Oxidative stress-mediated induction of pulmonary oncogenes, inflammatory, and apoptotic markers following time-course exposure to ethylene glycol monomethyl ether in rats

Abstract

Ethylene glycol monomethyl ether (EGME) has been used in many products usually handled by humans including inks, paints, polishes, brake fluids and so on. This present study therefore, investigated its effect on lung, in a time-course study in male Wistar rats. Animals were orally administered 50 mg/kg body weight of EGME for a period of 7, 14, and 21 days. Following 7 days of oral exposure to EGME, activities of GPx and SOD were significantly increased, as well as levels of K-Ras, c-Myc, p53, caspase-3, TNF-α and, IL-6, while NO level and GST activity were significantly reduced compared with control. At the end of 14 days exposure, GSH level was significantly decreased, while levels of K-Ras, c-Myc, p53, caspase-3, TNF-α, IL-6, NO and the activities of SOD and GPx were significantly elevated with respect to control. After 21 days of EGME administration, levels of Bcl-2, IL-10, GSH and NO as well as GST activity were significantly decreased, while levels of K-Ras, c-Myc, p53, Bax, caspase-3, IL-6, IL-1β, TNF-α, as well as GPx, CAT, and SOD activities were significantly elevated compared with control. Lung histopathology revealed chronic disseminated alveolar inflammation, bronchiolitis, severe alveolar and bronchi hyperplasia, severe disseminated inflammation, thrombosis, and thickened vessels as a result of EGME exposures. Exposures to EGME could trigger lung damage via the disorganization of the antioxidant system, eliciting the up-regulation of inflammatory, apoptotic, and oncogenic markers in rats.

Keywords: Apoptosis; Bax, Bcl-2 associated X; Bcl-2, B-cell lymphoma 2; CAT, catalase; Ethylene glycol monomethyl ether; GPx, glutathione peroxidase; GSH, reduced glutathione; GST, glutathione S-transferase; Histopathology; IL-1β, interleukin-1 beta; IL-6, interleukin-6; Inflammation; K-Ras, Kirsten rat sarcoma viral oncogene; Lung; MDA, malondialdehyde; NO, nitric oxide; Oncogenes; Oxidative stress; SOD, superoxide dismutase; TNF-α, tumor necrosis factor alpha; c-myc, myelocytomatosis; p53, tumor suppressor protein.

Fig. 1

Time course effect of EGME on relative lung weight. Values are expressed as mean ± standard error of the mean (n = 5). Bars labeled with different letters are statistically significant (p < 0.05).

Fig. 2

Time course effect of EGME on lung MDA (2A), NO (2B), and GSH (2C) concentrations. Values are expressed as mean ± standard error of the mean (n = 5). Bars labeled with different letters are statistically significant (p < 0.05).

Fig. 3

Time course effect of EGME on lung GPx (3A), GST (3B), SOD (3C), and CAT (3D) activities. Values are expressed as mean ± standard error of the mean (n = 5). Bars labeled with different letters are statistically significant (p < 0.05).

Fig. 4

Time course effect of EGME on lung TNF-α (4A), IL-6 (4B), IL-1β (4C), and IL-10 (4D) levels. Values are expressed as mean ± standard error of the mean. Bars labeled with different letters are statistically significant (p < 0.05).

Fig. 5

Time course effect of EGME on lung p53 (5A), caspase-3 (5B), Bax (5C) and Bcl-2 (5D) levels. Values are expressed as mean ± standard error of the mean. Bars labeled with different letters are statistically significant (p < 0.05).

Fig. 6

Time course effect of EGME on lung c-myc (6A) and K-Ras (6B) levels. Values are expressed as mean ± standard error of the mean. Bars labeled with different letters are statistically significant (p < 0.05).

Fig. 7

Lung microphotographs (x 100) showing (A) normal architecture; (B) disseminated alveolar inflammation, peribronchiolar inflammation, thickened vessels, thrombosis, and alveolar hyperplasia; (C) bronchiolitis, severe alveolar hyperplasia, severe disseminated inflammation, thrombosis, and thickened vessels; and (D) chronic disseminated alveolar inflammation, bronchiolitis, severe alveolar and bronchi hyperplasia, severe disseminated inflammation, thrombosis, and thickened vessels. A = Day 0; B = Day 7; C = Day 14; D = Day 21.