters the central circulation system, protecting extrahepatic tissues from furan’s toxic effects. , Lungs are susceptible to toxicity when furan is administered by inhalation . It is noteworthy that the lung cells targeted by an acute exposure to inhaled furan are club cells, which are rich in CYP2E1 .…”

“…15,47 Lungs are susceptible to toxicity when furan is administered by inhalation. 13 It is noteworthy that the lung cells targeted by an acute exposure to inhaled furan are club cells, which are rich in CYP2E1. 48 The larger bioavailability of inhaled furan may also cause other CYP2E1-expressing organ systems to be at risk.…”