Carcinogenesis, Vol 19, 1655-1663, Copyright © 1998 by Oxford University Press
RR Newbold, RB Hanson, WN Jefferson, BC Bullock, J Haseman and JA McLachlan
Prenatal exposure to diethylstilbestrol (DES) has been associated with the
subsequent development of reproductive tract abnormalities, including poor
reproductive outcome and neoplasia, in experimental animals and humans.
Experimental animal studies with chemical carcinogens have raised the
possibility that adverse effects of DES may be transmitted to succeeding
generations. To evaluate this possibility and to determine if there is a
sensitive window of developmental exposure, outbred CD-1 mice were treated
with DES during three stages of development: group 1 was treated on days
9-16 of gestation (2.5, 5 or 10 microg/kg maternal body wt), the time of
major organogenesis; group II was treated once on day 18 of gestation (1000
microg/kg maternal body wt) just prior to birth; group III was treated on
days 1- 5 of neonatal life (0.002 microg/pup/day). Female mice (F1) in each
group were raised to sexual maturity and bred to control males. As
previously reported, fertility of the F1 DES-exposed females was decreased
in all groups. Female offspring (DES lineage or F2) from these matings were
raised to maturity and housed with control males for 20 weeks. The
fertility of these DES lineage female mice was not affected by DES exposure
of their 'grandmothers'. DES lineage mice were killed at 17-19 and 22-24
months of age. An increased incidence of malignant reproductive tract
tumors, including uterine adenocarcinoma, was seen in DES lineage mice but
not in corresponding controls; the range and prevalence of tumors increased
with age. Because uterine adenocarcinomas were seen in all three DES
groups, all developmental exposure periods were considered susceptible to
the adverse effects of DES. These data suggest that the reduced fertility
observed in the DES F1 female mice was not transmitted to their
descendants; however, increased susceptibility to tumor formation is
apparently transmitted to subsequent generations.
ARTICLES
Increased tumors but uncompromised fertility in the female descendants of mice exposed developmentally to diethylstilbestrol
Developmental Endocrinology Section, Laboratory of Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. newbold1@niehs.nih.gov
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