The overall goal of this proposal is to determine the molecular events that take place in preB cells during PAH mediated apoptosis. Delineating the mechanism of action of these compounds will increase our understanding of how they exert their immunotoxicity. The central hypothesis of this proposal is that polycyclic aromatic hydrocarbons (PAHs) cause death of preB cells by inducing apoptosis in lymphocytes via caspase-8 in a Type I manner. This hypothesis is supported by my preliminary data, which show that treatment of preB cells with DMBA activates caspase-8 and caspase-3, and to a lesser extent caspase-9. Further evidence is provided that soluble FasL is able to induce caspase-8 and apoptosis in preB cells. In the proposed project I will extend these findings further by: 1) characterizing the specific pattern of caspase activation and accessory protein induction in the preB cell/stromal cell co-culture system; 2) determine if the Fas/FasL pathway is necessary for in vivo bone marrow toxicity, by treating gld and lpr knockout mice with DMBA; 3) define the relationship between immunotoxicity of the PAHs and caspase activating, using other members of the PAH family in the in vivo and in vitro systems developed in the first two aims.
| Page, Todd J; MacWilliams, Peter S; Suresh, M et al. (2004) 7-12 Dimethylbenz[a]anthracene-induced bone marrow hypocellularity is dependent on signaling through both the TNFR and PKR. Toxicol Appl Pharmacol 198:21-8 |
| Page, Todd J; O'Brien, Scott; Holston, Karrie et al. (2003) 7,12-Dimethylbenz[a]anthracene-induced bone marrow toxicity is p53-dependent. Toxicol Sci 74:85-92 |
| Page, Todd J; O'Brien, Scott; Jefcoate, Colin R et al. (2002) 7,12-Dimethylbenz[a]anthracene induces apoptosis in murine pre-B cells through a caspase-8-dependent pathway. Mol Pharmacol 62:313-9 |
