ToxSci Advance Access originally published online on January 8, 2008
Toxicological Sciences 2008 102(2):392-412; doi:10.1093/toxsci/kfn002
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Two-Generation Reproductive Toxicity Evaluation of Dietary 17β-Estradiol (E2; CAS No. 50-28-2) in CD-1 (Swiss) Mice
* Health Sciences Unit, RTI International, Research Triangle Park, North Carolina 27709
Experimental Pathology Laboratories, Inc., Research Triangle Park, North Carolina 27709
GE Plastics, Pittsfield, Massachusetts 01201
Toxicology/Regulatory Services, Inc., Charlottesville, Virginia 22911
¶ Bayer MaterialScience, Pittsburgh, Pennsylvania 15205
|| Bayer Healthcare AG, Wuppertal, Germany D-42096
||| The Dow Chemical Co., Midland, Michigan 48674
|||| American Chemistry Council, Arlington, Virginia
1 To whom correspondence should be addressed at RTI International, 3040 Cornwallis Road, P.O. Box 12194, Hermann Laboratory Bldg., Research Triangle Park, NC 27709-2194. Fax: (919) 541-5956. E-mail: rwt{at}rti.org.
Received September 17, 2007; accepted December 27, 2007
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Abstract |
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No information exists on reproductive/developmental effects in mice exposed to dietary 17β-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 (
0, 0.2, 1, 10, 30, or 100 µg E2/kg body weight/day) for 8 weeks prebreed, 2 weeks mating, 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 (1 µg/kg/day). Therefore, the mouse model is sensitive to E2 by oral administration, with effects on reproductive development at doses of 10- 100 µg/kg/day.
Key Words: 17β-estradiol; CD-1 mice; 2-generation reproductive toxicity study; OECD 416; acquisition of puberty; estrous cyclicity; andrology.