Increased tumors but uncompromised fertility in the female descendants of mice exposed developmentally to diethylstilbestrol.
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.
Developmental Endocrinology Section, Laboratory of Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. newbold1@niehs.nih.gov
R R
RR
Newbold
R B
RB
Hanson
W N
WN
Jefferson
B C
BC
Bullock
J
J
Haseman
J A
JA
McLachlan
D000818:Animals; D004054:Diethylstilbestrol / Q000633:toxicity*; D005260:Female; D005298:Fertility / Q000187:drug effects*; D005333:Fetus / Q000187:drug effects*; D005833:Genital Neoplasms, Female / Q000139:chemically induced*; D051379:Mice; D008813:Mice, Inbred ICR; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects
D004054:Diethylstilbestrol