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ToxSci Advance Access first published online on January 8, 2008
This version published online on January 27, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn002
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Two-Generation Reproductive Toxicity Evaluation of Dietary 17ß-Estradiol (E2; CAS No. 50-28-2) in CD-1 (Swiss) Mice

Rochelle W. Tyl*, Christina B. Myers*, Melissa C. Marr*, Carol S. Sloan*, Nora P. Castillo*, M. Michael Veselica*, John C. SeelyH, Stephen S. DimondI, John P. Van Millerni, Ronald S. Shiotsuka, Gisela D. Stropp11, John M. Waechter, Jr111 and Steven G. Hentges#

* Health Sciences Unit, RTI International, Research Triangle Park, NC 27709 (rwt{at}rti.org) H Experimental Pathology Laboratories, Inc., Research Triangle Park, NC 27709 (jseely{at}epl-inc.com) I GE Plastics, Pittsfield, MA 01201 (Stephen.Dimond{at}ge.com) ni Toxicology/Regulatory Services, Inc., Charlottesville, VA 22911 (jvanmiller{at}toxregserv.com) Bayer MaterialScience, Pittsburgh, PA 15205 (ron.shiotsuka{at}bayerbms.com) 11 Bayer Healthcare AG, Wuppertal, Germany D-42096 (gisela.stropp{at}bayerhealthcare.com) 111 The Dow Chemical Co., Midland, MI 48674 (JMWaechterJr{at}dow.com) # American Chemistry Council, Arlington, VA (Steve_Hentges{at}americanchemistry.com)

Rochelle W. Tyl, Ph.D., RTI International, 3040 Cornwallis Road, P.O. Box 12194, Hermann Laboratory Bldg., Research Triangle Park, NC 27709-2194, rwt{at}rti.org, Fax: 919-541-5956, Tel: 919-541-5972

Received September 17, 2007; revision received December 26, 2007; accepted December 27, 2007


  Abstract

No information exists on reproductive/developmental effects in mice exposed to dietary 17ß-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 (1/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 3/sex/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 (NOEL) 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.

The article title, keywords and final paragraph of the article have been updated.


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