Superfund Research Program
Activation Of Orphan Receptors By Chlorinated Hydrocarbons
Project Leader: David J. Waxman
Grant Number: P42ES007381
Funding Period: 1995 - 2000
Project Summary (1995-2000)
Recent findings in these studies include the following: (1) PPAR activation induced by chlorinated hydrocarbons such as TCE and DCE derives from the activity of their acidic metabolites, trichloroacetic acid and dichloroacetic acid; (2) the peroxisome proliferative activity of the adrenal steroid dehydroepiandrosterone-3b-sulfate (DHEA-S) is mediated by PPARa, as judged from the unresponsiveness of PPARa-knockout mice to DHEA-S, despite the fact that PPARa activation cannot be demonstrated for this naturally-occurring steroidal PPAR activator in cell transfection studies; (3) JAK/STAT signaling pathways, which can be activated by a wide range of cytokines, growth factors and hormones, can exert cross-talk with PPARa-activated signaling pathways, resulting in an inhibition of foreign chemical-stimulated PPAR activity. Given the inhibitory nature of these interactions, these findings suggest that endogenous hormones may play an important role in moderating some of the hepatocarcinogenic effects of foreign chemicals such as TCE and PCE.