Cytotoxicity and Expression of c-fos, HSP70, and GADD45/153 Proteins in Human Liver Carcinoma (HepG 2 ) Cells Exposed to Dinitrotoluenes

Konsuela Y. Glass, Cecilia R. Newsome and Paul B. Tchounwou
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Konsuela Y. Glass: Molecular Toxicology Research Laboratory, NIH-Center for Environmental Health, School of Science and Technology, Jackson State University, 140 Lynch Street, P.O. Box 18540, Jackson, MS 39217, USA
Cecilia R. Newsome: Molecular Toxicology Research Laboratory, NIH-Center for Environmental Health, School of Science and Technology, Jackson State University, 140 Lynch Street, P.O. Box 18540, Jackson, MS 39217, USA
Paul B. Tchounwou: Molecular Toxicology Research Laboratory, NIH-Center for Environmental Health, School of Science and Technology, Jackson State University, 140 Lynch Street, P.O. Box 18540, Jackson, MS 39217, USA

IJERPH, 2005, vol. 2, issue 2, 1-7

Abstract: Dinitrotoluenes (DNTs) are byproducts of the explosive trinitrotoluene (TNT), and exist as a mixture of 2 to 6 isomers, with 2,4-DNT and 2,6-DNT being the most significant. The main route of human exposure at ammunition facilities is inhalation. The primary targets of DNTs toxicity are the hematopoietic system, cardiovascular system, nervous system and reproductive system. In factory workers, exposure to DNTs has been linked to many adverse health effects, including: cyanosis, vertigo, headache, metallic taste, dyspnea, weakness and lassitude, loss of appetite, nausea, and vomiting. Other symptoms including pain or parasthesia in extremities, abdominal discomfort, tremors, paralysis, chest pain, and unconsciousness have been documented. An association between DNTs exposure and increased risk of hepatocellular carcinomas and subcutaneous tumors in rats, as well as renal tumors in mice, has been established. This research was therefore designed targeting the liver to assess the cellular and molecular responses of human liver carcinoma cells following exposure to 2,4-DNT and 2,6-DNT. Cytotoxicity was evaluated using the MTT assay. Upon 48 hrs of exposure, LC 50 values of 245 + 14.72?g/mL, and 300 + 5.92?g/mL were recorded for 2,6-DNT and 2,4-DNT respectively, indicating that both DNTs are moderately toxic, and 2,6-DNT is slightly more toxic to HepG 2 cells than 2,4-DNT. A dose response relationship was recorded with respect to the cytotoxicity of both DNTs. Western blot analysis resulted in a significant expression (p<0.05) of the 70-kDa heat shock protein in 2,6-DNT-treated cells compared to the control cells and at the 200 ?g/mL dose for 2,4-DNT. A statistically significant expression in c-fos was also observed at the 200 and 250 ?g/mL treatment level for 2,4- and 2,6-DNT, respectively. However, no statistically significant expression of this protooncogene-related protein was observed at the doses of 0, 100, or 300 ?g/mL or within the dose range of 0-200 ?g/mL for 2,6-DNT. The 45-kDa growth arrest and damage protein was significantly expressed at the dose range of 200 – 250?g/mL for 2,6-DNT and at the dose range of 200 - 400?g/mL for 2,4-DNT. Expression of 153-kDa growth arrest and DNA damage protein was significant at the 100, 200, and 250?g/mL doses for 2,6-DNT and at the 200 ?g/mL dose for 2,4-DNT. Overall, these results indicate the potential of DNTs to induce cytotoxic, proteotoxic (HSP70), and genotoxic (GADD45/153) effects, as well as oxidative stress and pro-inflammatory reactions ( c-fos ).

Keywords: dinitrotoluenes; cytotoxicity; c-fos; HSP70; GADD45; GADD153; HepG2 cells (search for similar items in EconPapers)
JEL-codes: I I1 I3 Q Q5 (search for similar items in EconPapers)
Date: 2005
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