Alterations in behavior, steroid hormones and natural killer cell activity in male transgenic TGF alpha mice

The expression of transforming growth factor alpha (TGF alpha) is widely distributed throughout many normal and neoplastic tissues, but its physiological significance remains unclear. We have utilized male transgenic mice overexpressing the gene encoding human TGF alpha in multiple tissues to further identify those functions which are influenced by this protein. Male TGF alpha mice develop hepatocellular carcinoma at the age of 10-15 months. At the age of 2-3 months these mice, compared to age matched CD-1 controls, spent significantly longer times immobile in Porsolt's swim test, a model of stress and depressive behavior, and exhibiting aggressive behavior in the resident-intruder test. In contrast, the transgenic TGF alpha mice did not differ from the controls in either the plusmaze test of anxiety, or in their voluntary alcohol intake. Significantly, the TGF alpha mice exhibited a 25% lower Natural Killer (NK) cell activity and a four-fold increase in the plasma levels of 17-beta-estradiol (E2) than the controls. No significant changes in plasma testosterone or corticosterone levels were noted. The results indicate that transgenic male mice overexpressing TGF alpha exhibit behaviors characteristic of both an impaired ability to cope with stress and an increased aggressivity. The TGF alpha mice also show reduced NK cell activity and increased plasma estradiol concentrations. The present data suggest that TGF alpha may be important in influencing behavioral, immunological and hormonal systems prior to the onset of tumors. It remains to be determined whether hepatocarcinoma is associated with the direct proliferative and transforming effects of TGF alpha and/or indirect effects mediated through immune, hormonal and behavioral mechanisms.