Browsing by Author "Kamendulis, Lisa"

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    Estrogenic Activity of the Polybrominated Diphenyl Ether Flame Retardant Mixture DE-71
    (2008-03-05T20:08:04Z) Mercado-Feliciano, Minerva; Bigsby, Robert M.; Klaunig, James E.; Jeng, Meei-Huey; Kamendulis, Lisa; Skaar, Todd; Sullivan, William J., Jr.
    Polybrominated diphenyl ethers (PBDEs) are widely used flame retardants suspected to act as endocrine disruptors. We tested the commercial PBDE mixture DE-71 and its in vivo metabolites for estrogenic activity. MCF-7 breast cancer cells culture, ERE-luciferase gene expression, 3H-β-estradiol displacement from recombinant ERα, and ovariectomized (OVX) mice served as bioassays. Although DE-71 did not bind ERα, it was able to increase MCF-7 cell proliferation and this was prevented by the antiestrogen fulvestrant. DE-71 co-treatment reduced the effect of estradiol in MCF-7 cells. In the OVX mouse (BALB/c) 3-day assay, DE-71 administered alone had no effect on uterine or vaginal tissues but when administered subcutaneously potentiated estradiol’s effect on uterine weight in a dose-dependent manner. DE-71 administered SQ to BALB/c mice for 34 days slightly increased uterine epithelial height (UEH), vaginal epithelial thickness (VET) and mammary ductal lumen area, and attenuated the estradiol-induced increase in UEH; these effects were not seen in C57BL/6 mice. DE-71 increased liver weight in BALB/c, C57BL/6 and estrogen receptor-alpha knockout (ERαKO) mice. Liver cytochrome P450 1A (CYP1A) and CYP2B activities increased 2.5-fold and 7-fold respectively when DE-71 was administered PO, but only CYP2B increased (5-fold) after SQ treatment. Six OH-PBDE metabolites were found in mice after 34-day DE-71 treatment and all were able to bind recombinant ERα. Para-hydroxylated metabolites displayed a 10- to 30-fold higher affinity for ERα compared to ortho-hydroxylated PBDEs. Para-OH-PBDEs induced ERE-luciferase and produced an additive effect when coadministered with β-estradiol. DE-71 was also additive with β-estradiol. At high concentrations (≥ 5x10-5 M), ortho-OH-PBDEs were antiestrogenic in the ERE-luciferase assay. In conclusion, DE-71 behaves as a weak estrogen in both MCF-7 breast cancer cells and ovariectomized adult mice. Mice strain, treatment route and duration determined if DE-71 was estrogenic. BALB/c mice are more susceptible to DE-71 effects in estrogen target tissues than C57BL/6 mice. DE-71 increased liver weight, 5%-51% depending on mouse strain and treatment regime, independently of ERα. The observations that the DE-71 mixture does not displace 3H-β-estradiol from ERα while the hydroxylated metabolites do, suggest that the cellular and tissue effects were due to a metabolic activation of individual congeners.
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    Serum mercury concentration and the risk of ischemic stroke: The REasons for Geographic and Racial Differences in Stroke Trace Element Study
    (Elsevier, 2018-08) Chen, Cheng; Xun, Pengcheng; McClure, Leslie A.; Brockman, John; MacDonald, Leslie; Cushman, Mary; Cai, Jianwen; Kamendulis, Lisa; Mackey, Jason; He, Ka; Neurology, School of Medicine
    BACKGROUND: Although biologically plausible, epidemiological evidence linking exposure to methylmercury with increased risk of ischemic stroke is limited. The effects of methylmercury may be modified by selenium, which is an anti-oxidant that often co-exists with mercury in fish. OBJECTIVES: To examine the association between serum mercury levels with the incidence of ischemic stroke and to explore the possible effect modifications by serum selenium levels and demographic and geographic factors. METHODS: A case-cohort study was designed nested in the REasons for Geographic and Racial Differences in Stroke cohort, including 662 adjudicated incident cases of ischemic stroke and 2494 participants in a randomly selected sub-cohort. Serum mercury was measured using samples collected at recruitment. Multivariable-adjusted hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were estimated using the Barlow-weighting method for the Cox proportional hazards regression model. RESULTS: No statistically significant association was observed between serum mercury concentration and the incidence of ischemic stroke (the highest vs. lowest quintile of mercury levels: HR = 0.82; 95% CI = 0.55-1.22; P for linear trend = 0.42). Sex (P for interaction = 0.06), but not serum selenium levels, modified the association; a more evident trend toward lower incidence of ischemic stroke with higher mercury levels was observed among women. CONCLUSION: This study does not support an association between mercury and the incidence of ischemic stroke within a population with low-to-moderate level of exposure. Further studies are needed to explore the possibility of mercury-induced ischemic stroke toxicity in other populations at higher exposure levels.