2008
Kummer, Vladimír; Masková, Jarmila; Zralý, Zdenek; Neca, Jirí; Simecková, Pavlína; Vondrácek, Jan; Machala, Miroslav
Estrogenic activity of environmental polycyclic aromatic hydrocarbons in uterus of immature Wistar rats. Journal Article
In: Toxicology letters, vol. 180, no. 3, pp. 212–221, 2008, ISSN: 0378-4274, (Place: Netherlands).
Abstract | Links | BibTeX | Tags: Animals, Cytochrome P-450 CYP1A1/metabolism, Endocrine Disruptors/*toxicity, Environmental Pollutants/*toxicity, Epithelium/drug effects, Estradiol/metabolism, Estrogen Receptor alpha/metabolism, Estrogens/*biosynthesis, Female, Hydroxylation, Immunohistochemistry, Liver/drug effects/metabolism, Microsomes, Organ Size/drug effects, Ovary/drug effects, Phosphorylation, Polycyclic Aromatic Hydrocarbons/*toxicity, Rats, Tumor Suppressor Protein p53/metabolism, Uterus/drug effects/*metabolism, Wistar
@article{kummer_estrogenic_2008,
title = {Estrogenic activity of environmental polycyclic aromatic hydrocarbons in uterus of immature Wistar rats.},
author = {Vladimír Kummer and Jarmila Masková and Zdenek Zralý and Jirí Neca and Pavlína Simecková and Jan Vondrácek and Miroslav Machala},
doi = {10.1016/j.toxlet.2008.06.862},
issn = {0378-4274},
year = {2008},
date = {2008-08-01},
journal = {Toxicology letters},
volume = {180},
number = {3},
pages = {212–221},
abstract = {Polycyclic aromatic hydrocarbons (PAHs) are an important group of environmental pollutants, known for their mutagenic and carcinogenic activities. Many PAHs are aryl hydrocarbon receptor (AhR) ligands and several recent studies have suggested that PAHs or their metabolites may activate estrogen receptors (ER). The present study investigated possible estrogenic/antiestrogenic effects of abundant environmental contaminants benzo[a]pyrene (BaP), benz[a]anthracene (BaA), fluoranthene (Fla) and benzo[k]fluoranthene (BkF) in vivo, using the immature rat uterotrophic assay. The present results suggest that BaA, BaP and Fla behaved as estrogen-like compounds in immature Wistar rats, when applied for 3 consecutive days at 10mg/kg/day, as documented by a significant increase of uterine weight and hypertrophy of luminal epithelium. These effects were likely to be mediated by ERalpha, a major subtype of ER present in uterus, as they were inhibited by treatment with ER antagonist ICI 182,780. BaA, the most potent of studied PAHs, induced a significant estrogenic effect within a concentration range 0.1-50mg/kg/day; however, it did not reach the maximum level induced by reference estrogens. The proposed antiestrogenicity of the potent AhR agonist BkF was not confirmed in the present in vivo study; the exposure to BkF did not significantly affect the uterine weight, although a weak suppression of ERalpha immunostaining was observed in luminal and glandular epithelium, possibly related to its AhR-mediated activity. The PAHs under study did not induce marked genotoxic damage in uterine tissues, as documented by the lack of Ser-15-phoshorylated p53 protein staining. With the exception of Fla, all three remaining compounds increased CYP1-dependent monooxygenation activities in liver at the doses used, suggesting that the potential tissue-specific antiestrogenic effects of PAHs mediated by metabolization of 17beta-estradiol also cannot be excluded. Taken together, these environmentally relevant PAHs induced estrogenic effects in vivo, which might affect their toxic impact and carcinogenicity.},
note = {Place: Netherlands},
keywords = {Animals, Cytochrome P-450 CYP1A1/metabolism, Endocrine Disruptors/*toxicity, Environmental Pollutants/*toxicity, Epithelium/drug effects, Estradiol/metabolism, Estrogen Receptor alpha/metabolism, Estrogens/*biosynthesis, Female, Hydroxylation, Immunohistochemistry, Liver/drug effects/metabolism, Microsomes, Organ Size/drug effects, Ovary/drug effects, Phosphorylation, Polycyclic Aromatic Hydrocarbons/*toxicity, Rats, Tumor Suppressor Protein p53/metabolism, Uterus/drug effects/*metabolism, Wistar},
pubstate = {published},
tppubtype = {article}
}
Polycyclic aromatic hydrocarbons (PAHs) are an important group of environmental pollutants, known for their mutagenic and carcinogenic activities. Many PAHs are aryl hydrocarbon receptor (AhR) ligands and several recent studies have suggested that PAHs or their metabolites may activate estrogen receptors (ER). The present study investigated possible estrogenic/antiestrogenic effects of abundant environmental contaminants benzo[a]pyrene (BaP), benz[a]anthracene (BaA), fluoranthene (Fla) and benzo[k]fluoranthene (BkF) in vivo, using the immature rat uterotrophic assay. The present results suggest that BaA, BaP and Fla behaved as estrogen-like compounds in immature Wistar rats, when applied for 3 consecutive days at 10mg/kg/day, as documented by a significant increase of uterine weight and hypertrophy of luminal epithelium. These effects were likely to be mediated by ERalpha, a major subtype of ER present in uterus, as they were inhibited by treatment with ER antagonist ICI 182,780. BaA, the most potent of studied PAHs, induced a significant estrogenic effect within a concentration range 0.1-50mg/kg/day; however, it did not reach the maximum level induced by reference estrogens. The proposed antiestrogenicity of the potent AhR agonist BkF was not confirmed in the present in vivo study; the exposure to BkF did not significantly affect the uterine weight, although a weak suppression of ERalpha immunostaining was observed in luminal and glandular epithelium, possibly related to its AhR-mediated activity. The PAHs under study did not induce marked genotoxic damage in uterine tissues, as documented by the lack of Ser-15-phoshorylated p53 protein staining. With the exception of Fla, all three remaining compounds increased CYP1-dependent monooxygenation activities in liver at the doses used, suggesting that the potential tissue-specific antiestrogenic effects of PAHs mediated by metabolization of 17beta-estradiol also cannot be excluded. Taken together, these environmentally relevant PAHs induced estrogenic effects in vivo, which might affect their toxic impact and carcinogenicity.
2002
Bláha, Ludek; Kapplová, Petra; Vondrácek, Jan; Upham, Brad; Machala, Miroslav
Inhibition of gap-junctional intercellular communication by environmentally occurring polycyclic aromatic hydrocarbons. Journal Article
In: Toxicological sciences : an official journal of the Society of Toxicology, vol. 65, no. 1, pp. 43–51, 2002, ISSN: 1096-6080 1096-0929, (Place: United States).
Abstract | Links | BibTeX | Tags: Animals, Carcinogens/toxicity, Cell Communication/*drug effects, Cell Line, Dose-Response Relationship, Drug, Environmental Pollutants/*toxicity, Epithelium/drug effects, Gap Junctions/*drug effects, Liver/cytology/drug effects, Molecular Structure, Polycyclic Aromatic Hydrocarbons/chemistry/*toxicity, Rats, Tetradecanoylphorbol Acetate/toxicity, United States, United States Environmental Protection Agency/standards
@article{blaha_inhibition_2002,
title = {Inhibition of gap-junctional intercellular communication by environmentally occurring polycyclic aromatic hydrocarbons.},
author = {Ludek Bláha and Petra Kapplová and Jan Vondrácek and Brad Upham and Miroslav Machala},
doi = {10.1093/toxsci/65.1.43},
issn = {1096-6080 1096-0929},
year = {2002},
date = {2002-01-01},
journal = {Toxicological sciences : an official journal of the Society of Toxicology},
volume = {65},
number = {1},
pages = {43–51},
abstract = {Polycyclic aromatic hydrocarbons (PAHs) are a broad class of ubiquitous environmental pollutants with known or suspected carcinogenic properties. Tumor promotion is a cell-proliferative step of cancer that requires the removal of cells from growth suppression via the inhibition of gap-junctional intercellular communication (GJIC). Inhibition of GJIC measured with an in vitro WB-F344 rat liver epithelial cell system was used to assess the relative potencies of 13 PAHs suggested by the U.S. Environmental Protection Agency (EPA) as the principal contaminants and 22 other PAHs, most of them identified in environmental samples. Maximal inhibition of GJIC was detected after 30 min of exposure, followed by a recovery in intercellular communication after an additional 30 min of exposure, suggesting a transient character of inhibition. Although microM concentrations of PAHs were required to reach the inhibition level equal to the model tumor promoter phorbol 12-myristate 13-acetate (IC50 = 8 nM), 12 of the PAHs under study were found to be strong inhibitors of GJIC (strongest effects were observed with fluoranthene, picene, 5-methylchrysene and nine additional PAHs). The other nine PAHs, including benzo[a]pyrene, inhibited GJIC only up to 50-75% of the control level. Interestingly, several high molecular weight PAHs with known strong carcinogenic properties possessed only weak (dibenzopyrenes) or no inhibition potency (dibenzofluoranthenes, naphtho[2,3-a]pyrene and benzo[a]perylene). Based on the IC50 values related to the reference PAH benzo[a]pyrene, we suggested arbitrary values of inhibition equivalency factors (GJIC-IEFs) ranging from 0 (noninhibiting PAHs) to 10.0 (strongest inhibitors), suitable for the purposes of environmental risk assessment.},
note = {Place: United States},
keywords = {Animals, Carcinogens/toxicity, Cell Communication/*drug effects, Cell Line, Dose-Response Relationship, Drug, Environmental Pollutants/*toxicity, Epithelium/drug effects, Gap Junctions/*drug effects, Liver/cytology/drug effects, Molecular Structure, Polycyclic Aromatic Hydrocarbons/chemistry/*toxicity, Rats, Tetradecanoylphorbol Acetate/toxicity, United States, United States Environmental Protection Agency/standards},
pubstate = {published},
tppubtype = {article}
}
Polycyclic aromatic hydrocarbons (PAHs) are a broad class of ubiquitous environmental pollutants with known or suspected carcinogenic properties. Tumor promotion is a cell-proliferative step of cancer that requires the removal of cells from growth suppression via the inhibition of gap-junctional intercellular communication (GJIC). Inhibition of GJIC measured with an in vitro WB-F344 rat liver epithelial cell system was used to assess the relative potencies of 13 PAHs suggested by the U.S. Environmental Protection Agency (EPA) as the principal contaminants and 22 other PAHs, most of them identified in environmental samples. Maximal inhibition of GJIC was detected after 30 min of exposure, followed by a recovery in intercellular communication after an additional 30 min of exposure, suggesting a transient character of inhibition. Although microM concentrations of PAHs were required to reach the inhibition level equal to the model tumor promoter phorbol 12-myristate 13-acetate (IC50 = 8 nM), 12 of the PAHs under study were found to be strong inhibitors of GJIC (strongest effects were observed with fluoranthene, picene, 5-methylchrysene and nine additional PAHs). The other nine PAHs, including benzo[a]pyrene, inhibited GJIC only up to 50-75% of the control level. Interestingly, several high molecular weight PAHs with known strong carcinogenic properties possessed only weak (dibenzopyrenes) or no inhibition potency (dibenzofluoranthenes, naphtho[2,3-a]pyrene and benzo[a]perylene). Based on the IC50 values related to the reference PAH benzo[a]pyrene, we suggested arbitrary values of inhibition equivalency factors (GJIC-IEFs) ranging from 0 (noninhibiting PAHs) to 10.0 (strongest inhibitors), suitable for the purposes of environmental risk assessment.