Women's Health Research Day 2006

BENZO(a)PYRENE, A CIGARETTE SMOKE TOXICANT, INDUCES CELL CYCLE ARREST AND p53 ACTIVATION IN HUMAN UTERINE ENDOMETRIAL CELLS: PROTECTION BY VITAMIN E

Medrano, Theresa, M.S.; Sellers, Samantha; Kitzman, Jamie, BS; McGarry, Michelle, PhD; Shiverick, Kathleen, PhD; Dept of Pharmacology & Therapeutics, University of Florida.

Maternal cigarette smoking is known to produce infertility and disrupt placental function. The polyaromatic hydrocarbon benzo(a)pyrene (BaP) is a major toxicant in cigarette smoke that has been shown to alter placental cell function. This study investigated the effects of BaP, a ligand for the aryl hydrocarbon (Ah) receptor, on proliferation and cell cycle progression in the human uterine endometrial RL95-2 cell line. BaP significantly inhibited proliferation in a dose-dependent manner characterized by G2/M cell cycle phase arrest. No evidence of apoptosis was detected following BaP exposure. Although BaP had no effect on total cellular p53 levels, phosphorylation of p53 at serine 15 (p53-Ser15phos) was markedly increased. In this regard, ATM, a serine/threonine kinase, is known to function as a primary sensor of DNA damage in cells through activation of p53 phosphorylation. The presence of Wortmannin, an inhibitor of ATM kinase, decreased BaP-induced p53-Ser15phos. In addit!
 ion, the presence of the antioxidant vitamin E significantly decreased BaP-induced p53 phosphorylation and CYP1A1 protein expression. Vitamin E further suppressed BaP-induced G2/M arrest. Thus, the anti-proliferative effect of BaP involves activation of a p53-dependent pathway involving cell cycle arrest at G2/M, providing evidence of oxidative stress and activation of a DNA damage response pathway in endometrial RL95-2 cells. The results of the present study further indicate that the nutritional antioxidant vitamin E may help to reduce the reproductive toxicity of an environmental exposure such as cigarette smoking.

Sponsor: NIH - ES07375