Preferential alteration of inducible gene expression in vivo by carcinogens that induce bulky DNA lesions

Hamilton, Joshua W.; Louis, Claudine A.; Doherty, Kristen A.; Hunt, Steven R.; Reed, Michael J.; Treadwell, Melinda D.

doi:10.1002/mc.2940080109

Cited by 25 publications

(13 citation statements)

References 56 publications

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“…Our results to date [Hamilton and Wetterhahn, 1989;Hamilton et al, 1993;McCaffrey and Hamilton, 1994b;McCaffrey et al, 19941, taken together with previous results in other systems [Wogan and Friedman, 1968;Kensler et al, 1976a,b;Gayda and Pariza, 1983;Yeoh et al, 1983;Huang et al, 1984;Miller and Wogan, 19861, strongly support the general hypothesis that inducible gene expression is a target for carcinogen-induced DNA damage in vivo. However, the mechanistic basis for these effects is not yet clear.…”

Section: Discussionsupporting

confidence: 89%

Preferential effects of the chemotherapeutic DNA crosslinking agent mitomycin C on inducible gene expression in vivo

Caron¹,

Hamilton²

1995

Environ and Mol Mutagen

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The immediate effects of a single dose of the chemotherapeutic DNA crosslinking agent, mitomycin C (MMC), on the expression of several constitutive and drug-inducible genes were examined in a simple in vivo system, the 14 day chick embryo. We observed no effect of MMC on the steady-state mRNA expression of the constitutively expressed beta-actin, transferrin, or albumin genes. In contrast, MMC treatment significantly altered both the basal and drug-inducible mRNA expression of two glutethimide-inducible genes, 5-aminolevulinic acid (ALA) synthase and cytochrome P450 CYP2H1. The basal expression of these genes was transiently but significantly increased over a 24 hr period following a single dose of MMC. Conversely, MMC significantly suppressed the glutethimide-inducible expression of these genes when administered 1 to 24 hr prior to the inducing drug. The effects of MMC on both basal and drug-inducible ALA synthase and CYP2H1 mRNA expression were principally a result of changes in the transcription rates of these genes. In contrast, MMC treatment had little or no effect on glutethimide-induced expression of ALA synthase or CYP2H1 when administered 1 hr after the inducing drug, suggesting that a very early event in the induction process represents the target for these MMC effects. Covalent binding studies demonstrated that the effects of MMC on gene expression were closely correlated temporally with formation of [3H]-porfiromycin-DNA adducts. These results support the hypothesis that genotoxic chemicals specifically target their effects to inducible genes in vivo.

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Section: Discussionsupporting

confidence: 89%

Preferential effects of the chemotherapeutic DNA crosslinking agent mitomycin C on inducible gene expression in vivo

Caron¹,

Hamilton²

1995

Environ and Mol Mutagen

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“…In contrast, none of the constitutively expressed genes tested (p-actin, transferrin, albumin, and ax-tubulin) were responsive. Effects on inducible gene expression have been observed in both the rat and chick embryo in vivo (10,13,34,55,59) and in primary chick embryo, adult rat, and rat embryo hepatocytes and rat hepatoma cell lines in culture (56)(57)(58). All of these systems show similar responses.…”

Section: Discussionmentioning

confidence: 98%

“…We have postulated that inducible genes are strongly affected by chemicallyinduced DNA damage as a result of both targeting of DNA damage and the intrinsic structural and biochemical properties of those genes, and have proposed a model in which these effects occur as a consequence of chromatin structure and/or nuclear architecture (10,13 (14), had profound effects on expression of several inducible genes while having no effect on expression of several constitutively expressed genes (10). Both the basal and inducible expression of the inducible 5'-aminolevulinate synthase, cytochrome P450 CYP2HI, and phosphoenolpyruvate carboxykinase (PEPCK) genes were markedly affected by the chromium treatment, whereas the albumin, transferrin, and ,-actin genes were refractory to this treatment.…”

Section: Introductionmentioning

confidence: 99%

Molecular basis for effects of carcinogenic heavy metals on inducible gene expression.

Hamilton

Kaltreider

Bajenova

et al. 1998

Environ Health Perspect

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Certain forms of the heavy metals arsenic and chromium are considered human carcinogens, although they are believed to act through very different mechanisms. Chromium(VI) is believed to act as a classic genotoxic and mutagenic agent, and DNANchromatin appears to be the principal target for its effects. In contrast, arsenic(lll) is considered nongenotoxic, but is able to target specific cellular proteins, principally through sulfhydryl interactions. We had previously shown that various genotoxic chemical carcinogens, including chromium(VI), preferentially altered expression of several inducible genes but had little or no effect on constitutive gene expression. We were therefore interested in whether these carcinogenic heavy metals might target specific but distinct sites within cells, leading to alterations in gene expression that might contribute to the carcinogenic process. Arsenic(lll) and chromium(V1) each significantly altered both basal and hormone-inducible expression of a model inducible gene, phosphoenolpyruvate carboxykinase (PEPCK), at nonovertly toxic doses in the chick embryo in vivo and rat hepatoma H411E cells in culture. We have recently developed two parallel cell culture approaches for examining the molecular basis for these effects. First, we are examining the effects of heavy metals on expression and activation of specific transcription factors known to be involved in regulation of susceptible inducible genes, and have recently observed significant but different effects of arsenic(lll) and chromium(Vl) on nuclear transcription factor binding. Second, we have developed cell lines with stably integrated PEPCK promoter-luciferase reporter gene constructs to examine effects of heavy metals on promoter function, and have also recently seen profound effects induced by both chromium(V1) and arsenic(lil) in this system. These model systems should enable us to be able to identify the critical cis (DNA) and trans (protein) cellular targets of heavy metal exposure leading to alterations in expression of specific susceptible genes. It is anticipated that such information will provide valuable insight into the mechanistic basis for these effects as well as provide sensitive molecular biomarkers for evaluating human exposure. Environ Health Perspect 1 06(Suppl 4):1 005-1015 (1998). http://ehpnet1.niehs.nih.gov/docs/1998/Suppl4/ 1005-1015hamilton/abstract.html

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“…Little is known about the formation and tissue distribution of PAH adducts in avian embryos in ovo. Both DNA and RNA adducts have previously been demonstrated in liver and lung from 14‐d‐old chicken embryos treated with B a P [25]. DNA adducts have also been found in B a P‐ and DMBA‐treated chicken aorta homogenates and cultured chick embryo hepatocytes and fibroblasts [26–28].…”

Section: Discussionmentioning

confidence: 99%

Formation of benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene adducts in vascular endothelia of cytochrome P4501A–induced chicken embryos

Granberg¹,

Brunström²,

Brandt³

2003

Environmental Toxicology and Chemistry

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Polycyclic aromatic hydrocarbons (PAHs) are widespread in the environment and birds may be exposed to PAHs via diet, from preening feathers contaminated with oil, or through contamination of the eggshell during embryo development. In the present study, tissue distribution and the cell-specific binding of two labeled PAHs, benzo[a]pyrene ([3H]BaP) and 7,12-dimethylbenz[a]anthracene ([3H]DMBA), were examined in chicken embryos exposed in ovo to CYP1A inducers. Tape-section autoradiograms revealed high concentrations of radioactivity in the bile, liver, kidneys, heart, and leptomeninges. Light microscopy autoradiography of solvent-extracted tissue slices showed a high and selective binding in endothelial cells in certain blood vessels in brain, heart, lung, and chest muscle. Binding was also observed in blood vessel endothelial cells in the chorioallantoic membrane (CAM), an extraembryonal tissue lining the eggshell. Endothelial binding was confirmed in CAM exposed in vitro, implying that tissue-binding metabolites were formed in situ. The CYP1A inhibitor ellipticine abolished bleeding in the target endothelial cells in CAM. It is thus concluded that blood vessel endothelia in various tissues in birds can bioactivate environmental contaminants and be targets for their toxicity. In view of its critical position beneath the shell, the CAM could be an important target for toxicants following external exposure in oviparous species.

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Preferential alteration of inducible gene expression in vivo by carcinogens that induce bulky DNA lesions

Cited by 25 publications

References 56 publications

Preferential effects of the chemotherapeutic DNA crosslinking agent mitomycin C on inducible gene expression in vivo

Preferential effects of the chemotherapeutic DNA crosslinking agent mitomycin C on inducible gene expression in vivo

Molecular basis for effects of carcinogenic heavy metals on inducible gene expression.

Formation of benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene adducts in vascular endothelia of cytochrome P4501A–induced chicken embryos

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