Preconception urethane or chromium(III) treatment of male mice: Multiple neoplastic and non-neoplastic changes in offspring

Increase in neoplasia in offspring after preconception exposure of parents presents puzzling features such as high frequency of effects and lack of Me ndelian inheritance. The present study examined the hypothesis that preconc eption carcinogenesis involves an increase in the rate of occurrence of neo plasms with a spontaneous incidence. Male NIH Swiss mice (12 per group) wer e exposed 2 weeks before mating (once, ip) to urethane (1.5 g/kg) or chromi um(III) chloride (1 mmol/kg). Offspring (48-78/sex/group) were examined for all grossly apparent changes when moribund or at natural death, followed b y histopathological diagnosis and statistical analysis. Significant exposur e-related changes occurred in multiple organs. Ten to 20 percent of offspri ng showed changes related to paternal exposure, including at least one sire d by most treated males. Pheochromocytomas occurred in both male: and femal e offspring after both treatments, with none in controls. These neoplasms a re rare in mice and suggest endocrine dysfunction as a component of preconc eption carcinogenesis. This was supported by increases in thyroid follicula r cell and Harderian gland tumors, ovarian cysts, and uterine abnormalities . Lung tumors were increased in female offspring only. Effects seen in offs pring only after paternal urethane exposure were an increase in preneoplasi a/neoplasia in the glandular stomach (males) and in females, increased lymp homa but decreased incidence of histiocytic sarcoma. Increases in incidence of male reproductive gland tumors and of renal non-neoplastic lesions occu rred only after chromium exposure. Thus, preconception exposure of fathers to toxicants had a significant impact on both neoplastic and nonneoplastic changes in almost all tissues in which these lesions often occur naturally during the aging process. (C) 1999 Academic Press.