Dietary factors and environmental pollutants initiate signaling cascades that converge on AhR:Nrf2:NF-kappaB transcription factor (TF) networks and, in turn, affect the health of the organism through its effects on the expression of numerous genes. Reactive oxygen metabolites (ROMs) have been hypothesized to be common mediators in these pathways. alpha-Tocopherol (AT) is a potent, lipophilic, scavenger of ROMs in vitro and has been hypothesized to be a major chain-breaking anti-oxidant in lipoproteins and biological membranes in vivo. The lung offers a vital organ to test the various postulated actions of AT in vivo. Lung AT concentrations can be manipulated by several methods that include dietary and genetic techniques. In this study we have used mice with severe AT deficiency inflicted at birth by the deletion of AT transfer protein (ATTP) which is abundantly expressed in the liver and regulates systemic concentrations of AT. Mice and humans deficient in ATTP are AT deficient. Female ATTP-deficient (ATTP-KO) mice and their congenic ATTP normal (WT) mice fed a diet containing 35 IU AT/kg diet were used to test our hypothesis. The mice (n=5/group) were exposed to either air or cigarette smoke (CS, total suspended particles 60 mg/m(3), 6h/day), a source of ROM, for 3 or 10 days. Post-exposure lung tissue was dissected, RNA extracted from each lung and it was pooled group-wise and processed for GeneChip analysis (Affymetrix 430A 2.0). Differential analysis of the transcriptomes ( approximately 16,000 mRNAs) identified CS sensitive genes that were modulated by lung AT-concentration. CS activated AhR driven genes such as cyp1b1 whose induction was augmented in CS-exposed, AT-deficient lungs. However, CS-induced expression of some of the Nrf2 driven genes was not potentiated in the AT-deficient lungs. Largest clusters of CS-AT sensitive genes were lymphocyte and leukocyte specific genes. These gene-clusters included those encoding cytokines and immunoglobulins, which were repressed by CS and were modulated by lung AT concentrations. Our genome-wide analysis suggests reciprocal regulation of xenobiotic and immune response genes by CS and a modulatory role of lung AT concentration on the expression of these clusters of genes. These data suggest that in vivo network of AT, AT-metabolites and ATTP affects the transcription of genes driven by AhR, Nrf2 and NF-kappaB, transcription factor networks that transduce cellular metabolic signals and orchestrate adaptive responses of lungs to inhaled environmental pollutants.