Toxicological Sciences 59, 231-240 (2001)
Copyright © 2001 by the Society of Toxicology
ENDOCRINE TOXICOLOGY |
Hydroxylated Benzo[a]pyrene Metabolites Are Responsible for in Vitro Estrogen Receptor-Mediated Gene Expression Induced by Benzo[a]pyrene, but Do Not Elicit Uterotrophic Effects in Vivo
Department of Biochemistry and Molecular Biology, and National Food Safety and Toxicology Center, Michigan State University, Lansing, Michigan 48824
The estrogenic activities of benzo[a]pyrene (B[a]P) and 10 metabolites (1, 3-, 7-, and 9-hydroxy-B[a]P; 4,5-, 7,8-, and 9,10-dihydrodihydroxy-B[a]P; and 1,6-, 3,6-, and 6,12-B[a]P-dione) were investigated. In vitro, B[a]P did not displace tritiated 17ß-estradiol ([3H]E2) from either a bacterially expressed fusion protein consisting of glutathione-S-transferase linked to the D, E, and F domains of human ER
(GST-hERdef), or from full-length human ERß (hERß) at concentrations as high as 60 µM. However, 10 µM B[a]P demonstrated partial agonist activity in human Gal4-ERdef and mouse Gal4-ERßdef reporter gene assays in transiently transfected MCF-7 cells, relative to 10 nM E2. 1-, 3-, 7-, and 9-hydroxy-B[a]P were found to bind to both receptor isoforms, each showing a higher affinity for the ß isoform. At 10 µM the four monohydroxylated metabolites were able to induce Gal4-hERdef- and Gal4-mERßdef–mediated reporter gene expression to levels 20–100% of that caused by 10 nM E2, suggesting that these metabolites, and not the parent compound, induced reporter gene expression following B[a]P treatment of transiently transfected MCF-7 cells. In addition, the effect of B[a]P on two estrogen-inducible end points, uterine weight and lactoferrin mRNA levels, was determined in ovariectomized DBA/2 and C57BL/6 mice. Neither orally administered B[a]P at doses as high as 10 mg/kg body weight nor subcutaneously injected 3- or 9-hydroxy-B[a]P at doses as high as 20 mg/kg induced effects on uterine wet weight or uterine lactoferrin mRNA levels in either strain. These data suggest that B[a]P metabolites that are estrogenic at high concentrationsin vitro do not induce estrogenic effects in the mouse uterus.
Key Words: benzo[a]pyrene; polycyclic aromatic hydrocarbon; metabolism; estrogen receptor; receptor isoform; endocrine disrupter.
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