Journal Article

Hydroxylated Benzo[a]pyrene Metabolites Are Responsible for <i>in Vitro</i> Estrogen Receptor-Mediated Gene Expression Induced by Benzo[a]pyrene, but Do Not Elicit Uterotrophic Effects <i>in Vivo</i>

Kirsten C. Fertuck, Jason B. Matthews and Tim R. Zacharewski

in Toxicological Sciences

Volume 59, issue 2, pages 231-240
Published in print February 2001 | ISSN: 1096-6080
Published online February 2001 | e-ISSN: 1096-0929 | DOI:
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

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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 17β-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 ERα (GST-hERαdef), or from full-length human ERβ (hERβ) at concentrations as high as 60 μM. However, 10 μM B[a]P demonstrated partial agonist activity in human Gal4-ERαdef and mouse Gal4-ERβdef 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 β isoform. At 10 μM the four monohydroxylated metabolites were able to induce Gal4-hERαdef- and Gal4-mERβdef–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.

Keywords: benzo[a]pyrene; polycyclic aromatic hydrocarbon; metabolism; estrogen receptor; receptor isoform; endocrine disrupter

Journal Article.  7485 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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