Indirect Genotoxicity in Metal Carcinogenesis

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Anatoly  Zhitkovich
Organization: BROWN UNIVERSITY
Fiscal Year: 2024
Award: $365,625
Funding agency: National Institute of Environmental Health Sciences

Project Summary
Mutations in various oncogenes and tumor-suppressor genes as well as other genome rearrangements
are a principal cause of human cancers. Lung tumors have especially high burdens of mutations.
Despite this dependence of cancer development on multiple genetic events, many human lung
carcinogens are tested as nonmutagenic in standard assays. Our current lack of knowledge about the
causes of genetic damage by seemingly nonmutagenic carcinogens negatively impacts public health
actions and precludes early detection of this class of dangerous chemicals. Metals is one important
group of widespread carcinogens that are largely nonmutagenic, including lung cancer-causing nickel
(Ni). Ni is a large-volume industrial metal with inhalation exposures occurring daily among millions of
workers. This metal is also a common environmental pollutant that is abundantly released during fossil
fuel burning, incineration of municipal waste and many other processes. Ni is found at > 50% of
Superfund toxic sites. In this project, we will test a conceptually novel hypothesis that Ni(II) disrupts a
unique biochemical process and the resulting metabolic dysfunction causes gross genetic alterations
and cancerous transformation of human lung cells. Our main hypothesis will be tested in three
complementary aims. The proposed studies will determine (1) mechanisms of Ni(II)-induced changes
in cell metabolites, (2) initial and secondary genetic abnormalities resulting from Ni(II)-altered
metabolism and protective functions of ATR kinase, and (3) importance of Ni-induced metabolic
dysfunction in tumorigenic cell transformation. The completion of the proposed work is expected to
establish a novel mechanism for indirect genotoxicity by a major human carcinogen. This mechanism
can be applicable to other nonmutagenic carcinogens possessing a specific chemical reactivity. The
project should also provide a valuable mechanistic information needed for modeling of cancer risks at
low-dose Ni exposures and identify targets for development of potential chemopreventive approaches.

Terms: <Aberrant Chromosome><Alloys><Anabolism><Anti-Oncogenes><Antioncogenes><Assay><Atmosphere><Binding><Bioassay><Biochemical Process><Biological Assay><Biological Markers><Cancer Cause><Cancer Causing Agents><Cancer Etiology><Cancer Genes><Cancer Model><Cancer Suppressor Genes><Cancer-Promoting Gene><CancerModel><Cancerous><Cancers><Carcinogen Tests><Carcinogen-DNA Adducts><Carcinogenesis Tests><Carcinogenic Activity Tests><Carcinogenic Potency Tests><Carcinogenicity Tests><Carcinogens><Cell Body><Cell Communication and Signaling><Cell Cycle><Cell Division Cycle><Cell Signaling><Cells><Chemicals><Chemoprevention><Chemopreventive><Chemopreventive Agent><Chromosomal Aberrations><Chromosomal Abnormalities><Chromosomal Alterations><Chromosomal, Gene, or Protein Abnormality><Chromosome Aberrations><Chromosome Alterations><Chromosome Anomalies><Chromosome Fragile Sites><Chromosome abnormality><Cr(VI)><Cytogenetic Aberrations><Cytogenetic Abnormalities><Cytogenetic or Molecular Genetic Abnormality><DNA><DNA Adducts><DNA Alteration><DNA Damage><DNA Injury><DNA Sequence Alteration><DNA mutation><DNA replication fork><Dangerousness><Deoxyribonucleic Acid><Dependence><Development><Dose><Drugs><Early Diagnosis><Emerogenes><Environment><Environmental Pollutants><Enzyme Gene><Enzymes><Epidemiological data><Epidemiology data><Event><Exposure to><Fiber><Fossil Fuels><Fragile Site><Genetic><Genetic Abnormality><Genetic Alteration><Genetic Change><Genetic defect><Genetic mutation><Genome><Genomics><Genotoxic Stress><Genotoxins><Goals><Human><Impairment><Incineration><Individual><Industrialization><Inhalation Exposure><Intermediary Metabolism><Intracellular Communication and Signaling><Kinases><Knowledge><Large Subunit Ribonucleotide Reductase><Lung><Lung Neoplasms><Lung Respiratory System><Lung Tumor><M1 Subunit Ribonucleotide Reductase><Malignant Melanoma><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Medication><Melanoma><Metabolic Processes><Metabolic dysfunction><Metabolism><Metal Carcinogenesis><Metals><Methodology><Modeling><Modern Man><Molecular Abnormality><Molecular Interaction><Municipalities><Mutagens><Mutation><Ni element><Nickel><Occupational Exposure><Onco-Suppressor Genes><Oncogenes><Oncogenes-Tumor Suppressors><Oncogenic><Oncogens><Pharmaceutical Preparations><Phenotype><Phosphotransferase Gene><Phosphotransferases><Play><Population><Predisposition><Preventative strategy><Prevention strategy><Preventive strategy><Process><Production><Public Health><Pulmonary Cancer><Pulmonary Neoplasms><Pulmonary malignant Neoplasm><R1 Gene><R1 Subunit Gene Ribonucleotide Reductase><R1 protein><R2 Gene><RR2 Gene><RRM1><RRM1 gene><RRM2><RRM2 gene><Recessive Oncogenes><Repression><Research><Ribonucleoside-Diphosphate Reductase M2 Chain Gene><Ribonucleotide Reductase><Ribonucleotide Reductase M2 Polypeptide Gene><Ribonucleotide Reductase R1 Subunit><Ribonucleotide Reductase Small Chain Gene><Risk><Risk Assessment><Rodent><Rodentia><Rodents Mammals><Role><S Period><S phase><Sequence Alteration><Signal Transduction><Signal Transduction Systems><Signaling><Single-Stranded DNA><Site><Source><Specificity><Stainless Steel><Structure><Superfund><Susceptibility><Synthesis Period><Synthesis Phase><TMP synthetase><Testing><Thermal Destruction><Thymidylate Synthase><Thymidylate Synthetase><Transforming Genes><Transphosphorylases><Tumor Suppressing Genes><Tumor Suppressor Genes><Tumorigenicity Tests><Work><anti-carcinogenic><anticarcinogenic><bio-markers><biologic marker><biological signal transduction><biomarker><biosynthesis><cancer risk><carcinogenicity><cell transformation><chemoprevention agent><chromium hexavalent ion><chromium(VI)><chromosomal defect><chromosome defect><dTMP Synthase><developmental><drug/agent><early detection><environmental contaminant><epidemiologic data><experiment><experimental research><experimental study><experiments><genome mutation><genomic alteration><genotoxic agent><genotoxicity><hexavalent chromium><improved><lung cancer><malignancy><molecular aberrations><neoplasm/cancer><novel><oncogenic agent><oncosuppressor gene><potential biological marker><potential biomarker><pulmonary><replication fork><social role><ssDNA><transformed cells><tumorigenic><wasting><workplace exposure>