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 17beta-estradiol (E2) resulted from an interaction between TCDD and E2 could be associated with gender difference. Previously, we reported that methoxylestradiols (MeOE2), especially 4MeOE2, accumulated in human lung cells (BEAS-2B) co-treated with TCDD and E2. In the present study, we demonstrate unique accumulation of 4MeOE2, as a result of TCDD╱E2 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 were also detected in 4MeOE2- treated cells. Quantitative Comet assay showed increased oxidative DNA damage in the 4MeOE2-treated H1355 cells, which could be significantly reduced by the antioxidant Nacetylcysteine (NAC). However, inhibition of cell growth and increase in mitotic arrest induced by 4MeOE2 was unaffected by NAC. We concluded that 4MeOE2 accumulation resulting from TCDD and E2 interaction would contribute to the higher vulnerability on lung pathogenesis in females when exposed to TCDD.
