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Transcriptional Activation of Stress Genes and Cytotoxicity in Human Liver Carcinoma (HepG2) Cells Exposed to Pentachlorophenol
Molecular Toxicology Research Laboratory, NIH-Center for Environmental Health, School of Science and Technology, Jackson State University, 1400 Lynch Street, P.O. Box 18540, Jackson, Mississippi 39217, USA
Xenometrix Research Laboratory, Xenometrix, Inc., Boulder, Colorado 80301, USA
* Author to whom correspondence should be addressed.
Received: 7 June 2002 / Accepted: 30 September 2002 / Published: 30 September 2002
Abstract: Pentachlorophenol (PCP) is a biocidal chemical with several industrial, agricultural, and domestic applications. There is accumulating evidence indicating that PCP is highly toxic to humans, with major target organs including the lung, liver, kidneys, heart, and brain. Little is known regarding the molecular basis by which PCP induces toxicity, mutagenesis, and carcinogenesis. Therefore, this research was designed to assess the cellular and molecular responses of HepG2 cells following exposure to PCP. The cytotoxicity experiment yielded a LD50 value of 23.4 + 9.7 μg PCP/mL upon 48 hrs of exposure, indicating that PCP is acutely toxic. A dose-response relationship was recorded with respect to gene induction. For example, fold inductions of CYP1A1 were 1.0 + 0.0, 1.0 + 0.0, 1.3 + 0.5, 6.3 + 4.3, and 22.5 + 3.5 for 0, 6.2, 12.5, 25, and 50 μg PCP/mL, respectively. Overall, five out of the thirteen recombinant cell lines tested showed inductions to statistically significant levels (p < 0.05). At 50 μg PCP/mL, the average fold inductions were 22.5 + 3.5, 52.8 + 2.5, 8.4 + 1.9, 6.16 + 2.4, and 12.5 + 6.8, for CYP1A1, XRE, HMTIIA, c-fos, and GADD153, respectively. These results indicate the potential of PCP to undergo Phase I biotransformation in the liver (CYP1A1, XRE), to cause cell proliferation (c-fos), growth arrest and DNA damage (GADD153), and to influence the toxicokinetics of metal ions (HMTIIA). Marginal inductions were recorded for HSP70, CRE, RARE, GADD45, and GRP78. Within the dose range (0-100 μg/mL) tested, no significant inductions (p < 0.05) were observed for GSTYa, NFkBRE, and p53RE.
Keywords: Pentachlorophenol; cytotoxicity; gene expression; HepG2 cells
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Dorsey, W.C.; Tchounwou, P.B.; Ishaque, A.B.; Shen, E. Transcriptional Activation of Stress Genes and Cytotoxicity in Human Liver Carcinoma (HepG2) Cells Exposed to Pentachlorophenol. Int. J. Mol. Sci. 2002, 3, 992-1007.
Dorsey WC, Tchounwou PB, Ishaque AB, Shen E. Transcriptional Activation of Stress Genes and Cytotoxicity in Human Liver Carcinoma (HepG2) Cells Exposed to Pentachlorophenol. International Journal of Molecular Sciences. 2002; 3(9):992-1007.
Dorsey, Waneene C.; Tchounwou, Paul B.; Ishaque, Ali B.; Shen, Elaine. 2002. "Transcriptional Activation of Stress Genes and Cytotoxicity in Human Liver Carcinoma (HepG2) Cells Exposed to Pentachlorophenol." Int. J. Mol. Sci. 3, no. 9: 992-1007.