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ToxSci Advance Access published online on December 2, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfh017
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received August 12, 2003; accepted October 10, 2003
© 2003 Society of Toxicology

Reproductive and Developmental Toxicology

Serum Hormone Characterization and Exogeneous Hormone Rescue of Bromodichloromethane-Induced Pregnancy Loss in the F344 Rat

Susan R. Bielmeier 1, Deborah S. Best 2, and Michael G. Narotsky 2*

1 Curriculum of Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC
2 Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

* To whom correspondence should be addressed. E-mail: narotsky.michael{at}epa.gov.


  Abstract

Previously, we demonstrated that bromodichloromethane (BDCM), a drinking water disinfection by-product, causes pregnancy loss in F344 rats when given on gestational days (GD) 6-10, encompassing the luteinizing hormone (LH)-dependent period of pregnancy (GD 7-10). Pregnancy loss, i.e., full-litter resorption, was associated with reduced serum progesterone levels; however, we were unable to identify an effect on serum LH. Here, we re-evaluated serum LH levels using the more sensitive technique, DELFIA®. We further sought to better define the temporal pattern of endocrine disruption caused by BDCM during pregnancy with more frequent sampling. Lastly, we attempted to prevent BDCM-induced pregnancy loss using exogenous progesterone or human chorionic gonadotropin (hCG), an LH-agonist. BDCM, in 10% Alkamuls®, was dosed at 75 mg/kg/d by gavage to F344 rats on GD 6-10 (plug day = GD 0). BDCM-induced pregnancy loss was associated with marked reductions in serum progesterone and LH on GD 10. The decrease in serum LH consistently preceded the decrease in progesterone. In the hormone replacement studies, BDCM and progesterone were administered on GD 6-10, hCG on GD 8-10. BDCM was delivered at 100 mg/kg/d, progesterone at 10 mg/kg twice daily, and hCG at 0.5 IU/0.2 ml/rat. Both progesterone and hCG prevented BDCM-induced pregnancy loss. Thus, BDCM-induced pregnancy loss was associated with marked GD-10 reductions in serum LH and corresponding decreases in progesterone. Furthermore, co-administration of an LH agonist prevented pregnancy loss, supporting the hypothesis that BDCM-induced pregnancy loss in the rat occurs via an LH-mediated mode of action.

Key Words: bromodichloromethane, disinfection by-product, pregnancy loss, progesterone, luteinizing hormone, hormonal pregnancy rescue .


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