4-Methoxyestradiol-induced oxidative injuries in human lung epithelial cells

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 17β-estradiol (E2) resulted from an interaction between TCDD and E2 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 E2. In the present study, we demonstrate unique accumulation of 4-MeOE2, 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, 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 E2 interaction would contribute to the higher vulnerability on lung pathogenesis in females when exposed to TCDD.