Superfund Research Program
Bromodichloromethane and Pregnancy Loss
Background: Human pregnancy involves complex cellular interactions, cell proliferation, and cell differentiation and migration in both time and space – all of which are highly vulnerable and likely more sensitive than other physiological events to exposure to environmental contaminants. Despite the vulnerability of pregnant women and their fetuses, few studies have focused on the effects of environmental contaminants on reproductive outcomes.
In humans, the establishment of implantation and successful pregnancy outcome are dependent on specific endocrine signals and a specialized subset of trophoblasts that penetrate the uterus, tap into maternal circulation and remodel the spiral arteries. Because these patterns are not mirrored in rodents, extrapolation from rodent models to humans may not be appropriate for the study of contaminant exposures of pregnant women and their fetuses. Dr. Bill Lasley at the University of California, Davis SBRP directs a team of researchers developing and applying biomarker methods to monitor pregnancy loss.
One focus of their research regards the effects of total trihalomethanes (TTHM) – a group of four chemicals (chloroform, bromodichloromethane (BDCM), dibromochloromethane (DBCM), and bromoform). Epidemiological studies have reported an increased risk of small-for-gestational-age births, stillbirths, spontaneous abortions, and low birth weight for women exposed to TTHM with the greatest association with BDCM for stillbirth. US EPA toxicologists subsequently found that oral administration of BDCM caused full-litter resorption in F344 rats.
Dr. Jiangang (Jay) Chen, a former SBRP trainee, led research to test the hypothesis that BDCM targets the human placenta, specifically trophoblasts, which perform a variety of roles including hormone production and nutrient and oxygen transport to the fetus. Mononucleated cytotrophoblast cells can differentiate to a multinucleated phenotype (syncytiotrophoblast) that forms the outer layer of the villous placenta and is, eventually, in direct contact with maternal blood. The syncytiotrophoblast is the source of chorionic gonadotropin (CG), which is secreted into the mother's circulation to support ovarian function.
Advances: Collaborating with US EPA scientists, the Lasley research group has established a plausible time-critical linkage between BDCM exposure and adverse pregnancy outcome. To begin, the researchers exposed human multinucleated syncytiotrophoblasts to BDCM and found a dose-dependent decrease in the secretion of CG. Neither trophoblast morphology nor viability was impacted by exposure to BDCM. In a follow-on study, Lasley’s group tested the idea that BDCM disrupts trophoblast differentiation by adding BDCM to trophoblast cultures during the differentiation process and monitoring the formation of multinucleated syncytiotrophoblast and CG secretion. They found that the BDCM blocked the normal differentiation process of trophoblasts and significantly inhibited CG secretion. The degree of inhibition of CG secretion was much greater than in the earlier study. Importantly, the adverse effect occurred at a concentration above, but near the range of reported BDCM peak levels in human blood.
Undifferentiated cytotrophoblast cultures produce low levels of CG, and the formation of syncytiotrophoblast-like cultures is accompanied by an increase in the secretion of CG. The greater inhibition of CG secretion seen in the second study is consistent with the inhibition of syncytiotrophoblast formation. These findings substantiate and extend Dr. Lasley’s findings that BDCM targets the human placenta and trophoblasts in particular. Because these cells are the sole source of CG during normal human pregnancy and play a major role in the maintenance of the conceptus, a decrease in the amount of CG could have adverse effects on pregnancy outcome.
Significance: The Lasley lab undertook the research effort to support efforts by the US EPA to understand earlier epidemiological studies. These in vitro studies indicate that the placenta could be a target for BDCM and the hypothesis is consistent with epidemiological studies showing increased incidence of stillbirth in women exposed to BDCM. The findings warrant further in vivo studies with primates having similar reproductive physiology as humans.
It has been reported that certain environmental contaminants including organophosphate pesticides can cross the placental barrier and might directly cause embryo death or affect fetal neurodevelopment and growth, and others may directly affect sperm/oocyte quality. This work provides the foundation for development of an efficient in vitro screening system to look at the adverse effect of xenobiotics on placental function.
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To learn more about this research, please refer to the following sources:
- Bielmeier SR, Best DS, Narotsky MG. 2004. Serum hormone characterization and exogeneous hormone rescue of bromodichloromethane-induced pregnancy loss in the F344 rat. Toxicol Sci 77(1):101-108. PMID:14657523
- Chen J, Thirkill TL, Lohstroh PN, Bielmeier SR, Narotsky MG, Best DS, Harrison RA, Natarajan K, Pegram RA, Overstreet JW, Lasley BL, Douglas GC. 2004. Bromodichloromethane inhibits human placental trophoblast differentiation. Toxicol Sci 78(1):166-174. PMID:14691210
- Chen J, Douglas GC, Thirkill TL, Lohstroh PN, Bielmeier SR, Narotsky MG, Best DS, Harrison RA, Natarajan K, Pegram RA, Overstreet JW, Lasley BL. 2003. Effect of bromodichloromethane on chorionic gonadotrophin secretion by human placental trophoblast cultures. Toxicol Sci 76(1):75-82. PMID:12970577
- Bielmeier SR, Best DS, Guidici DL, Narotsky MG. 2001. Pregnancy loss in the rat caused by bromodichloromethane. Toxicol Sci 59(2):309-315. PMID:11158724
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