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STRAIN COMPARISON IN PREGNANT RATS OF ENDOCRINE RESPONSE TO BROMODICHLOROMETHANE: A DRINKING WATER DISINFECTION BY-PRODUCT
Citation:
Bielmeier, S. R., D S. Best, AND M G. Narotsky. STRAIN COMPARISON IN PREGNANT RATS OF ENDOCRINE RESPONSE TO BROMODICHLOROMETHANE: A DRINKING WATER DISINFECTION BY-PRODUCT. Presented at Endocrine Disruptors and the Water Industry Symposium, The American Water Works Association, Cincinnati, Ohio, April 18-20, 2002.
Description:
Bromodichloromethane (BDCM), a trihalomethane, is a by-product of the chlorination of drinking water. In an epidemiological study, consumption of drinking water with high levels of BDCM was associated with an increased risk of spontaneous abortion in pregnant women (Waller et al.,1998, Epidemiology 9:134-40). To investigate its reproductive toxicity, we exposed rats to BDCM during gestation. We reported that BDCM causes pregnancy loss, i.e. full-litter resorption, in F344 rats. The critical period of exposure encompassed the luteinizing hormone (LH)-dependent period of pregnancy in the rat. BDCM-induced pregnancy loss in the F344 rat was associated with marked reductions in serum progesterone and corresponding decreases in LH. Although an effect on luteal responsiveness has not been entirely ruled out, these findings strongly suggested that BDCM alters LH secretion, possibly via an effect on the hypothalamus or pituitary gland. Since Sprague-Dawley (SD) rats are used in many reproductive studies involving disinfection by-products, we compared F344 and SD rats for their sensitivity to BDCM-induced pregnancy loss. There was a dramatic difference in response to BDCM; we found that unlike F344 rats, SD rats were resistant to BDCM-induced pregnancy loss, even at a higher dose. In the current experiments we sought to compare endocrinological responses in the two strains by characterizing their serum hormone levels; we examined the effects of BDCM on serum progesterone and LH levels. BDCM, in 10% Alkamuls 620?, was dosed by oral aqueous gavage on gestational days (GD) 6-10 (plug day = GD 0) at 75 mg/kg/d in the F344 rat, and 100 or 200 mg/kg/d in the SD rat. Blood samples were collected from the lateral tail vein once daily on GD 6-11; serum progesterone and LH were measured using a dissociation-enhanced lanthanide flourometric immunoassay (DELFIA?). The rats were allowed to deliver and pups were examined postnatally. Pregnancy loss was confirmed by staining uterine resorption sites with 10% ammonium sulfide. As expected, the SD rats were insensitive to BDCM-induced pregnancy loss. F344 rats had an 88% (7/8) incidence of pregnancy loss at 75 mg/kg/d, whereas SD rats had 0% (0/10, 0/9) incidences at both 100 and 200 mg/kg/d. Endocrinologically, the strains differed in two ways. First, the SD rats had much higher initial serum LH values than the F344 rats. On GD 6, control serum LH values were significantly higher in SD (mean ? SE values were 0.46 ? 0.06 ng/ml) than in F344 rats (0.29 ? 0.06 ng/ml). Second, the SD rats responded differently to BDCM treatment. The SD rats showed consistent significant LH reductions starting on GD 7, compared to same-strain control. However, at all times these reduced LH values were significantly greater than the F344 reduced values. The SD LH reduced values were comparable with the F344 control values. Also the SD rats maintained their progesterone levels at all time points examined. On GD 10, SD dams receiving 200 mg/kg/d had LH levels of 0.24 ? 0.06 ng/ml, whereas control values were 0.49 ? 0.06 ng/ml. In contrast, the F344 rats displayed significant reductions in serum LH on GD 7 and 10, and reduced progesterone levels on GD 10, compared to same-strain controls. On GD 10, BDCM-treated F344 dams with pregnancy loss had LH levels of 0.07 ? 0.04 vs. 0.15 ? 0.02 ng/ml for controls; respective progesterone values were 4.0 ? 1.0 and 65 ? 10 ng/ml.These findings further demonstrate that F344 and SD rats have contrasting sensitivities to BDCM-induced pregnancy loss. These data suggest the SD rat may be protected from pregnancy loss because of their naturally higher serum LH levels. Although serum LH levels were significantly reduced by BDCM in both strains, we speculate that the SD LH levels remained above a threshold needed to maintain luteal progesterone secretion. In contrast, the F344 LH levels appeared to be reduced below this apparent threshold, leading to decreased progesterone levels and pregnancy loss. Thus, these dramatic differences in baseline LH levels and susceptibility to BDCM-induced pregnancy loss exemplify the importance of strain as a consideration when assessing reproductive toxicity. It is clear that the more we understand about the endocrinological differences among strains, the better we can conduct efficient and appropriate assessments of toxicants that affect the endocrine system.