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DABT 2025 > Chemical Carcinogens > Flashcards

Chemical Carcinogens Flashcards

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1
Q

What are common chemical carcinogens?

A

Benzo[a]pyrene (tobacco smoke), aflatoxin B1 (mold), arsenic (water), vinyl chloride (plastics), chromium (VI) (industrial).

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2
Q

What is the mechanism of benzo[a]pyrene carcinogenicity?

A

Metabolized to BPDE by CYP1A1, forms DNA adducts leading to mutations.

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3
Q

What is the mechanism of aflatoxin B1 carcinogenicity?

A

Metabolized to epoxide by CYP3A4, forms DNA adducts causing liver cancer.

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4
Q

What is the mechanism of arsenic carcinogenicity?

A

Inhibits DNA repair enzymes and alters gene expression via epigenetic changes.

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5
Q

What are biomarkers for chemical carcinogenicity?

A

DNA adducts (e.g., BPDE-DNA), micronuclei formation, chromosomal aberrations.

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6
Q

What are testing methods for chemical carcinogenicity?

A

Ames test (mutagenicity), rodent bioassays (long-term), comet assay (DNA damage).

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7
Q

What are endpoints for chemical carcinogenicity?

A

Tumor formation (e.g., liver cancer from aflatoxin), increased cancer incidence.

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8
Q

How does vinyl chloride cause cancer?

A

Metabolized to chloroethylene oxide, forms DNA adducts leading to liver angiosarcoma.

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9
Q

What is the role of chromium (VI) in carcinogenicity?

A

Reduced to Cr(III), generates ROS causing oxidative DNA damage.

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10
Q

How does TCDD contribute to carcinogenicity?

A

Activates AhR, promotes cell proliferation and inhibits apoptosis.

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11
Q

What is the prototypical agonist of the Aryl hydrocarbon receptor (AhR), and how does its activation contribute to carcinogenicity in rodents?

A

TCDD (dioxin) is the prototypical AhR agonist. It promotes tumors in rodents by binding to AhR, translocating to the nucleus, and altering gene expression (e.g., CYP1A1, CYP1B1). This mechanism is not observed in AhR knockout mice.

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12
Q

Which DNA adduct is an established biomarker of oxidative stress caused by alkylating electrophiles?

A

8-hydroxyguanine is a prevalent oxidative DNA adduct and a key biomarker of oxidative stress caused by alkylating electrophiles.

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13
Q

Which Salmonella strains in the Ames test are used to detect point mutations?

A

Salmonella strains TA100 and TA1535 are used in the Ames test to detect point mutations.

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14
Q

What is the primary target organ for tumors caused by aromatic amines used in the dye industry?

A

The urinary bladder is the primary target organ for tumors caused by aromatic amines used in the dye industry, due to their metabolic activation and DNA adduct formation.

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15
Q

In which study was 2-acetylaminofluorene used to investigate chemical carcinogenesis?

A

2-Acetylaminofluorene, an aromatic amine, was used in the megamouse study to evaluate its carcinogenic potential, particularly for bladder tumors.

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16
Q

What characterizes a benign neoplasm, such as a liver cell adenoma?

A

A benign neoplasm, like a liver cell adenoma, is characterized by expansive growth with slow proliferation and no invasion of surrounding tissues.

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17
Q

How are mutations detected in the Big Blue mouse model?

A

In the Big Blue mouse model, mutations are detected by observing blue plaques in a petri dish, as the model has a lacZ gene inserted to indicate mutagenic events.

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18
Q

What is the primary function of the BRCA1 gene, and in which cancers is it commonly mutated?

A

BRCA1 is a tumor suppressor gene involved in DNA repair, commonly mutated in breast and ovarian cancers.

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19
Q

What is a strategy for chemoprevention of cancer?

A

A strategy for chemoprevention includes blocking DNA adduct formation using agents like glutathione, N-acetylcysteine, or ascorbic acid to prevent tumor initiation.

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20
Q

Which gene is targeted in the Chinese Hamster Ovary test for mutagenicity?

A

The Chinese Hamster Ovary test targets the HGPRT gene, which is involved in purine metabolism, to assess mutagenicity.

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21
Q

What is the primary method used in chronic testing for carcinogenicity?

A

Chronic testing for carcinogenicity primarily involves in vivo bioassays in rats and mice, using 2-3 doses with the highest being the maximum tolerated dose (MTD), followed by autopsy and histopathological examination.

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22
Q

What defines a complete carcinogen?

A

A complete carcinogen possesses both genotoxic (DNA-damaging) and non-genotoxic (e.g., promoting cell proliferation) properties, contributing to all stages of carcinogenesis.

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23
Q

How does chloroform induce liver tumors, and what is the significance of its threshold dose?

A

Chloroform induces liver tumors at doses causing liver injury, resulting in cytotoxicity and cell death, which has a threshold dose for tumor formation.

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24
Q

What can result from DNA adducts during DNA replication if not repaired?

A

If not repaired, DNA adducts can lead to DNA strand breaks during replication, either due to incomplete excision repair or alkylation on the phosphodiester backbone.

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25
How does DNA methylation typically affect gene transcription, and what dietary factors influence it?
DNA methylation at the 5-position of cytosine, mediated by DNMTs, usually decreases transcription. Methionine and choline are dietary sources of methyl groups that influence this process.
26
What is the mechanism by which diethanolamine induces tumors?
Diethanolamine, used in chemical and cosmetic industries, depletes choline, altering DNA methylation and leading to liver tumors.
27
Which chemical, given to pregnant women, resulted in a higher incidence of vaginal tumors in offspring?
Diethylstilbestrol, a synthetic estrogen, was given to pregnant women and caused vaginal tumors in their offspring due to its estrogenic activity.
28
What is the primary concern with bisphenol-A in terms of carcinogenicity?
The primary concern with bisphenol-A, used in polycarbonate plastics, is its weak estrogenic activity, which may induce tumors in estrogen-dependent tissues.
29
What are gap-junctions, and how do they relate to carcinogenesis?
Gap-junctions are aggregates of connexins forming conduits between cells. Their disruption can promote carcinogenesis by impairing intercellular communication.
30
What characterizes genotoxic carcinogens?
Genotoxic carcinogens (initiators) damage DNA structure, are mutagenic, and have no theoretical threshold for regulatory purposes.
31
Name a direct-acting genotoxic carcinogen and explain its action.
Nitrogen mustard is a direct-acting genotoxic carcinogen that tests positive in the Ames test without microsomes, alkylating DNA without requiring metabolic activation.
32
What term is used for indirect-acting genotoxic carcinogens requiring metabolic activation?
Indirect-acting genotoxic carcinogens are called procarcinogens, requiring metabolic activation to become ultimate carcinogens that bind DNA.
33
Name a feature that is NOT a hallmark of cancer.
Enhancing DNA repair is not a hallmark of cancer. Hallmarks include sustaining proliferation, evading immune destruction, and inducing angiogenesis.
34
What is hormesis in the context of chemical carcinogenesis?
Hormesis is a U-shaped dose-response where low-dose exposure may have beneficial effects, while high doses are harmful in the context of chemical carcinogenesis.
35
Which chemical is classified by IARC as a human carcinogen, and what cancers is it associated with?
Arsenic is classified by IARC as a human carcinogen, associated with bladder, kidney, lung, and skin cancers, primarily via drinking water exposure.
36
How does immunosuppression contribute to chemical carcinogenesis?
Immunosuppression, caused by some environmental chemicals, increases the risk of tumor development by impairing immune surveillance.
37
What is the primary exposure route for arsenic, and which form is non-carcinogenic?
Arsenic exposure primarily occurs via drinking water, and arsenobetaine, found in fish, is non-carcinogenic.
38
Which oxidation state of chromium is carcinogenic, and what is the primary target organ?
Chromium VI is carcinogenic, producing lung tumors in rats and humans, particularly through occupational exposure.
39
What cancers are associated with occupational exposure to nickel compounds?
Occupational exposure to nickel compounds is associated with increased lung and nasal tumors.
40
How can liver carcinogenicity testing differentiate between initiators and promoters?
Liver carcinogenicity testing differentiates initiators (DNA damage) from promoters (cell proliferation) by staining for pre-neoplastic foci, such as GSHT-P.
41
What distinguishes malignant neoplasms from benign neoplasms?
Malignant neoplasms, such as carcinomas and sarcomas, exhibit invasive growth and can metastasize, unlike benign neoplasms, which do not invade or metastasize.
42
What are metastases in the context of cancer?
Metastases are secondary tumor growths derived from cells of the primary malignant tumor, spreading to other organs.
43
How do microRNAs regulate gene expression in cancer?
MicroRNAs (21-25 nucleotides) regulate gene expression in cancer by repressing transcription or increasing mRNA degradation.
44
What does the micronucleus test detect, and how is it visualized?
The micronucleus test detects chromosomal abnormalities by observing micronuclei, formed from unequal DNA distribution, visible with a microscope.
45
What is the target gene in the mouse lymphoma assay, and what is measured?
The mouse lymphoma assay targets the thymidine kinase gene in L5178Y cells, measuring resistance to trifluorothymidine to assess mutations.
46
What is the role of an initiator in multistage carcinogenesis?
An initiator in multistage carcinogenesis covalently binds to DNA, forming adducts that can become fixed mutations if not repaired.
47
What is a key feature of tumor promotion in multistage carcinogenesis?
Tumor promotion in multistage carcinogenesis involves selective clonal expansion of initiated cells, is reversible upon removal of the promoter, and has a dose-dependent threshold.
48
What occurs during the progression stage of carcinogenesis?
During the progression stage, multiple genotoxic events lead to chromosomal damage and the irreversible conversion of pre-neoplastic lesions to neoplasms.
49
Name a nitrosamine associated with genotoxic carcinogenicity.
Diethylnitrosamine is a genotoxic nitrosamine that forms DNA adducts, contributing to carcinogenesis.
50
What is a feature of non-genotoxic carcinogens?
Non-genotoxic carcinogens, often promoters, have a threshold, are reversible, and increase cell division without directly damaging DNA.
51
What is the origin of oncogenes, and how do they contribute to cancer?
Oncogenes arise from mutated proto-oncogenes, normal genes involved in cell proliferation, leading to uncontrolled growth when mutated.
52
What type of mutation is commonly caused by oxidative stress?
Oxidative stress from ROS commonly causes G to T transversions, particularly in mitochondrial DNA.
53
What is the role of p16 in cancer prevention?
P16 is a cyclin-dependent kinase inhibitor that prevents uncontrolled cell division by inhibiting CDK activity and arresting the cell cycle.
54
How does p53 prevent tumor formation, and what happens when it is mutated?
p53 induces p21 to arrest the cell cycle at G1 for DNA repair. When mutated, it fails to stop damaged cells from cycling, increasing cancer risk.
55
What is the mechanism by which benzo[a]pyrene causes tumors?
Benzo[a]pyrene, a PAH, is metabolized by P450 and epoxide hydrolase to form a reactive epoxide that binds DNA, causing mutations (e.g., in Hras).
56
Name a prototype PPARα agonist and its effect in rodents.
Clofibrate, a PPARα agonist, induces liver tumors in rodents by increasing peroxisome proliferation and cell proliferation, not observed in PPARα knockout mice.
57
How does phenobarbital induce liver tumors in rodents?
Phenobarbital activates CAR, inducing CYP2B enzymes, increasing cell proliferation, and inhibiting apoptosis, leading to liver tumors in rodents.
58
Which chemical is used as a promoter in skin carcinogenicity testing?
TPA (phorbol ester) is used as a promoter in skin carcinogenicity testing to promote cell division.
59
What is the mechanism by which phenobarbital induces thyroid tumors in rodents?
Phenobarbital enhances T3/T4 excretion, decreasing plasma levels, increasing TSH, and stimulating thyroid cell proliferation, leading to tumors.
60
What is the role of the Wilms tumor gene in cancer?
The Wilms tumor gene is a tumor suppressor and transcription factor critical for kidney development, preventing Wilms tumor when functional.
61
How does aflatoxin contribute to carcinogenesis?
Aflatoxin, a fungal toxin, is metabolized to form DNA adducts and alters p53, contributing to liver tumors, particularly in rats but not mice.
62
What type of cancer is associated with vinyl chloride exposure?
Vinyl chloride, used in PVC production, is a genotoxic carcinogen associated with liver angiosarcoma in humans.
63
Which nitrogen mustard is used in cancer chemotherapy?
Cyclophosphamide, a nitrogen mustard, is a genotoxic agent used in chemotherapy, alkylating DNA to kill cancer cells.
64
What is the carcinogenic mechanism of ethylene oxide?
Ethylene oxide is a direct-acting genotoxin that alkylates DNA, forming adducts that contribute to carcinogenesis.
65
Why is TCDD more toxic to guinea pigs than hamsters?
TCDD is 1000x more toxic in guinea pigs than hamsters due to species-specific differences in AhR binding affinity.
66
What does the Pig-a gene mutation assay measure?
The Pig-a gene mutation assay quantifies mutations by detecting loss of GPI-anchored proteins on RBCs via flow cytometry.
67
How are mutations detected in the MutaMouse assay?
In the MutaMouse assay, mutations are detected as clear plaques in a petri dish, using a bacteriophage encoding B-galactosidase.
68
What is the effect of phthalate plasticizers in rodents, and why is it not relevant to humans?
Phthalate plasticizers induce PPARα-mediated liver tumors in rodents, but this mechanism is not relevant to humans, as humans lack PPARα response.
69
Which proto-oncogene is involved in cell signaling and mutated in benzo[a]pyrene-induced tumors?
The Hras proto-oncogene is mutated (codon 12) by benzo[a]pyrene epoxides, contributing to lung and skin tumors.
70
What is the function of the retinoblastoma gene in cancer prevention?
The retinoblastoma gene encodes a protein that binds E2F, inhibiting the G1 to S transition to prevent uncontrolled cell division.
71
What type of cancer is associated with formaldehyde exposure in rats?
Formaldehyde exposure in rats is linked to nasal carcinoma, though its relevance to humans requires careful qualification.
72
How does saccharin induce bladder tumors in rats?
Saccharin forms insoluble precipitates in the rat bladder, causing chronic irritation, cell proliferation, and tumors, not relevant to humans.
73
Why is limonene-induced renal tumor formation in male rats not relevant to humans?
Limonene binds alpha-2-globulin, causing renal tumors in male rats, a mechanism not relevant to female rats, mice, or humans.
74
What type of tumors does BHA induce in rodents, and by what route?
BHA (butylated hydroxyanisole) induces forestomach tumors in rodents when administered via gavage, a rodent-specific effect.
75
How are Toxicity Equivalent Factors (TEF) used to assess the risk of TCDD-related compounds?
Toxicity Equivalent Factors (TEF) compare the concentration of a chemical needed to activate AhR with that of TCDD, assessing the risk via AhR-mediated toxicity.

DABT 2025 (16 decks)

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