Effect of neonatal exposure to 5-bromo-2'-deoxyuridine on life span, estrus function and tumor development in rats--an argument in favor of the mutation theory of aging?

Abstract

Outbred LIO rats were exposed to subcutaneous injections (3.2 mg) of a synthetic analogue of thymidine, 5-bromo-2'-deoxyuridine (BrdUrd), on days 1 and 3, or days 1, 3, 7 and 21 of postnatal life. The mean life span decreased by 31% and 38% in male and by 14% and 27% in female rats that received 2 and 4 injections of BrdUrd, respectively, in comparison to untreated controls. The opening of the vagina was delayed, whereas age-related changes in the length of the estrous cycle and in the incidence of persistent estrus and/or anestrus were observed earlier in BrdUrd-injected female rats than in untreated ones. Inhibition of compensatory ovarian hypertrophy induced by hemiovariectomy at the age of 3 months was found in females exposed neonatally to BrdUrd as compared to untreated rats, while the uterus weight increase induced by the administration of human chorionic gonadotropin was similar in both control and BrdUrd-treated infantile rats. These data suggest that exposure to BrdUrd in early life impairs pituitary gonadotropic function in female rats. It was also shown that neonatal administration of BrdUrd to rats doubles the incidence of chromosome aberrations in peripheral blood lymphocytes in comparison to controls and is followed by a dose-related increase in tumor incidence. Our observations on the decrease in mean and maximum life span, acceleration of age-related changes in reproductive system function, increase in chromosome aberration and tumor incidence and decrease in tumor latency in rats exposed to BrdUrd in early life suggest that this model could be used as a model of accelerated aging and that some of the results can be interpreted as arguments in favor of the mutation theory of aging.