Peroxisome proliferating agents, retinoid metabolism, and macrophage activation

Peroxisome proliferating agents (PPAs) are common environmental pollutants that alter hepatic fatty acid metabolism, which often leads to liver disease in PPA-sensitive species. The production of reactive oxygen intermediates (ROIs) and nitric oxide (NO) by activated macrophages is associated with the development of liver pathologies. Retinoids are potent modulators of macrophage activity, and we are testing the hypothesis that PPA-inducible cytochrome P450s metabolize retinoids resulting in altered macrophage function. Preliminary evidence indicates that in vivo exposure of mummichog (Fundulus heteroclitus) to retinoic acid significantly increases immunostimulated anterior kidney macrophage ROI production, and induces hepatic NO synthase (iNOS, which generates NO). The direct effects of retinoic acid on macrophages were confirmed by in vitro exposure. We have also demonstrated that PPAs can modulate macrophage activity: in vivo exposure of mummichogs to clofibrate suppresses anterior kidney macrophage ROI production, but induces hepatic iNOS. Studies with 2,4-dichlorophenoxyacetic acid (1–21 days exposure) demonstrate both time- and tissue-dependent modulation of macrophage activity. Enhanced iNOS expression was generally associated with induction of PPA-responsive CYP2K1 and/or CYP2M1. The observed PPA-induced macrophage activation could lead to tissue damage in the liver. Moreover, altered macrophage function in general could result in immune system dysfunction.