Transcriptional Activation of Stress Genes and Cytotoxicity in Human Liver Carcinoma (HepG2) Cells Exposed to Pentachlorophenol

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 HepG 2 cells following exposure to PCP. The cytotoxicity experiment yielded a LD 50 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.

Neuregulin 1-Βeta Cytoprotective Role in AML 12 Mouse Hepatocytes Exposed to Pentachlorophenol

“…We have previously reported that the overexpression of the HSP70 gene protein is a dose-dependent event in HepG 2 cells exposed to PCP [18, 23]. …”

Mitogenic and Cytotoxic Effects of Pentachlorophenol to AML 12 Mouse Hepatocytes

“…Previous investigations in our laboratory have shown that PCP induces acute toxicity and transcriptionally activates a constellation of stress genes in HepG 2 cells [24]. From our laboratory findings, we demonstrated that PCP has the ability to undergo Phase I biotransformation in the liver (CYP1A1 and XRE), to cause cell proliferation (c-fos), to cause growth arrest and DNA damage (GADD153 and p53), to influence the toxicokinetics of metal ions (HMTIIA), and to induce proteotoxic effects (HSP70 and GRP78) in HepG 2 cells [1,24]. Our laboratory has recently reported that PCP exerts both cytotoxic and mitogenic effects in human liver carcinoma (HepG 2 ) cells [1], and primary culture of catfish hepatocytes [2].…”

“…It is believed that the mechanism by which PCP exerts its toxic action involves uncoupling mitochondrial oxidative phosphorylation, thereby causing accelerated aerobic metabolism and increasing heat production [22,23]. Previous investigations in our laboratory have shown that PCP induces acute toxicity and transcriptionally activates a constellation of stress genes in HepG 2 cells [24]. From our laboratory findings, we demonstrated that PCP has the ability to undergo Phase I biotransformation in the liver (CYP1A1 and XRE), to cause cell proliferation (c-fos), to cause growth arrest and DNA damage (GADD153 and p53), to influence the toxicokinetics of metal ions (HMTIIA), and to induce proteotoxic effects (HSP70 and GRP78) in HepG 2 cells [1,24].…”

Asymmetric patterns in the cranial skeleton of zebrafish (Danio rerio) exposed to sodium pentachlorophenate at different embryonic developmental stages

“…It has been suggested that chlorinated organic compounds interact with retinoic acid (RA) receptors (Inoue et al, 2010); a possible explanation may be that NaPCP modifies natural ligand signalling in the RA pathway, similar to the effects of PCP on retinoic acid response elements (Dorsey et al, 2002). RA is essential for various developmental processes since it acts on certain genes (e.g.…”