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© 1991 Oxford University Press

research-article

Validation of Protocols for Assessing Early Pregnancy Failure in the Rat: Clomiphene Citrate1

AUDREY M. CUMMINGS*, SALLY D. PERREAULT* and SANDRA T. HARRIS{dagger}

*Reproductive Toxicology Branch, Developmental Toxicology Division, Health Effects Research Laboratory, U.S. Environmental Protection Agency Research Triangle Park, North Carolina 27711 {dagger}NSI Technology Services Corporation, Environmental Sciences Research Triangle Park, North Carolina 27709

Received May 29, 1990; accepted December 13, 1990

Validation of Protocols for Assessing Early Pregnancy Failure in the Rat: Clomiphene Citrate. CUMMINGS, A. M., PERREAULT, S. D., AND HARRIS, S. T. (1991). Fundam. Appl. Toxicol. 16, 506–516. A battery of protocols for the assessment of maternally mediated toxicity during early pregnancy in the rat is being evaluated for its utility in detecting and denning mechanisms of early pregnancy failure. In this report, clomiphene citrate (CC), an estrogen agonist/antagonist, was used as a model compound in this evaluation process. The protocols involve dosing rats with CC during, and evaluation of multiple endpoints following, (a) the first 8 days of pregnancy; (b) early pseudopregnancy, accompanied by decidual induction; and (c) the pre- and postimplantation intervals of early pregnancy. In addition, the effect of CC on embryo transport rate was assessed. Eight days of dosing with CC during early pregnancy produced a dose-dependent reduction in the number of implantation sites seen on Day 9, concomitant with alterations in maternal hormonal parameters. No effect on the decidual cell response was found, indicating that the mechanism of fertility reduction was not mediated via compromised uterine decidualization. The preimplantation period was highly vulnerable to the toxic effects of CC while no postimplantation resorptions were seen. When embryo transport rate was measured, a statistically significant embryo transport rate acceleration was detected, but this was insufficient to account for all of the observed preimplantation loss. The data suggest an effect of CC on embryo viability, on the embryo's ability to implant, or on the reproductive tract resulting in compromised embryo survival as the potential mechanism(s) mediating CC-induced early pregnancy failure. The battery of protocols was thus successful in identifying CC as a reproductive toxicant and in elucidating the causes of the observed early pregnancy failure.


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