Information-dependent enrichment analysis reveals time-dependent transcriptional regulation of the estrogen pathway of toxicity.

The twenty-first century vision for toxicology involves a transition away from high-dose animal studies to in vitro and computational models (NRC in Toxicity testing in the 21st century: a vision and a strategy, The National Academies Press, Washington, DC, 2007). This transition requires mapping pathways of toxicity by understanding how in vitro systems respond to chemical perturbation. Uncovering transcription factors/signaling networks responsible for gene expression patterns is essential for defining pathways of toxicity, and ultimately, for determining the chemical modes of action through which a toxicant acts.

Formation of two novel estrogen guanine adducts and HPLC/MS detection of 4-hydroxyestradiol-N7-guanine in human urine.

Estrogen-DNA adducts are potential biomarkers for assessing the risk of developing of a number of hormonally modified cancers, including breast cancer. Formation of the 4-hydroxyestradiol-N(7)-guanine (4-OHE2-N(7)-guanine) adduct from the reaction of estradiol-3,4-quinone with DNA and its detection in vivo has been established. With the ultimate goal of exploring estrogen-DNA adducts as biomarkers in experimental and human investigations, the 4-OHE2-N(7)-guanine was synthesized, and preliminary studies demonstrated that this adduct was detectable in all 10 female human urine samples examined.

Enhanced mitochondrial gene transcript, ATP, bcl-2 protein levels, and altered glutathione distribution in ethinyl estradiol-treated cultured female rat hepatocytes.

Ethinyl estradiol (EE) is a strong promoter and weak hepatocarcinogen in rats. Previously, we demonstrated that EE enhanced the transcript levels of nuclear genome- and mitochondrial genome-encoded genes and respiratory chain activity in female rat liver, and also inhibited transforming growth factor beta (TGFbeta)-induced apoptosis in cultured liver slices and hepatocytes from female rats. In this study, using cultured female rat hepatocytes, we observed that EE, within 24 h, increased the transcript levels of the mitochondrial genome-encoded genes cytochrome oxidase subunits I, II, and III.

The effects of catechol-O-methyltransferase inhibition on estrogen metabolite and oxidative DNA damage levels in estradiol-treated MCF-7 cells.

Many of the major identified risk factors for breast cancer are associated with exposure to endogenous estrogen. In addition to the effects of estrogen as a growth factor, experimental and epidemiological evidence suggest that catechol metabolites of estrogen also contribute to estrogen carcinogenesis by both direct and indirect genotoxic mechanisms. O-Methylation catalyzed by catechol-O-methyltransferase (COMT) is a Phase II metabolic inactivation pathway for catechol estrogens.

Inhibition of TGF-beta-induced apoptosis by ethinyl estradiol in cultured, precision cut rat liver slices and hepatocytes.

Ethinyl estradiol (EE) is a strong promoter of hepatocarcinogenesis in the rat. Treatment with EE and other hepatic promoters induces transient growth stimulation followed by growth inhibition (mitosuppression) in hepatocytes. Previously, we identified several genes whose transcript levels were increased during EE-induced mitosuppression, including transforming growth factor beta (TGF-beta), which inhibits growth and induces apoptosis in hepatocytes.