Title: Gender-Dependent Mechanisms of Alpha-Tocopherol Protection from Benzo[a]pyrene Exposure in Rats.

Polycyclic aromatic hydrocarbons (PAHs), including benzo[a]pyrene (B[a]P), are environmental pollutants linked to increased disease susceptibilities. Alpha-Tocopherol (αT) supplementation decreases B[a]P-DNA adducts in smokers, particularly women; but the mechanism is unknown. To test the hypothesis that αT protection from B[a]P exposure is gender-dependent, male and female rats received 7 daily subcutaneous (SQ) injections of αT (100 mg αT / kg body wt) or vehicle, followed by a single intraperitoneal injection of B[a]P (20 mg/kg, spiked with 3 H-B[a]P) on day 9. Urine and bile were collected pre- and post-B[a]P; plasma and tissues were collected 5 or 24 h post-B[a]P. αT supplementation increased αT levels to a greater extent in females than in males. Compared to vehicle, αT supplementation increased total urinary and biliary excretion of B[a]P and/or B[a]P metabolites more than 2.5-fold in females, but decreased total excretion in males (p<0.05). αT prevented B[a]P-induced increases in urine 8-isoprostanes (males) and decreased tissue malondialdehyde levels in a tissue- and gender-dependent manner. Thus, αT protection from B[a]P exposure is gender-dependent and occurs by both antioxidant and non-antioxidant mechanisms. Further elucidation of the mechanism(s) of αT protection against environmental toxins may lead to the development of protective strategies for occupational PAH exposures