Superfund Research Program
Tracking Down the Mechanisms of Trichloroethylene-Induced Toxicity
Trichloroethylene (TCE) is the country's most frequently detected contaminant in groundwater from where it continues to migrate into drinking water supplies. Based on state and national surveys, anywhere from 9% to 34% of the country's drinking water supplies may contain TCE levels that average above federal drinking water standards. From these contaminated water supplies, humans are readily exposed to TCE by drinking or showering in contaminated tapwater.
Some studies of people exposed to high levels of the compound have found associations between TCE exposures and a variety of adverse health effects including liver, kidney, lung, and nerve damage. High doses of TCE can also increase the incidence of tumors in rats and mice; however, a clear association between TCE exposure and cancer in humans has not been established.
Because many people are exposed to low levels of TCE, whether through contaminated drinking water or in the workplace, it is important to develop an in-depth understanding of the biological mechanisms underlying the toxic effects of TCE. Mechanistic research, in general, seeks to comprehend the cause of toxicity at the biochemical and molecular levels where life processes take place. With a clearer view of the mechanisms involved in TCE-induced toxicity and carcinogenicity, understanding the nature of the risk of low TCE exposures is then possible.
Researchers in the Boston University Superfund Basic Research Program are investigating the mechanisms by which TCE and related chlorinated hydrocarbons activate the human peroxisome proliferator-activated receptor (PPAR). PPAR normally acts as a transcription factor in the cell, activating a number of genes that produce enzymes involved in fatty acid metabolism. In rodent models the PPAR also mediates some of the hepatotoxic and hepatocarcinogenic effects of TCE.
When activated in rodent liver cells, this receptor stimulates a dramatic increase in both the size and the abundance of peroxisomes. This activity is known as "peroxisome proliferation" and it is strongly correlated with the production of liver tumors in mice. However, these same links have not been sorted out in humans. In particular, it is still not clear whether peroxisome proliferator mediated carcinogenesis is a mechanism that is operative in humans.
In studies using cell transfection methodologies, these researchers recently discovered that the stimulation of mouse and human PPAR by TCE is due to the activity of its oxidative cytochrome P450 metabolites, trichloroacetic acid and dichloroacetic acid. TCE by itself did not activate the receptor in these studies. These important findings suggest that pathways exist in human cells for the activation of TCE to metabolites that activate the human PPAR.
Other experiments carried out by the Boston University researchers demonstrate that several cytochrome P450 enzymes expressed in human liver tissue can carry out the initial step in oxidation of TCE that ultimately yields trichloroacetic and dichloroacetic acid. One of these P450 enzymes is inducible in humans by exposure to ethanol and other chemicals, indicating that the susceptibility of individuals to TCE toxicity is influenced by concomitant exposure to other chemicals.
However, the researchers also found that PPAR initiated signaling is inhibited by simultaneous signaling in another important cellular pathway found in humans known as the Jak-STAT signaling pathway. The Jak-STAT pathway is used in cells to signal the activation of specific genes and it is known to "cross-talk" with other signal transduction pathways in human cells. What the results of this research suggest is that when the Jak-STAT pathway is active, the effects of TCE on human PPAR signaling may be diminished.
A wide range of cytokines, growth factors, and hormones can activate Jak-STAT signaling pathways. Thus, the novel finding by this group of researchers suggests that endogenous regulatory substances such as hormones may play an important role in moderating the hepatocarcinogenic effects of TCE in humans. This finding may also explain how differences in hormone patterns, such as those that would be found between sexes or species, might affect how TCE produces adverse effects.
These advances are important for evaluating the risks of low level exposures to an important environmental contaminant that is of special interest to Superfund cleanup efforts. With a focus on understanding the response of human cells and genes to TCE, these studies help to define the biochemical and molecular mechanisms of TCE-induced toxicity in humans. The findings also allow for useful comparisons to animal models, thereby helping to broaden our understanding of how species- and sex-differences impact the health risks of TCE exposures.
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To learn more about this research, please refer to the following sources:
- Zhou Y, Waxman DJ. 1999. STAT5b down-regulates peroxisome proliferator-activated receptor alpha transcription by inhibition of ligand-independent activation function region-1 trans-activation domain. J Biol Chem 274(42):29874-29882. PMID:10514468
- Zhou Y, Waxman DJ. 1998. Activation of peroxisome proliferator-activated receptors by chlorinated hydrocarbons and endogenous steroids. Environ Health Perspect 106Suppl.4:983-988. PMID:9703482
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