You are here:
ANIMAL MODELS FOR STUDYING MISCARRIAGE: ILLUSTRATION WITH STUDY OF DRINKING WATER DISINFECTION BY-PRODUCTS
Citation:
Narotsky, M G. AND S. R. Bielmeier. ANIMAL MODELS FOR STUDYING MISCARRIAGE: ILLUSTRATION WITH STUDY OF DRINKING WATER DISINFECTION BY-PRODUCTS. Presented at Teratology Society Meeting, Vancouver, British Columbia, Canada, June 26 - July 1, 2004.
Description:
Animal models for studying miscarriage: Illustration with study of drinking water disinfection by-products
Authors & affiliations:
Narotsky1, M.G. and S. Bielmeier Laffan2.
1Reproductive Toxicology Division, NHEERL, ORD, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina and 2GlaxoSmithKline, King of Prussia, Pennsylvania
Abstract:
No single animal model is ideal for investigating spontaneous abortion. However, different species (e.g., rat, mouse, nonhuman primate) do offer research opportunities that can provide insights into possible causes of miscarriage. In the Fischer-344 (F344) rat, several chemicals (e.g., trichloroethylene, atrazine, amitraz, bromodichloromethane) have been shown to cause pregnancy loss, i.e., full-litter resorption. Bromodichloromethane (BDCM), a drinking water disinfection by-product, is of particular interest because of epidemiological evidence implicating an association with spontaneous abortion. In the rat, BDCM?s disruption of pregnancy is an all-or-none effect in that surviving litters appear to be unaffected. The F344 strain is particularly sensitive to this effect whereas the Long-Evans stock is moderately sensitive and the Sprague Dawley stock appears to be insensitive. Several lines of evidence indicate that BDCM disrupts pregnancy in the rat by a luteinizing hormone (LH)-mediated mode of action: 1)BDCM?s effect requires exposure during the LH-dependent period of pregnancy; full-litter resorptiondoesnot occurfrom exposures after this critical period. 2)BDCM decreases serum levels of LH (and progesterone) in rats with pregnancy loss. BDCM also inhibits LH pulsatilityin ovariectomized rats. 3)Treatment with hCG, an LH agonist, rescues BDCM-exposed pregnancies from full-litter resorption. 4)Corpora lutea cultured in BDCM are less responsive to hCG stimulation in vitro, suggesting that altered LH responsiveness may play a contributory role. Given that LH and hCG bind to the same luteal receptor, responsiveness to LH in rats is analogous to responsiveness to hCG in humans. Regarding LH secretion, if BDCM disrupts LH secretion in the rat via altered GnRH signaling, this could be relevant to human pregnancy in that placental secretion of hCG is also regulated by GnRH. Indeed, recent data demonstrate that BDCM inhibits human placental trophoblast differentiation and hCG secretion in vitro. Thus, animal models may give important insights into the causes of miscarriage,and offer guidance for further research. [This abstract does not necessarily reflect EPA policy.]