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Papers by Max Costa

Mutation Research-reviews in Mutation Research, 1997

This paper will explore emerging concepts related to alternative carcinogenic mechanisms of 'non-... more This paper will explore emerging concepts related to alternative carcinogenic mechanisms of 'non-mutagenic,' and hence epigenetic, carcinogens that may heritably alter DNA methylation without changing the underlying DNA sequence. In this review, we will touch on the basic concepts of DNA methylation, and will elaborate in greater detail on related topics including chromatin condensation, and heterochromatin spreading that is well known to induce gene silencing by position effect variegation in Drosophila and other species. Data from our model transgenic G12 cell system will be presented to support our hypothesis that certain carcinogens, such as nickel, may be carcinogenic not primarily because of their overt mutability, but rather as the result of their ability to promote DNA hypermethylation of important cancer-related genes. We will conclude with a discussion of the broader relevance of our findings and its application to other so-called 'epigenetic' carcinogens.

Critical Reviews in Toxicology, 2006

Chromium is a human carcinogen primarily by inhalation exposure in occupational settings. Althoug... more Chromium is a human carcinogen primarily by inhalation exposure in occupational settings. Although lung cancer has been established as a consequence of hexavalent chromium exposure in smokers and nonsmokers, some cancers of other tissues of the gastrointestinal and central nervous systems have also been noted. Except for a few reports from China, little is known about the health risks of environmental exposures to chromium. Likewise, there has been a lack of epidemiological studies of human exposure to hexavalent Cr by drinking water or ingestion, and it has been suggested that humans can perhaps tolerate hexavalent Cr at higher levels than the current drinking water standard of 50 ppb. This review highlights the most recent data on the induction of skin tumors in mice by chronic drinking-water exposure to hexavalent chromium in combination with solar ultraviolet light. This experimental system represents an important new animal model for chromate-induced cancers by ingestion of drinking water, and it suggests by extrapolation that chromate can likely be considered a human carcinogen by ingestion as well. The potential use of this animal model for future risk assessment is discussed.

Molecular and Cellular Biochemistry, 2004

Arsenic is a metalloid compound that is widely distributed in the environment. Human exposure of ... more Arsenic is a metalloid compound that is widely distributed in the environment. Human exposure of this compound has been associated with increased cancer incidence. Although the exact mechanisms remain to be investigated, numerous carcinogenic pathways have been proposed. Potential carcinogenic actions for arsenic include oxidative stress, genotoxic damage, DNA repair inhibition, epigenetic events, and activation of certain signal transduction pathways leading to abberrant gene expression. In this article, we summarize current knowledge on the molecular mechanisms of arsenic carcinogenesis with an emphasis on ROS and signal transduction pathways.

Toxicology and Applied Pharmacology, 1997

Advisory Document (EPA, 1986). As a result of this project, Carcinogenicity Assessment of Selecte... more Advisory Document (EPA, 1986). As a result of this project, Carcinogenicity Assessment of Selected Nickel Compounds. the International Committee on Nickel Carcinogenesis in OLLER, A. R., COSTA, M., AND OBERDÖ RSTER, G. (1997). Toxicol. Man (ICNCM) was formed (as a joint effort between indus-Appl. Pharmacol. 143, 152-166.

Chemical Research in Toxicology, 1991

... Forum The Role of Oxidative Processes in Metal Carcinogenesis Catherine B. Klein,* Krystyna F... more ... Forum The Role of Oxidative Processes in Metal Carcinogenesis Catherine B. Klein,* Krystyna Frenkel, and Max Costa Institute of Environmental Medicine, New York University Medical Center, 550 First Avenue, New York, New York 10016 Received July 8, 1991 ...

Science, 1991

Transfer of a normal Chinese hamster X chromosome (carried in a mouse A9 donor cell line) to a ni... more Transfer of a normal Chinese hamster X chromosome (carried in a mouse A9 donor cell line) to a nickel-transformed Chinese hamster cell line with an Xq chromosome deletion resulted in senescense of these previously immortal cells. At early passages of the A9/CX donor cells, the hamster X chromosome was highly active, inducing senescence in 100% of the colonies obtained after its transfer into the nickel-transformed cells. However, senescence was reduced to 50% when Chinese hamster X chromosomes were transferred from later passage A9 cells. Full senescing activity of the intact hamster X chromosome was restored by treatment of the donor mouse cells with 5-azacytidine, which induced demethylation of DNA. These results suggest that a senescence gene or genes, which may be located on the Chinese hamster X chromosome, can be regulated by DNA methylation, and that escape from senescence and possibly loss of tumor suppressor gene activity can occur by epigenetic mechanisms.

Critical Reviews in Toxicology, 1997

The toxicity and carcinogenicity of hexavalent chromium (Cr) in animal and human models are revie... more The toxicity and carcinogenicity of hexavalent chromium (Cr) in animal and human models are reviewed. The focus of this review is not on the well-established fact that hexavalent Cr compounds of low and high water solubility can induce respiratory cancers, but rather this review addresses other types of cancers induced by exposure to hexavalent Cr compounds. Additionally, non-cancer endpoints are also discussed with documentation of human and animal studies showing non-cancer health effects of hexavalent Cr exposure on the respiratory system, GI system, immune system, liver, and kidney. There is an emerging understanding that because hexavalent chromate is isostructural with phosphate and sulfate, it is readily taken up by the G.I. tract and penetrates to many tissues and organs throughout the body. This is supported by animal studies and experiments using human volunteers. From the epidemiological studies, there is suggestive evidence that hexavalent Cr causes increased risk of bone, prostate, lymphomas, Hodgkins, leukemia, stomach, genital, renal, and bladder cancer, reflecting the ability of hexavalent chromate to penetrate all tissues in the body. A high accumulation of Cr(III) in all tissues and organs is a strong indication of the wide toxic potential of exposure to soluble hexavalent Cr in the drinking water and in the ambient environment.

Critical Reviews in Toxicology, 1989

The toxicity and carcinogenicity of nickel compounds are considered in three broad categories: (1... more The toxicity and carcinogenicity of nickel compounds are considered in three broad categories: (1) systemic toxicology, (2) molecular toxicology, and (3) carcinogenicity. The systemic toxicity of nickel compounds is examined based upon human and animal studies. The major organs affected are discussed in three categories: (1) kidney, (2) immune system, and (3) other organs. The second area of concentration is molecular toxicology, which will include a discussion of the chemistry of nickel, its binding to small and large molecular weight ligands, and, finally, its cellular effects. The third major area involves a discussion of the carcinogenicity and genotoxicity of nickel compounds. This section focuses on mechanisms, using studies conducted in vivo and in vitro. It also includes a discussion of the assessment of the carcinogenicity of nickel compounds.

Critical Reviews in Toxicology, 1993

Chromium, like many transition metal elements, is essential to life at low concentrations yet tox... more Chromium, like many transition metal elements, is essential to life at low concentrations yet toxic to many systems at higher concentrations. In addition to the overt symptoms of acute chromium toxicity, delayed manifestations of chromium exposure become apparent by subsequent increases in the incidence of various human cancers. Chromium is widely used in numerous industrial processes, and as a result is a contaminant of many environmental systems. Chromium, in its myriad chemical forms and oxidation states, has been well studied in terms of its general chemistry and its interactions with biological molecules. However, the precise mechanisms by which chromium is both an essential metal and a carcinogen are not yet fully clear. The following review does not seek to embellish upon the proposed mechanisms of the toxic and carcinogenic actions of chromium, but rather provides a comprehensive review of these theories. The chemical nature of chromium compounds and how these properties impact upon the interactions of chromium with cellular and genetic targets, including animal and human hosts, are discussed.

Environmental factors influence carcinogenesis by interfering with a variety of cellular targets.... more Environmental factors influence carcinogenesis by interfering with a variety of cellular targets. Carcinogenic nickel compounds, although generally inactive in most gene mutation assays, induce chromosomal damage in heterochromatic regions and cause silencing of reporter genes when they are located near telomere or heterochromatin in either yeast or mammalian cells. We studied the effects of nickel on the lysine acetylation status of the NH 2 -terminal region of histone H4. At nontoxic levels, nickel decreased the levels of histone H4 acetylation in vivo in both yeast and mammalian cells, affecting only lysine 12 in mammalian cells and all of the four lysine residues in yeast. In yeast, lysine 12 and 16 were more greatly affected than lysine 5 and 8. Interestingly, a histidine Ni 2؉ anchoring site is found at position 18 from the NH 2 -terminal tail of H4. Nickel was also found to inhibit the acetylation of H4 in vitro using purified recombinant histone acetyltransferase. To our knowledge, this is the first agent shown to decrease histone H4 acetylation at nontoxic levels.

Molecular and Cellular Biology, 2002

Hypoxia causes the accumulation of the transcription factor hypoxia-inducible factor 1 (HIF-1), c... more Hypoxia causes the accumulation of the transcription factor hypoxia-inducible factor 1 (HIF-1), culminating in the expression of hypoxia-inducible genes such as those for vascular endothelial growth factor (VEGF) and NDRG-1/Cap43. Previously, we have demonstrated that intracellular calcium (Ca 2؉ ) is required for the expression of hypoxia-inducible genes. Here we found that, unlike with hypoxia or hypoxia-mimicking conditions, the elevation of intracellular Ca 2؉ neither induced the HIF-1␣ protein nor stimulated HIF-1-dependent transcription. Furthermore, the elevation of intracellular Ca 2؉ induced NDRG-1/Cap43 mRNA in HIF-1␣deficient cells. It also increased levels of c-Jun protein, causing its phosphorylation. The protein kinase inhibitor K252a abolished c-Jun induction and activator protein 1 (AP-1)-dependent reporter expression caused by Ca 2؉ ionophore or hypoxia. K252a also significantly decreased hypoxia-induced VEGF and NDRG-

Since non-functional p53 was expressed in both HOS and SA-8 cells, acute Ni treatment induced HIF... more Since non-functional p53 was expressed in both HOS and SA-8 cells, acute Ni treatment induced HIF-1α protein and HIF-1-dependent transcription without affecting p53. In MCF-7 and A549, human cancer cells with the wild-type p53, both functional p53 and HIF-1α proteins accumulated following exposure to Ni. The induction of HIF-1α and wild-type p53 by Ni was detected after 6 h and was most pronounced by 24 h. These results suggest that acute Ni treatment causes accumulation of HIF-1α protein and simultaneous accumulation of wild-type, but not mutant, p53. We suggest that the induction of hypoxia-like conditions in Ni-treated cells with subsequent selection for increased HIF-1-dependent transcription is involved in Niinduced carcinogenesis.

To better understand the molecular mechanism(s) involved in the essentiality, toxicity, and/or ca... more To better understand the molecular mechanism(s) involved in the essentiality, toxicity, and/or carcinogenicity of nickel compounds, a niKN A differential display technique was used to identify gene(s) that were specifically induced by these carcinogens. Differential expression of sev eral genes was observed in human lung A549 cells exposed to nickel subsulfide. One gene, Cap43, which expressed a 3.0-kb niKNA encoding a U, 43,000 protein, was found to be induced within 4-6 h by either Ni.S, or Ni( I. in A549 cells and attained a level as high as 30-fold within 24-36 h of treatment. Twelve other tested metal compounds failed to induce Cap43 expression, leading to the conclusion that, with regard to metals, the induction of this gene was nickel-specific. Oxidative stress that is often caused by metals and heat shock did not induce Cap43 further, suggesting a specific nature in the signaling pathway involved in Cap43 induction. Activation of signaling pathways with vanadate did not induce Cap43 nor did trifluoperazine block its induction by nickel; however, okadaic acid, a serine/threonine phosphatase inhibitor, induced Cap43 to a greater extent than any nickel compound tested. Homocysteine did not induce Cap43 in a number of cell lines, with the exception of human endothelial cells. The

Carcinogenic nickel compounds alter the program of gene expression in normal cells and induce a p... more Carcinogenic nickel compounds alter the program of gene expression in normal cells and induce a pattern of gene expression similar to that found in nickel-induced cancers. Here we have demonstrated that nickel exposure induced hypoxic signaling pathways by inducing hypoxia-inducible transcription factor-1 (HIF-1), which mediated the induction of genes required by cells to survive hypoxia. We also show that a new gene, Cap43, is dependent upon HIF-1 because only HIF-1-proficient cells induced Cap43 when exposed to either hypoxia or nickel. We also show that glyceraldehyde-3-phosphate dehydrogenase, a gene induced by hypoxia through HIF-1, was similar to Cap43 in that it required HIF-1-proficient cells to be induced by either nickel or hypoxia. These data demonstrate that nickel exposure turns on signaling for hypoxic stress, which may be important in its carcinogenesis.