OXIDATIVE STRESS REGULATES THE EXPRESSION AND ACTIVITY OF TRANSCRIPTION FACTOR ACTIVATOR PROTEIN-1 IN RAT CONCEPTUS

The transcription factor activator protein-1 (AP-1), composed of the F os and Jun families of proto-oncogenes, is induced in response to extr acellular signals as part of an immediate-early gene response. We hypo thesize that teratogens such as oxidative stress induce AP-1 activity in the rat conceptus and that this AP-1 response may either trigger ab normal development or protect the embryo against insult. To test this hypothesis, the AP-1 response was assessed in whole embryos in culture . There was a significant elevation in the oxidized to reduced glutath ione ratio in the embryo and yolk sac within 0.25 hr of the initiation of culture, peaking at 0.5 hr; this is indicative of heightened oxida tive stress. At 0.5 hr protein oxidation was also enhanced, as demonst rated by increased protein reactivity with 2,4-dinitrophenylhydrazine. In the conceptus, the steady-state concentrations of c-fos, c-jun, ju nB and junD mRNAs were induced, peaking at 0.5 hr and returning to bas e line by 1 to 2 hr in the embryo and by 1 to 6 hr in the yolk sac. El ectrophoretic mobility shift assays showed enhanced AP-1 DNA-binding a ctivity in both the embryo (elevated by 0.5 hr and persisting for 1 hr ) and the yolk sac (persisting for 3 hr). Thus, there are tissue-speci fic differences in the duration of the AP-1 response in the conceptus. Addition of the antioxidants catalase and superoxide dismutase, but n ot vitamin E, prevented the rise in the oxidized to reduced glutathion e ratio and also inhibited the induction of AP-1 mRNAs and DNA-binding activity. The AP-1 response to oxidative stress may determine how the conceptus responds to insult.