Epidemiological studies indicated that people exposed to dioxins were prone to the development of lung diseases including lung cancer. Animal studies demonstrated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increased liver tumors and promoted lung metaplasia in females. Metabolic changes in 17 beta-estradiol (E-2) resulted from an interaction between TCDD and E-2 could be associated with gender difference. Previously, we reported that methoxylestradiols (MeOE2), especially 4-MeOE2, accumulated in human lung cells (BEAS-2B) co-treated with TCDD and E-2. In the present study, we demonstrate unique accumulation of 4-MeOE2, as a result of TCDD/E-2 interaction and revealed its bioactivity in human lung epithelial cell line (H1355). 4-Methoxyestradiol treatment significantly decreased cell growth and increased mitotic index. Elevation of ROS and SOD activity, with a concomitant decrease in the intracellular GSH/GSSG ratio, was also detected in 4-MeOE2-treated cells. Quantitative comet assay showed increased oxidative DNA damage in the 4-MeOE2-treated H1355 cells, which could be significantly reduced by the anti-oxidant N-acetylcysteine (NAC). However, inhibition of cell growth and increase in mitotic arrest induced by 4-MeOE2 were unaffected by NAC. We concluded that 4-MeOE2 accumulation resulting from TCDD and E-2 interaction would contribute to the higher vulnerability on lung pathogenesis in females when exposed to TCDD. (c) 2007 Elsevier Inc. All rights reserved.
