Two-generation reproductive toxicity evaluation of dietary 17beta-estradiol (E2; CAS No. 50-28-2) in CD-1 (Swiss) mice.
No information exists on reproductive/developmental effects in mice exposed to dietary 17beta-estradiol (E2) over multiple generations. Therefore, under OECD Test Guideline 416 with enhancements, CD-1 mice (F0 generation, 25 mice/sex/group) were exposed to dietary E2 at 0, 0.001, 0.005, 0.05, 0.15, or 0.5 ppm ( approximately 0, 0.2, 1, 10, 30, or 100 mug E2/kg body weight/day) for 8 weeks prebreed, 2 weeks mating, approximately 3 weeks gestation, and 3 weeks lactation. At weaning, selected F1 offspring (F1 parents; 25/sex/group) and extra retained F1 males (one per litter) were exposed to the same dietary concentrations and durations as the F0 generation; study termination occurred at F2 weaning; F1/F2 weanlings (up to three per sex per litter) were necropsied with organs weighed. At 0.5 ppm, effects were increased F1/F2 perinatal loss, prolonged F0/F1 gestational length, reduced numbers of F2 (but not F1) litters/group, reduced F1/F2 litter sizes, accelerated vaginal patency (VP) and delayed preputial separation (PPS), increased uterus + cervix + vagina weights (UCVW) in F0/F1 adults and F1/F2 weanlings, and decreased testes and epididymides weights (TEW) in F1/F2 weanlings. At 0.15 ppm, effects were increased UCVW in F0/F1 adults and F1/F2 weanlings, accelerated VP, delayed PPS, and reduced TEW in F1/F2 weanlings. At 0.05 ppm, UCVW were increased in F1/F2 weanlings, and PPS was delayed only in extra retained F1 males. There were no biologically significant or treatment-related effects on F0/F1 parental body weights, feed consumption, or clinical observations, or on F0/F1 estrous cyclicity, F0/F1 andrology, or F1/F2 anogenital distance at any dose. The no observable effect level was 0.005 ppm E2 ( approximately 1 mug/kg/day). Therefore, the mouse model is sensitive to E2 by oral administration, with effects on reproductive development at doses of 10- 100 mug/kg/day.
Tyl
Rochelle W
RW
Health Sciences Unit, RTI International, Research Triangle Park, North Carolina 27709, USA.
Myers
Christina B
CB
Marr
Melissa C
MC
Sloan
Carol S
CS
Castillo
Nora P
NP
Veselica
M Michael
MM
Seely
John C
JC
Dimond
Stephen S
SS
Van Miller
John P
JP
Shiotsuka
Ronald S
RS
Stropp
Gisela D
GD
Waechter
John M
JM
Hentges
Steven G
SG
D000284:Administration, Oral; D000818:Animals; D004032:Diet; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D004958:Estradiol / Q000633:toxicity*; D004967:Estrogens / Q000633:toxicity*; D005260:Female; D005835:Genitalia / Q000187:drug effects / Q000473:pathology; D008098:Litter Size / Q000187:drug effects; D008136:Longevity / Q000187:drug effects; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D051379:Mice; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects; D018812:Paternal Exposure / Q000009:adverse effects*; D011247:Pregnancy; D012098:Reproduction / Q000187:drug effects*; D012741:Sexual Maturation / Q000187:drug effects / Q000502:physiology; D014621:Vagina / Q000187:drug effects / Q000254:growth & development
D004967:Estrogens; D004958:Estradiol